[Federal Register Volume 76, Number 238 (Monday, December 12, 2011)]
[Rules and Regulations]
[Pages 77330-77360]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2011-31542]



[[Page 77329]]

Vol. 76

Monday,

No. 238

December 12, 2011

Part II





Department of Justice





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 Drug Enforcement Administration





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21 CFR Part 1308





Schedules of Controlled Substances: Placement of Carisoprodol Into 
Schedule IV; Final Rule

  Federal Register / Vol. 76 , No. 238 / Monday, December 12, 2011 / 
Rules and Regulations  

[[Page 77330]]


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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1308

[Docket No. DEA-333]


Schedules of Controlled Substances: Placement of Carisoprodol 
Into Schedule IV

AGENCY: Drug Enforcement Administration, Department of Justice.

ACTION: Final rule.

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SUMMARY: With the issuance of this final rule, the Administrator of the 
Drug Enforcement Administration (DEA) places the substance 
carisoprodol, including its salts, isomers, and salts of isomers, 
whenever the existence of such salts, isomers, and salts of isomers is 
possible, into Schedule IV of the Controlled Substances Act (CSA). This 
action is pursuant to the CSA which requires that such actions be made 
on the record after opportunity for a hearing. The decision of the 
Administrator is reprinted in its entirety below.

DATES: Effective Date: January 11, 2012.

FOR FURTHER INFORMATION CONTACT: Rhea D. Moore, Drug Enforcement 
Administration, 8701 Morrissette Drive, Springfield, Virginia 22152; 
Telephone (202) 307-5268.

SUPPLEMENTARY INFORMATION: 

ALJ Docket No. 10-46

Background

    This is a proceeding under 21 U.S.C. 811(a) for the issuance of a 
rule placing carisoprodol in schedule IV of the Controlled Substances 
Act (CSA). Under this provision, ``the Attorney General may, by rule,'' 
add a ``drug or other substance'' to one of the five schedules of 
controlled substances, ``if he * * * finds that such drug or other 
substance has a potential for abuse, and * * * makes with respect to 
such drug or other substance the findings prescribed by [21 U.S.C. 
812(b)] for the schedule in which such drug is to be placed.'' 21 
U.S.C. 811(a). However, a rule made under this provision ``shall be 
made on the record after opportunity for a hearing pursuant to the 
rulemaking procedures prescribed by subchapter II of chapter 5 of Title 
5.'' Id.
    ``[W]ith respect to each drug * * * proposed to be controlled,'' 
the CSA requires that the Attorney General consider eight factors in 
making the findings required under both subsections 811(a) and 812(b). 
These are:
    (1) [The drug's] actual or relative potential for abuse.
    (2) Scientific evidence of its pharmacological effect, if known.
    (3) The state of current scientific knowledge regarding the drug or 
other substance.
    (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.
    (8) Whether the substance is an immediate precursor of a substance 
already controlled under this subchapter.

21 U.S.C. 811(c).

    However, ``before initiating proceedings * * * to control a drug * 
* * and after gathering the necessary data,'' the Attorney General is 
required to ``request from the Secretary a scientific and medical 
evaluation, and his recommendations, as to whether such drug * * * 
should be controlled.'' Id. 811(b). The statute further provides that 
``[i]n making such evaluation and recommendations, the Secretary shall 
consider the Factors listed in paragraphs (2), (3), (6), (7), and (8) 
of subsection (c) * * * and any scientific or medical considerations 
involved in paragraphs (1), (4), and (5) of such subsection. The 
recommendations of the Secretary shall include recommendations with 
respect to the appropriate schedule, if any, under which such drug * * 
* should be listed.'' Id.
    Finally, ``[t]he recommendations of the Secretary to the Attorney 
General shall be binding as to such scientific and medical matters, and 
if the Secretary recommends that a drug * * * not be controlled, the 
Attorney General shall not control the drug * * *. If the Attorney 
General determines that these facts and all other relevant data 
constitute substantial evidence of potential for abuse such as to 
warrant control * * * he shall initiate proceedings for control * * * 
under subsection (a) of this section.'' Id.

Procedural History

    Pursuant to section 811(b), in March 1996, the Drug Enforcement 
Administration (DEA) requested from the Department of Health and Human 
Services (HHS) a scientific and medical evaluation of carisoprodol, and 
a recommendation as to whether it should be controlled. ALJ Ex 1, at 3. 
In February 1997, however, the U.S. Food and Drug Administration's 
(FDA) Drug Abuse Advisory Committee concluded that the then-available 
data did not support controlling carisoprodol. Id.
    Thereafter, at the direction of the National Institute on Drug 
Abuse (NIDA) and the College of Problems of Drug Dependence (CPDD), 
additional pharmacological studies of carisoprodol's abuse liability 
were conducted. In the meantime, DEA gathered additional new data on 
actual abuse and law enforcement encounters involving the drug, as well 
as other information, which it sent to HHS on November 14, 2005. FDA 
also acquired new data from the Drug Abuse Warning Network (DAWN), the 
National Survey on Drug Use and Health (NSDUH), Florida Medical 
Examiners Commission reports, FDA's Adverse Event Reporting System, as 
well as other information from a variety of sources.
    On October 6, 2009, HHS concluded its review of the evidence 
pertaining to the eight factors set forth in 21 U.S.C. 811 and 
recommended that carisoprodol be placed in schedule IV. GX 6, at 1. 
Thereafter, on November 17, 2009, DEA issued a Notice of Proposed 
Rulemaking, which proposed placing carisoprodol in schedule IV. ALJ 
Ex., at 1 (74 FR 59108). Therein, DEA invited all persons to submit 
written comments or objections to the proposed rule; DEA also notified 
``interested persons'' of their right to request a hearing. Id. at 2 
(citing 5 U.S.C. 556 and 557).
    DEA received seventeen comments on the proposed rule; sixteen of 
the commenters (which included law enforcement officials, medical 
professionals and state regulators) supported the proposed 
rulemaking.\1\ One entity, Meda Pharmaceuticals, Inc. (Meda), which 
manufactures the branded drug Soma, objected to the proposed rule on 
the ground that the ``the administrative record does not include 
substantial and reliable evidence of potential for abuse sufficient to 
warrant scheduling carisoprodol and because the proposal gives 
inadequate weight to the negative impact on patient care of scheduling 
carisoprodol.'' ALJ Ex. 2, at 3. Meda also requested a hearing. Id. at 
1. On March 21, 2010, I granted Meda's request and assigned the matter 
to the Agency's Office of Administrative Law Judges (ALJ). ALJ Ex. 3, 
at 2.
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    \1\ None of the commenters raised any issue as to the various 
Regulatory Certifications contained in the Notice of Proposed 
Rulemaking. See 74 FR at 59111. One commenter, which represents 
wholesale distributors, requested that if the proposed rule is 
finalized, its effective date be set at 120 days from the date of 
publication to provide adequate time to comply with various 
regulations.
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    Following pre-hearing procedures, an ALJ conducted a hearing on 
July 6, 8,

[[Page 77331]]

and 9, as well as on August 3-6, 2010. At the hearing, both the 
Government and Meda elicited the testimony of witnesses and introduced 
various documents into evidence. Thereafter, both the Government and 
Meda filed briefs containing their proposed findings of fact and 
conclusions of law.

The ALJ's Recommended Decision

    On December 8, 2010, the ALJ issued her recommended decision. 
Therein, prior to discussing the eight ``factors determinative of 
control,'' 21 U.S.C. 811(c), the ALJ discussed the weight to be given 
the FDA's findings as to scientific and medical matters. ALJ at 6; see 
also 21 U.S.C. 811(b). As explained more fully below, the ALJ adopted 
the Government's argument that the statute ``limits the scope of the 
administrative hearing to those issues outside of the medical and 
scientific fact-findings of the FDA,'' ALJ at 11, and concluded that 
``the plain language and legislative history of Sec.  811(b), federal 
case law, and [HHS's] process for conducting its administrative review, 
make clear that Congress intended that the Secretary's scientific and 
medical fact-findings bind the DEA during the hearing and the 
subsequent scheduling determination.'' Id. at 18.
    However, the ALJ then noted that ``not all of the conclusions that 
the FDA made in its review are scientific and medical'' in nature and 
that the FDA's conclusions based on data obtained from the Drug Abuse 
Warning Network (DAWN), the National Survey on Drug Use and Health 
(NSDUH), and the Florida Medical Examiners/Coroners Reports ``could 
equally fall under the umbrella of law enforcement or science and 
medicine.'' Id. at 19-20. The ALJ ultimately concluded that ``the data 
gathered by these sources [was] primarily statistical, and not medical, 
and [is] therefore capable of review by this agency.'' Id. at 20. The 
ALJ thus concluded that FDA's conclusions based on this data are ``not 
binding.'' Id. Moreover, notwithstanding her statement as to the scope 
of the hearing, the ALJ allowed Meda to introduce extensive evidence 
including expert testimony as to the various scientific and medical 
matters considered by the FDA.
    The ALJ then made extensive findings as to each of the eight 
section 811(c) factors. With respect to Factor One--the actual or 
relative potential for abuse--the ALJ first explained that ``abuse is 
using a drug for nonmedical purposes for [its] positive psychoactive 
effects.'' Id. at 82. The ALJ then noted the testimony of one of Meda's 
expert witnesses, who runs a drug treatment center, that he could not 
recall a single case of a person being treated at his center for 
dependence on carisoprodol and his opinion that ``the data and 
information presented by the FDA and DEA do not establish that 
carisoprodol has a potential for abuse similar'' to schedule IV 
controlled substances. Id.
    However, the ALJ found ``more compelling'' data compiled by Meda 
and the predecessor holders of the New Drug Application for 
carisoprodol which had been submitted to the FDA's Adverse Events 
Reporting System (AERS). Id. at 82. This data, which includes reports 
from consumers and healthcare practitioners, showed that between 
January 1979 and May 1, 2010, there had been ``731 spontaneous adverse 
event'' reports of which eighty-three used such terms as abuse, 
dependency or withdrawal. Id. at 82-83.
    The ALJ further noted that in 2009, FDA required that Meda re-write 
the drug's label to note the effects of chronic use, that there are 
``published case reports of human carisoprodol dependence,'' and that 
various animal studies indicate the drug has ``effects similar to the 
use of barbital, meprobamate, and chlordiazepoxide,'' all of which are 
controlled substances. Id. at 83. The ALJ also noted that Meda 
eventually accepted the labeling change. Id. at n.42. Based on the AERS 
data and the drug's label, the ALJ concluded that carisoprodol's 
``abuse potential is recognized,'' and that ``the record contains 
substance evidence of a potential for abuse when carisoprodol is 
chronically used.''
    With respect to Factors Two and Three--the scientific evidence of 
carisoprodol's pharmacological effect and the state of current 
scientific knowledge regarding the drug--the ALJ noted that ``[b]oth 
the DEA and the FDA relied on animal studies of self-administration, 
drug discrimination, and physical dependence to support their position 
that carisoprodol should be classified as a schedule IV drug.'' Id. at 
84. The ALJ then noted the testimony of Meda's Expert that ``while the 
animals reflected behavior patterns with respect to carisoprodol that 
suggest patterns similar to barbiturates, the limitations of animal 
studies `do not provide an adequate basis to make decisions concerning 
abuse potential in humans,' '' and that `` `certain drugs will 
substitute for drugs of abuse without themselves being subject to any 
significant drug abuse.' '' Id. The ALJ, however, then held that ``the 
FDA's conclusions regarding carisoprodol's pharmacology and withdrawal 
patterns [were] binding on this proceeding.'' Id.
    The ALJ then discussed three different human studies. With respect 
to the Fraser study,\2\ the ALJ noted that Meda's Expert interpreted 
the results as showing that ``ingestions `did not induce a 
characteristic barbiturate intoxication pattern * * *, nor did the 
abrupt withdrawal of carisoprodol reveal any signs of barbiturate-like 
abstinence' behavior.'' Id. at 85. However, the ALJ then noted that 
``the FDA and the DEA found that the subjective and objective effects 
were similar to those of barbiturates or alcohol and different from 
those of opiates'' and that the drug ``has sedative-like effects.'' Id. 
Here again, the ALJ found FDA's findings binding on the proceeding. Id.
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    \2\ While both parties and the ALJ cited this study as if it was 
an exhibit in the case, it was not included in the record forwarded 
to this Office and there is no indication that it was entered into 
evidence.
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    Next, the ALJ discussed the studies Meda had conducted to obtain 
FDA approval to market a smaller-strength dose. While these studies, 
which involved 4,000 patients, showed no evidence of diversion, misuse, 
or abuse, and none of the patients experienced withdrawal following 
discontinuation of the drug, the ALJ noted that the studies' subjects 
received only therapeutic doses and did so only ``for a period of one 
to two weeks.'' Id. The ALJ thus concluded that these trials ``did not 
test the effects of prolonged use of carisoprodol at ingestion levels 
above the levels for therapeutic use.'' Id.
    The ALJ then discussed a case study by doctors from the Mayo Clinic 
of a 51-year old man who had taken up to six times the maximum 
recommended daily dose, which concluded that the case ``demonstrates 
adverse effects of both carisoprodol toxicity and withdrawal.'' Id. at 
85-86. More specifically, the ALJ noted the study's findings that 
``abrupt discontinuation of high-dose carisoprodol may result in 
withdrawal symptoms including anxiety, psychosis, tremors, myoclonus, 
ataxia and seizures,'' and that ``[t]his withdrawal syndrome is likely 
underrecognized.'' Id. at 86.
    Finally, the ALJ noted the FDA's findings that ``carisoprodol 
possesses sedative properties which may underlie its therapeutic 
usefulness and its potential for abuse,'' that ``[r]ecent in vitro 
studies demonstrated that carisoprodol `possesses barbiturate-like 
effects,' '' that the drug ``has positive reinforcing effects and 
[that] its discriminative stimulus effects are similar to other 
schedule IV drugs such as barbital, meprobamate and chlordiazepoxide.'' 
Id. While the ALJ

[[Page 77332]]

noted that Meda's Expert had challenged the FDA's reliance on an in 
vitro study, she held again that the FDA's ``conclusion is binding on 
this proceeding.'' Id. Based on ``the totality of the record,'' the ALJ 
thus concluded that ``the record demonstrates that excessive 
carisoprodol use creates similar toxicity and withdrawal symptoms to 
other schedule IV drugs.'' Id.
    With respect to Factors Four and Five--the history and current 
pattern of abuse, and the scope, duration, and significance of abuse--
the ALJ began by noting the testimony of several law enforcement 
officials including the head of the DEA Office of Diversion Control, 
the Executive Director of the Ohio State Board of Pharmacy, and a 
Special Agent in Charge with the Tennessee Bureau of Investigation, 
each of whom testified that carisoprodol was being obtained for other 
than a legitimate medical purpose and being either abused or sold on 
the street.
    The ALJ then discussed data obtained from the National Forensic 
Laboratory Information System (NFLIS), the National Survey on Drug Use 
and Health (NSDUH), the Drug Abuse Warning Network (DAWN), Florida 
Medical Examiners, and the National Poison Data System (NPDS). While 
noting that the NFLIS data, which showed that carisoprodol was 
consistently among the top twenty-five drugs being seized during 
criminal investigations and analyzed by state and local forensic 
laboratories are ``not direct evidence of abuse,'' the ALJ concluded 
these data ``lead[] to an inference that [the drug] has been diverted 
and abused.'' Id. at 88.
    As for the NSDUH data, the ALJ noted that data for the years 2004 
through 2007 estimate that between 2,525,000 and 2,840,000 million 
individuals have used carisoprodol during their lifetime for a non-
medical reason. Id. at 89. While observing that the yearly estimates 
``may remain relatively consistent,'' the ALJ observed that ``they are 
still a significant number of nonmedical uses.'' Id. However, the ALJ 
then noted that ``these numbers are significantly lower than comparable 
numbers for the nonmedical use of benzodiazepines.'' Id.
    Next, the ALJ discussed the DAWN data. With respect to the DAWN 
Emergency Department data, the ALJ noted that these data show that the 
abuse frequency of carisoprodol ``is similar to that of diazepam, a 
schedule IV drug,'' and that the data show an ``increasing frequency of 
nonmedical use emergency department visits associated with 
carisoprodol.'' Id. However, the ALJ then noted the credited testimony 
of another of Meda's expert witnesses that there is a ``lack of 
transparency in the methods used to collect * * * and statistically 
extrapolate'' the data, that without ``understanding the nature and 
extent of the changes in case findings(s) during the last several 
years, it is impossible to conclusively say what proportion of the 
increases in DAWN ED national estimates is attributable to changes in 
methodology versus changes in the actual number of DAWN cases 
associated with a particular drug,'' and that ``[t]his hinders any 
effort to interpret'' the trends over time. Id. The ALJ thus agreed 
with Meda's expert that DAWN ED data ``may not be the best evidence in 
this record for concluding that the abuse of carisoprodol is increasing 
over time.'' Id.
    As for the DAWN Medical Examiner data, the ALJ noted that the 
``reporting [of] a drug in this reporting system means that the drug 
need only be implicated or suspected in the death.'' Id. at 90. Quoting 
the testimony of Meda's Expert, the ALJ found that `` `carisoprodol may 
not have been the actual cause of death, and it is not possible to 
conclude that carisoprodol `abuse' was the cause of death in these 
cases.' '' Id. However, the ALJ noted that the data ``showed a link, 
even if not direct evidence of a cause, between carisoprodol use in 
combination with other drugs and death in 434 cases of death in 2006.'' 
Id.
    Turning to the Florida Medical Examiner data, which show that 415 
carisoprodol-related deaths occurred in 2008, and an increase of 
``about 62 percent'' in the ``total occurrence of carisoprodol/
meprobamate in Florida drug abuse deaths,'' the ALJ again noted the 
testimony of Meda's Expert that ``carisoprodol may not be the cause of 
death, but rather it may be merely present in the body at the time of 
death.'' Id. However, the ALJ then found that the FDA ``determined that 
carisoprodol was considered the cause of death in 88 cases in 2007.'' 
Id.
    Next, the ALJ noted that the NPDS data show that in 2007, `` 
`carisoprodol was associated with 8,821 toxic exposure cases, including 
3,605 cases in which [it] was the sole drug mentioned,' '' and that 
``[c]ases of individuals treated in health-care facilities because of a 
major adverse health-outcome total 122 out of the 2,821 single exposure 
cases.'' Id. at 91. The ALJ then acknowledged the testimony of Meda's 
Expert that because the cases are self-reported and ``the reporting 
individual may misidentify the substance during the call to the poison 
center, `it [is] impossible to conclude that a mentioned drug was 
causally implicated in the exposure.' '' Id. However, the ALJ also 
noted the testimony of Meda's Expert that the `` `poison center data 
have some use, but must be interpreted with caution.' '' Id.
    The ALJ further found that while the ``the intentional exposure 
data'' for the years 2006 and 2007 show that the number of deaths 
attributable to ``single exposure cases'' had remained at one per year, 
the number of cases with ``major effects went from 105 to 122,'' and 
the number of cases with ``moderate effects went from 688 to 720.'' Id. 
at 91-92. The ALJ thus concluded that the increases in the major and 
moderate effects cases support the ``conclusion that `individuals are 
taking carisoprodol in amounts sufficient to cause hazard to their 
health.' '' Id. at 92.
    Finally, the ALJ observed that the FDA had ``found that data from 
`2002-2006 indicate that more than 25 percent of patients used the drug 
[for] longer than one month and 4.3 percent used the drug more than 360 
days,' '' and that `` `[l]onger term use may contribute to increased 
risks of misuse and abuse.' '' Id. The ALJ then noted that she 
``agree[d] with the FDA's conclusion.'' Id.
    With respect to Factor Six--the risk, if any, to public health--the 
ALJ again noted the testimony of the head of DEA Office of Diversion 
Control, the Executive Director of the Ohio State Board of Pharmacy, 
and the Special Agent in Charge with the Tennessee Bureau of 
Investigation to the effect that ``the failure to schedule carisoprodol 
poses a great risk to public health.'' Id. at 92-93. The ALJ further 
noted the FDA's conclusion that because carisoprodol is metabolically 
converted to meprobamate, a schedule IV controlled substance, ``the 
public health risks of carisoprodol may be similar to those of 
meprobamate''; the poison control center data which ``show that 
`individuals are taking carisoprodol in amounts sufficient to cause 
hazard to their health' ''; and FDA's finding that `` `the risks of 
carisoprodol to the public health are typical of other central nervous 
system depressants that are controlled' '' and that `` `[t]hese risks 
include central nervous system depression, respiratory failure, 
cognitive and motor impairment, addiction, dependence, and abuse.' '' 
Id. (citations omitted). The ALJ again found that the FDA's conclusions 
were ``binding on this proceeding.'' Id. at 93.
    The ALJ then noted Meda's evidence showing a decline in the number 
of prescriptions that occurred in four States which have controlled

[[Page 77333]]

carisoprodol, as well as Meda's contention that controlling the drug 
would have a chilling effect on the legitimate prescribing of the drug 
because of the reluctance of physicians to prescribe a controlled 
substance and that this would be ``to the detriment of those patients 
who would be best treated with carisoprodol.'' Id. at 93-94. The ALJ 
found, however, that ``anecdotal evidence in this record contradicts 
this prediction,'' because one of Meda's Experts testified that if 
carisoprodol was controlled, he would continue to prescribe it. Id. at 
94. The ALJ then found that DEA data showed that controlling other 
drugs ``did not result in physicians ceasing to prescribe'' them. Id.
    Finally, the ALJ found that ``carisoprodol has been implicated in 
cases of impaired driving, with symptoms consistent with other central 
nervous system depressants, especially alcohol,'' and that ``[a] 
Norwegian study also supported this proposition.'' Id. The ALJ was 
unpersuaded by Meda's argument ``that many uncontrolled drugs have 
labels warning against driving while taking such drugs,'' noting that 
``[i]mpaired driving is a risk to the public health,'' and thus 
supports the ``conclusion that published scientific reports indicate 
that taking carisoprodol is associated with risk to the public 
health.'' Id.
    With respect to Factor Seven--the drug's psychic or physiological 
dependence liability--the ALJ observed that ``[d]ependence includes 
both physical and psychological dependence.'' Id. While noting that 
``there are noncontrolled drugs for which an individual may have a 
physical dependence,'' a drug-taker's conduct must be ``viewed in 
total'' to determine if the person ``has a psychic drive or craving to 
obtain the drug.'' Id. at 95. The ALJ then noted that based on various 
scientific studies, the FDA had ``found that carisoprodol has a 
dependence liability that is similar to that of barbital, a Schedule IV 
central nervous system depressant, in its dependence potential,'' and 
that the FDA's finding was binding on the proceeding. Id. The ALJ also 
cited the testimony of a DEA witness that carisoprodol is abused by 
individuals to obtain a ``mellow euphoria.'' Id.
    The ALJ also found that two studies had shown that carisoprodol 
produces ``subjective and objective effects'' in ``human subjects 
[that] were similar to those of barbiturates or alcohol,'' the former 
being controlled substances listed in both schedules III and IV. Id. at 
96. The ALJ then noted the testimony of Meda's Expert that if 
``carisoprodol induced a barbiturate intoxication pattern, [this] could 
be a possible indicator that carisoprodol possesses barbiturate-like 
abuse liability.'' Id.
    Finally with respect to Factor Eight--whether carisoprodol is an 
immediate precursor to a substance already controlled--the ALJ found it 
undisputed that the drug ``is not an immediate chemical precursor or 
intermediary of a controlled substance.'' Id.
    The ALJ then addressed the three section 812(b) placement factors. 
With respect to Factor One--whether the drug has a low potential for 
abuse relative to the drugs in schedule III--the ALJ began by noting 
the FDA's recommendation (and the concurrence of the National Institute 
on Drug Abuse (NIDA)), that carisoprodol should be placed in schedule 
IV. Id. The ALJ found that ``[e]mpirical evidence supports the FDA's 
conclusion,'' including the evidence that carisoprodol metabolizes into 
meprobamate, a schedule IV controlled substance,'' and that various 
studies support the conclusion that carisoprodol has effects similar to 
barbiturates, which are schedule III and IV controlled substances. Id. 
at 96-97. The ALJ also found that notwithstanding that the DAWN ED 
data, which show that the ``abuse frequency of carisoprodol is similar 
to that of diazepam, a schedule IV drug,'' ``may be overly inclusive,'' 
this limitation would not result in ``any significant difference in ED 
visits between the reported drugs.'' Id. at 98. While acknowledging 
that the NSDUH data show that ``carisoprodol is being abused * * * at a 
rate significantly less than that of benzodiazepines,'' the ALJ found 
that ``the NSDUH and DAWN are two distinct studies, both on methodology 
and measurement, and therefore cannot adequately be compared.'' Id. at 
98-99.
    With respect to Factor Two--whether the drug has a currently 
accepted medical use in treatment in the United States--the ALJ found 
it undisputed that carisoprodol has been approved by the FDA for the 
treatment of ``acute, painful musculoskeletal conditions.'' Id. at 99-
100. The ALJ thus found that ``carisoprodol has a currently accepted 
medical use in the United States.'' Id. at 100.
    With respect to Factor Three--whether abuse of the drug may lead to 
limited physical or psychological dependence relative to the drugs in 
schedule three--the ALJ credited the testimony of two of Meda's experts 
to the effect that carisoprodol ``does not create abuse liability 
patterns typical of controlled drugs'' and that ``[t]here does not 
appear to be any patient `liking' that would indicate an abuse 
potential.'' Id. at 101. The ALJ nonetheless found that ``there is 
substantial evidence in the record based on the animal data, AERS 
reports, and Mayo Clinic data that carisoprodol produces dependence and 
withdrawal symptoms similar to other controlled substances in schedule 
IV.'' Id. The ALJ further held that ``FDA's conclusions regarding the 
psychological and physiological dependence of carisoprodol [were] 
binding on this proceeding.'' Id.
    The ALJ thus concluded that substantial evidence supports the 
controlling of carisoprodol under the eight factors of section 811(c). 
Id. at 102. The ALJ further concluded that substantial evidence 
supported the placement of carisoprodol in schedule IV. Id. (citing 21 
U.S.C. 812).
    Meda filed Exceptions to the ALJ's decision. Thereafter, the ALJ 
forwarded the record to me for final agency action.
    Having considered the entire record, including Meda's Exceptions 
(which are discussed more fully below), I agree with its contention 
that the ALJ erred in holding that the FDA's scientific and medical 
findings are binding on this proceeding. However, because the ALJ 
allowed Meda to put on extensive evidence as to the scientific and 
medical matters considered by the FDA, and because, as ultimate 
factfinder (see 5 U.S.C. 557(b)), I have considered Meda's evidence in 
deciding whether substantial evidence supports the scheduling of 
carisoprodol, I conclude that the ALJ's error is not prejudicial. 
Because I hold that the record as a whole contains substantial evidence 
to support the findings required to control carisoprodol and place it 
in schedule IV of the CSA, I will issue a rule placing carisoprodol in 
schedule IV.

The ALJ's Ruling on the Binding Nature of the FDA's Scientific and 
Medical Evaluation

    As noted above, ``before initiating proceedings * * * to control a 
drug or other substance,'' the Attorney General is required to 
``request from the Secretary a scientific and medical evaluation, and 
[her] recommendations, as to whether such drug or other substance 
should be so controlled.'' 21 U.S.C. 811(b). Congress specified that 
``[i]n making such evaluation and recommendations, the Secretary shall 
consider the factors listed in paragraphs (2), (3), (6), (7), and (8) 
of subsection (c) * * * and any scientific or medical considerations 
involved in paragraphs (1), (4) and (5) of such subsection.' '' Id. The 
Secretary is directed to provide the Attorney General with her 
``evaluation and * * * recommendations,'' which

[[Page 77334]]

``shall include recommendations with respect to the appropriate 
schedule, if any, under which such drug or other substances should be 
listed.'' Id.
    Subsection (b) further provides that ``[t]he recommendations of the 
Secretary to the Attorney General shall be binding as to such 
scientific and medical matters, and if the Secretary recommends that a 
drug or other substance not be controlled, the Attorney General shall 
not control the drug or other substance.'' Id. Moreover, ``[i]f the 
Attorney General determines that these facts and all other relevant 
data constitute substantial evidence of potential for abuse such as to 
warrant control * * * he shall initiate proceedings for control * * * 
under subsection (a),'' the provision which requires that a rule 
scheduling a substance ``be made on the record after opportunity for a 
hearing pursuant to the rulemaking procedures prescribed by'' 5 U.S.C. 
556 and 557.
    The ALJ held that ``the CSA limits the scope of the administrative 
hearing to those issues outside of the medical and scientific fact-
findings of the FDA.'' ALJ at 11. According to the ALJ, the ``the plain 
language and legislative history of [sections 811(a) and (b)] and 
federal case law indicate [that] Congress intended that the Secretary's 
scientific and medical fact-findings bind the [Agency] throughout the 
scheduling process.'' Id. The ALJ further rejected Meda's contention 
that construing the statute in this manner would deny it a meaningful 
hearing and render the hearing ``largely superfluous,'' concluding that 
``Respondent will be afforded the opportunity for a meaningful APA 
hearing without the opportunity to litigate the factual underpinnings 
of the [HHS] report.'' Id.
    The ALJ thus rejected Meda's contention that the FDA's findings as 
to medical and scientific matters are only binding on the Agency's 
decision as to whether to initiate a scheduling proceeding and that the 
Secretary's findings are not binding on either the ALJ or the 
Administrator in evaluating the record of the hearing. Id. at 9-11 
(discussing Meda Br. 15-18). As noted above, throughout her 
consideration of the factors, the ALJ held that she was bound by FDA's 
findings as to scientific and medical matters and that Meda was not 
entitled to challenge the Secretary's medical and scientific findings. 
See, e.g., ALJ at 85-86 (holding FDA's findings as to Factor Two 
(Section 811(c)) binding notwithstanding Meda's contrary evidence).
    I find the ALJ's reasoning confusing,\3\ and that she gave 
insufficient consideration to the most relevant judicial decisions; I 
therefore reject her legal conclusion. To be sure, the Supreme Court 
has recognized that ``[t]he CSA allocates decision making powers among 
statutory actors so that medical judgments * * * are placed in the 
hands of the Secretary,'' and that the ``[t]he structure of the CSA * * 
* conveys unwillingness to cede medical judgments to an Executive 
official who lacks medical expertise.'' Gonzales v. Oregon, 546 U.S. 
243, 265 (2006). Yet, the ALJ's sweeping conclusion that this 
``language supports the inference that the Supreme Court interpreted 
811(b) to indicate that those medical judgments are final and not 
subject to litigation before the DEA,'' ALJ at 13 (emphasis added), 
cannot be squared with other provisions of the statute. Moreover, the 
Court did not decide the issue.
---------------------------------------------------------------------------

    \3\ Compare ALJ at 11 (noting that dicta in Reckitt & Coleman, 
Ltd., v. Administrator, 788 F.2d 22, 27 n.8 (DC Cir. 1977), 
``highlights the inherent ambiguity in the statutory language''), 
with id. at 18 (holding that ``the plain language'' of section 
811(b) ``make[s] clear that Congress intended that the Secretary's 
scientific and medical fact-findings bind the DEA during the hearing 
and the subsequent scheduling determination'').
---------------------------------------------------------------------------

    As noted above, upon receiving the Secretary's evaluation and 
recommendation, the Attorney General is charged with the duty to 
``determine that these facts and all other relevant data constitute 
substantial evidence of potential for abuse such as to warrant 
control.'' 21 U.S.C. 811(b) (emphasis added). In the event the 
Secretary's evaluation and the other relevant data constitute 
substantial evidence such as to warrant control, the Attorney General 
may then initiate proceedings to control the drug. However, Congress 
further provided that ``Rules of the Attorney General [to control a 
drug] shall be made on the record after opportunity for a hearing 
pursuant to the rulemaking procedures prescribed by'' the 
Administrative Procedure Act (APA). 21 U.S.C. 811(a).
    Under this provision, a rule may not be ``issued except on 
consideration of the whole record or those parts thereof cited by a 
party and supported by and in accordance with the reliable, probative, 
and substantial evidence.'' 5 U.S.C. 556(d) (emphasis added). Were it 
the case that the Secretary's findings as to medical and scientific 
matters are not subject to litigation in the subsequent rulemaking 
hearing, the only issues left to be litigated would be the drug's 
``actual'' abuse, its ``history and current pattern of abuse'' and the 
``scope, duration, and significance of abuse.'' 21 U.S.C. 811(b). 
However, an on-the-record hearing (as opposed to notice and comment 
rulemaking) would hardly be necessary to determine whether the data 
proffered by the Agency is adequate to support the findings necessary 
to control a drug. As the DC Circuit explained in Reckitt,\4\ if HHS's 
medical and scientific findings are binding throughout a proceeding, 
``it is difficult to see what purpose the agency's on-the-record 
hearing [would] serve[.]'' \5\
---------------------------------------------------------------------------

    \4\ At issue in Reckitt & Coleman was a rulemaking which 
rescheduled buprenorphine from schedule II to schedule V, but which 
designated the drug as a narcotic based on the ground that it is a 
derivative of thebaine. See 788 F.2d at 22. In a footnote, the Court 
of Appeals discussed an argument advanced in the brief of a third-
party intervenor (which the Department endorsed at oral argument) 
that the Agency's conclusion could be upheld on the ground that 
``HHS's initial communication to DEA stated that buprenorphine is a 
thebaine derivative, and the Act makes HHS's recommendations as to 
`scientific and medical matters' binding on the DEA.'' 788 F.2d 27 
n.8 (citing 21 U.S.C. 811(b)). While the court concluded that it was 
unnecessary to reach the issue, as noted above, it expressed 
considerable skepticism as to the reasonableness of the view that 
the Attorney General is bound by the Secretary's finding on a 
scientific issue notwithstanding contrary evidence presented at a 
hearing. While the DC Circuit's discussion is not binding, it is 
dictum which the Agency ignores at its peril.
    \5\ As support for her holding, the ALJ also cited United States 
v. Spain, 825 F.2d 1426, 1428 (10th Cir. 1987), and United States v. 
Pastore, 419 F.Supp. 1318 (S.D.N.Y. 1976). As for the ALJ's reliance 
on Spain, that case addressed the Attorney General's authority under 
21 U.S.C. 811(h), which authorizes the ``scheduling of a substance 
in schedule I on a temporary basis [when] necessary to avoid an 
imminent hazard to the public safety.'' See 825 F.2d at 1427. Under 
this provision, the Attorney General is not required to obtain a 
scientific and medical evaluation from the Secretary before acting. 
Id. at 148-29. Thus, the case does not address the issue of whether 
the Secretary's medical and scientific evaluation and 
recommendations are subject to re-litigation at the hearing. See 825 
F.2d at 1427.
     Pastore involved a motion to dismiss an indictment which 
charged various offenses involving the unlawful distribution and 
obtaining of the controlled substances phendimetrazine and 
phentermine. See 419 F. Supp. at 1334-35. While the defendants 
raised various challenges to the Attorney General's decision 
scheduling these drugs, both drugs were scheduled without a formal 
on-the-record hearing. Id. at 1346-48. Here again, the case did not 
address the issue of whether the Agency is bound by the Secretary's 
finding on a scientific or medical issue in a formal rulemaking 
proceeding. See id.
---------------------------------------------------------------------------

    The ALJ's also found unpersuasive Grinspoon v. DEA, 828 F.2d 881 
(1st Cir. 1987). Grinspoon involved a petition to review the Agency's 
issuance of a final rule placing MDMA in schedule I. 828 F.2d at 882. 
In Grinspoon, the petitioner raised four different challenges to the 
Agency's rule. Id. at 882-83. These included, inter alia, that the 
``Administrator applied the wrong legal standard'' because he 
interpreted the ``phrases `accepted medical use in treatment in the 
United States,' and `accepted safety for use * * * under

[[Page 77335]]

medical supervision' '' as meaning ``approved for interstate marketing 
* * * under the'' Food, Drug and Cosmetic Act, id. at 884 (quoting 21 
U.S.C. 812(b)(1)(A)), as well as that ``the rule [was] based upon 
incomplete and arbitrary recommendations from the Secretary.'' Id. at 
883.
    The First Circuit held that the Administrator had erroneously 
interpreted the phrases ``accepted medical use in treatment in the 
United States'' and ``accepted safety for use * * * under medical 
supervision'' as meaning that the drug had not been approved by FDA for 
interstate marketing. Id. at 891. The Court thus vacated the rule and 
ordered the Agency to reconsider the scheduling determination. Id.
    The Court, however, also addressed the Petitioner's other 
challenges to the rule, including that HHS had acted in an arbitrary 
and capricious manner because it ``failed to look beyond its own files 
upon receiving the Administrator's section 811(b) request,'' that it 
did not ``consult any organization of medical professionals'' or FDA's 
``Drug Abuse Advisory Committee,'' that it simply rubber-stamped DEA's 
eight-factor analysis, and that it had failed to forward a letter from 
NIDA which questioned evidence pertaining to MDMA's abuse potential in 
animals. Id. at 897. In rejecting the Petitioner's contention, the 
court explained:

    [T]he HHS recommendation to schedule a substance is not binding 
and, indeed, serves to trigger an administrative hearing at which 
interested persons may introduce evidence to rebut the Secretary's 
scheduling recommendation. Ultimately, of course, responsibility 
rests with the Administrator, not HHS, to ensure that the final rule 
rests on permissible legal standards and substantial evidence.

Id. (footnote omitted).

    As Grinspoon makes clear, while the Secretary is the expert as to 
the scientific and medical matters at issue in the scheduling decision, 
the Attorney General is obligated to conduct a hearing and to consider 
contrary evidence even as to these issues. The legislative history 
buttresses this conclusion.\6\ As the House Report explains:

    \6\ Throughout her discussion, the ALJ explained that ``the CSA 
limits the scope of the administrative hearing to those issues 
outside of the medical and scientific fact-findings of the FDA,'' 
that ``Congress intended that the Secretary's scientific and medical 
fact-findings bind the DEA throughout the scheduling process,'' that 
``Respondent will be afforded the opportunity for a meaningful APA 
hearing without the opportunity to litigate the factual 
underpinnings of the [HHS] report,'' ALJ at 11, and that Gonzales 
``indicate[s] that [the FDA's] medical judgments are final and not 
subject to litigation before the DEA.'' Id. at 13.
     However, after concluding that Grinspoon does not support Meda 
and was distinguishable because the Agency had blindly relied on FDA 
approval as the sine qua non of the ``currently accepted medical 
use'' and ``accepted safety for use * * * under medical 
supervision'' standards, the ALJ quoted the passage set forth above 
and observed that ``[i]n light of th[e Administrator's] 
independence, and Meda's opportunity to present evidence relevant to 
the Administrator's decision, this tribunal would be hard-pressed to 
conclude that there was `` `no opportunity for consideration of the 
views of persons who would be adversely affected by control of the 
drug.' '' Id. at 16 (quoting H. Rep. No. 91-1444, at 23 (1970)). 
Yet, she subsequently concluded that ``the plain language and 
legislative history * * *, federal case law, and [HHS's] process for 
conducting its administrative review, make clear that Congress 
intended that the Secretary's scientific and medical fact-findings 
bind the DEA during the hearing and the subsequent scheduling 
determination.'' Id. at 18.
---------------------------------------------------------------------------

    The procedure which the Attorney General must then follow to 
control a drug involves rulemaking proceedings on the record after 
opportunity for a hearing. This provides opportunity for 
consideration of the views of persons who would be adversely 
affected by control of a drug, with judicial review available 
thereafter; however, this administrative proceeding is more 
streamlined in its operation than the existing procedures under 
section 701(e) of the Federal, Food, Drug, and Cosmetic Act, so that 
controls may be established expeditiously where necessary, with full 
consideration of all factors involved in the decision-law 
enforcement problems, medical, and scientific determinations, and 
the interests of parties affected by the decision to control.

H. Rep. No. 91-1444, 1970 U.S.C.C.A.N. at 4589.

    The ALJ also reasoned that the FDA's ``detailed administrative 
process [for] making its scientific and medical fact findings suggests 
that Congress did not intend the DEA to secondarily review those 
filings.'' ALJ at 17. Citing a 1999 Hearing Report of the Subcommittee 
on Oversight and Investigations of the House Committee on Commerce, the 
ALJ noted that the `` `the scientific and medical evaluation process is 
a complex one which is part of the balancing of the interests of 
various agencies' '' and that the process ``may extend over many years, 
[and] is subject to review by various components of the FDA and 
interagency review.'' Id. The ALJ further noted that under two 
different FDA regulations, Meda could have requested a hearing before 
the FDA. ALJ at 17-18 n.5; see also id. at 4 n.2.
    However, in enacting subsection 811(a), Congress did not bifurcate 
the hearing between the two Agencies. Rather, it tasked the Attorney 
General with the responsibility for conducting the hearing. Moreover, 
neither the statute nor the legislative history evidences that Congress 
intended that challenges to the Secretary's scientific and medical 
findings be litigated in a proceeding before HHS.
    In addition, both the statute and the legislative history make 
plain that Congress was concerned that scheduling proceedings be done 
in an expeditious manner. For instance, section 811(b) requires that 
the Secretary submit his report ``to the Attorney General within a 
reasonable time.'' 21 U.S.C. 811(b) (emphasis added). Likewise, in 
discussing the hearing provision, the House Report manifests Congress' 
intent ``that controls may be established expeditiously where 
necessary.'' 1970 U.S.C.C.A.N. at 4589. The ALJ's suggestion that Meda 
was required to request a hearing under either 21 CFR 14.172 or 21 CFR 
15.1(a), see ALJ at 17 & n.5,\7\ runs counter to Congress's manifest 
interest in the expeditious resolution of proceedings to control a 
drug.
---------------------------------------------------------------------------

    \7\ Under 21 CFR 14.172, ``[a]ny interested person may request, 
under Sec.  10.30, that a specific matter relating to a particular 
human prescription drug be submitted to an appropriate advisory 
committee for a hearing and review and recommendations * * *. The 
Commissioner may grant or deny the request.'' Under 21 CFR 15.1(a), 
the Commissioner may ``conclude[], as a matter of discretion, that 
it is in the public interest to permit persons to present 
information and views at a public hearing on any matter pending 
before the Food and Drug Administration.'' Notably, under both 
provisions, the decision as to whether to grant a hearing is within 
the Commissioner's discretion.
---------------------------------------------------------------------------

    In its Exceptions, Meda contends that ``the ALJ's decision in this 
proceeding is predicated upon an erroneous belief that Meda had an 
opportunity to challenge the scientific and medical fact-finding 
underlying'' the HHS recommendation. Meda Exc. at 1. The exception is 
well taken. Indeed, as set forth in footnote seven above, under both of 
these provisions, the decision as to whether to grant a hearing is 
discretionary. Requiring that Meda litigate the medical and scientific 
findings before an FDA forum would likely add several years of delay, 
and would raise a host of additional issues, including whether DEA was 
required to stay its proceeding while the findings were being 
challenged before an FDA forum, whether those findings are entitled to 
res judicata effect if a formal evidentiary hearing was not held, 
whether the FDA's decision was a final decision triggering the right to 
judicial review, and likely others.
    Also unpersuasive is the ALJ's reasoning that because the FDA's 
process for evaluating a scheduling request is complex and time-
consuming, ``Congress did not intend the DEA to secondarily review 
those findings.'' ALJ at 17. As the House Report makes plain,

[[Page 77336]]

in enacting the scheduling provisions, Congress manifested its 
intention that scheduling proceedings would be done in an expeditious 
fashion, but with ``full consideration of all factors involved in the 
decision,'' including the medical and scientific determinations 
involved in the decision. 1970 U.S.C.C.A.N. at 4589 (emphasis added). 
The ALJ's conclusion that the medical and scientific findings of FDA 
are binding and cannot be ``secondarily review[ed]'' in this 
proceeding, is contrary to this intent.
    Accordingly, consistent with the APA's requirement that the record 
as a whole must be considered, I hold that, notwithstanding the 
Secretary's expertise as to the scientific and medical matters, the 
Agency is (and the ALJ was) obligated to consider Meda's contrary 
evidence even as to the Secretary's medical and scientific findings and 
to determine whether substantial evidence supports the finding that 
carisoprodol ``has a potential for abuse,'' as well as the findings 
made in support of placing the drug in schedule IV. See 21 U.S.C. 
811(a).
    However, while the ALJ misconstrued the statute, she did allow Meda 
to put on evidence to rebut the Secretary's evaluation of the medical 
and scientific evidence. Because ``[t]he Agency, and not the ALJ, is 
the ultimate factfinder,'' Reckitt & Colman, 788 F.2d at 26, I conclude 
that ALJ did not commit prejudicial error. Cf. 5 U.S.C. 706 (``due 
account shall be taken of the rule of prejudicial error''). 
Accordingly, a remand is not necessary and I proceed to consider the 
evidence with respect to the section 811(c) factors.

Findings of Fact

    Since 1959, carisoprodol has been approved for marketing in the 
United States under the brand name of Soma; the drug, which is also 
available as a generic drug, is approved by the FDA for the ``relief of 
discomfort associated with acute, painful musculoskeletal conditions.'' 
GX 6, at 1 (letter of Howard H. Koh, M.D., Asst. Sec. for Health, HHS, 
to the Administrator (Oct. 6, 2009)). As noted above, on October 6, 
2009, HHS completed its review and recommended that carisoprodol be 
controlled and placed in schedule IV of the CSA. Id.
    FDA made extensive findings as to each of the eight section 811(c) 
factors. These findings are discussed below,\8\ along with additional 
evidence provided by DEA's witnesses and the testimony and exhibits 
submitted by Meda.
---------------------------------------------------------------------------

    \8\ Meda argues that the FDA review ``is entitled to very little 
weight'' because ``DEA counsel did not call any HHS or FDA witness 
to testify and justify the scientific, medical, and legal basis 
underlying the HHS recommendation.'' Meda. Br. 22. However, most of 
the findings in the FDA's evaluation were supported by citations to 
publicly available articles, and it is not clear why an FDA witness 
was required to testify as to the contents of articles which have 
been published in scientific and medical journals. Moreover, Meda 
did not seek to subpoena any of the FDA officials who were involved 
in the review. Finally, while the Government did not call an FDA or 
HHS witness ``to answer questions about the numerous weaknesses in 
the data,'' Meda was clearly able to put on an effective challenge 
to some of the data cited by the Government.
---------------------------------------------------------------------------

Factor 1--Carisoprodol's Actual or Relative Potential for Abuse

    The terms ``abuse'' and ``potential for abuse'' are not defined in 
the CSA. See generally 21 U.S.C. 802. However, the legislative history 
of the CSA explains that a drug or ``substance has a potential for 
abuse because of its depressant or stimulant effect on the central 
nervous system or its hallucinogenic effect'' based on the following 
indicators:

    1. Individuals are taking the substance in amounts sufficient to 
create a hazard to their health or to the safety of other 
individuals or to the community; or
    2. There is significant diversion of the drug or substance from 
legitimate drug channels; or
    3. Individuals are taking the substance on their own initiative 
rather than on the basis of medical advice from a practitioner 
licensed by law to administer such substance; or
    4. The substance is so related in its action to a substance 
already listed as having a potential for abuse to make it likely 
that it will have the same potential for abuse as such substance, 
thus making it reasonable to assume that there may be significant 
diversions from legitimate channels, significant use contrary to or 
without medical advice, or that it has a substantial capability of 
creating hazards to the health of the user or to the safety of the 
community.

Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep. 
No. 91-1444, reprinted in 1970 U.S.C.C.A.N. 4566, 4601.

    The legislative history also explains that a determination that a 
substance has ``potential for abuse'' should not ``be determined on the 
basis of isolated or occasional nontherapeutic purposes.'' Id. at 4602 
(other citation and int. quotations omitted). Rather, ``there must 
exist a substantial potential for the occurrence of significant 
diversions from legitimate channels, significant use by individuals 
contrary to professional advice, or substantial capability of creating 
hazards to the health of the user or the safety of the community.'' Id. 
However, the legislative history also makes clear that the Attorney 
General is not ``required to wait until a number of lives have been 
destroyed or substantial problems have already arisen before'' 
controlling a drug. Id.
    The legislative history further explains that ``[i]n speaking of 
`substantial' potential the term `substantial' means more than a mere 
scintilla of isolated abuse, but less than a preponderance.'' Id. Thus, 
evidence that ``several hundred thousand dosage units of a drug have 
been diverted would be `substantial' evidence of abuse despite the fact 
that tens of millions of dosage units of that drug are legitimately 
used in the same time period.'' Id. Moreover, ``[m]isuse of a drug in 
suicides and attempted suicides, as well as injuries resulting from 
unsupervised use are regarded as indicative of a drug's potential for 
abuse.'' Id.
    As the Assistant Secretary noted, ``there is no single test or 
assessment procedure that, by itself, provides a full and complete 
characterization of a substance's abuse potential, as this is a complex 
determination that is multidimensional.'' GX 6, at 3. Accordingly, in 
``assessing the abuse potential of a substance, the Secretary considers 
multiple factors, data sources and analyses,'' including ``the 
prevalence, frequency and manner of use in the general public and 
specific subpopulations, the amount of material that is available for 
illicit use, as well as evidence relevant to populations that may be of 
particular risk.'' Id.
    The Assistant Secretary further explained that:

[a]nimal, human, and epidemiological data are all used in 
determining a substance's abuse potential. Scientifically, a 
comprehensive evaluation of the relative abuse potential of a 
substance includes consideration of the drug's receptor binding 
affinity, preclinical pharmacology, reinforcing effects, 
discriminative stimulus effects, dependence producing potential, 
pharmacokinetics and routes of administration, toxicities, 
assessment[] of the clinical efficacy, safety database relative to 
actual abuse, clinical abuse potential studies and the public health 
risks following marketing of the substance. Epidemiological data can 
also be an important indicator of actual abuse. Finally, evidence of 
clandestine production and illicit trafficking of a substance are 
also important factors.

Id. Set forth below is the parties' evidence as to each of the four 
indicators of carisoprodol's potential for abuse.\9\
---------------------------------------------------------------------------

    \9\ I have considered Meda's argument that by relying on the 
four indicators of abuse set forth in the legislative history, the 
Agency ``has improperly attempted to redefine `abuse' to mean 
something much broader than what the Committee contemplated (i.e., 
use for nontherapeutic purposes).'' Med. Br. 13. However, as the 
Assistant Secretary noted, determining a substance's potential for 
abuse is a complex and multi-dimensional determination which 
includes an analysis of animal, human, and epidemiological studies, 
as well as other factors, GX 6, at 3; and the record contains 
extensive evidence as to the numerous considerations relevant in 
assessing a drug's abuse potential.

---------------------------------------------------------------------------

[[Page 77337]]

1. Use of Carisoprodol Results in Harm to Individuals and the Public

    The FDA found that an evaluation of published case reports and case 
series, the FDA Adverse Event Reporting System (AERS), and the SAMHSA 
DAWN databases, show that carisoprodol as currently used raises 
concerns not only for the health and safety of the users of this 
substance, but also for the public because of exposure to those who use 
carisoprodol. More specifically, the FDA found that these sources of 
information indicate that serious adverse events, including death, drug 
dependence, drug withdrawal symptoms, and non-intentional and 
deliberate overdose are related to the abuse of carisoprodol.
    The FDA further noted that adverse events have occurred both when 
carisoprodol is the sole drug of use, as well as when it is used in 
combination with other drugs, both licit and illicit (polypharmacy). In 
addition, the use of carisoprodol has been implicated as a factor in 
vehicle accidents due to driver impairment. The FDA thus concluded that 
there is evidence that individuals are taking the substance in amounts 
sufficient to create a hazard to their health or to the safety of other 
individuals or to the community.\10\
---------------------------------------------------------------------------

    \10\ The FDA more fully discussed the data under Factor Four--
carisoprodol's history and current patterns of use, and Factor Six--
what, if any, risk there is to public health. GX 6, at 3.
---------------------------------------------------------------------------

Drug Abuse Warning Network (DAWN) Data
    The Substance Abuse Mental Health Service's Administration (SAMHSA) 
administers the Drug Abuse Warning Network (DAWN, 2007; http://dawninfo.samhsa.gov/). DAWN is a national probability survey of U.S. 
hospitals with emergency departments (EDs) which is designed to obtain 
information on ED visits in which recent drug use is implicated. The 
data are gathered from a representative sample of hospital EDs and are 
weighted to produce national estimates. In addition to the DAWN ED 
data, DAWN also collects data on drug-related deaths investigated by 
Medical Examiners and Coroners (ME/C).\11\
---------------------------------------------------------------------------

    \11\ According to the FDA's report, DAWN mortality cases now 
include the following deaths: Completed suicides, Overmedication, 
Adverse reactions, Accidental ingestions, Homicide by drugs, 
Underage drinking and Other deaths related to drugs. The FDA further 
noted that ``[t]he mortality component of DAWN is not national in 
scope, and Medical Examiners or Coroners (ME/Cs) that report to DAWN 
are concentrated in metropolitan areas.'' GX 6, at 17. The FDA then 
acknowledged that because ``the report does not represent a 
scientific sample, results from participating jurisdictions cannot 
be extrapolated nationally,'' and that ``because participants can 
vary from year to year, it is not appropriate to compare aggregated 
death data between years.'' Id. Moreover, because ``[c]ertain 
jurisdictions within the metropolitan area may not participate in 
DAWN * * * selected data can not necessarily be generalized to an 
entire metropolitan area.'' Id.
     FDA further noted that ``[a]pproximately half of the 
carisoprodol-related deaths reported involve the use of meprobamate 
in combination with carisoprodol'' and that ``[d]ue to reporting 
method variability, it is difficult to determine if both drugs were 
taken in combination or if meprobamate was present in the deceased 
as a result of carisoprodol metabolism.'' Id. Finally, FDA noted 
that ``[t]he reporting of carisoprodol found by the ME/C following a 
post mortem examination does not necessarily imply that carisoprodol 
was the ultimate cause of death * * *, only that it was identified 
by the ME/C as involved in the death,'' and that ``[v]ery few deaths 
from 2003 and 2004 involve the use of carisoprodol by itself and are 
consistent with other data indicating that carisoprodol is used most 
often in combination with a variety of other agents.'' Id. at 18. 
Because of the numerous limitations with this data, I give no weight 
to the DAWN ME/C data.
---------------------------------------------------------------------------

DAWN ED Data
    According to FDA, many factors can impact the estimates of ED 
visits, GX 6, at 11; which ``are identified through a retrospective 
review of medical charts.'' MX 34, at 33 n.13. Individuals (whether 
patients or drug abusers) who use a drug may visit EDs for a variety of 
reasons, including treatment of a life threatening adverse event or to 
obtain a certification of need before entering a formal detoxification 
program. If multiple drugs are involved, DAWN may not be able to 
distinguish whether a single drug or the interaction of drugs caused 
the ED visit. Moreover, while ``DAWN tries to capture only drugs that 
are related to the ED visit and actively discourages the reporting of 
current medications that are unrelated to the visit[,] * * * it is not 
possible, given the limitations of medical record documentation, to 
eliminate completely the reporting of current medications.'' MX 34, at 
33.
    In addition, DAWN defines ``nonmedical use'' as ``use that does not 
meet the definition of medical use.'' Id. Under this definition, 
``nonmedical use of pharmaceuticals includes taking more than the 
prescribed dose of a prescription pharmaceutical * * *; taking a 
pharmaceutical prescribed for another individual; deliberate poisoning 
with a pharmaceutical by another person; and documented misuse or abuse 
of a prescription'' pharmaceutical. Id. Because of ``the limitations of 
medical record documentation, [DAWN has] concluded that distinguishing 
misuse from abuse reliably is not feasible.'' Id. n.13.
    Selected data from DAWN for 2004-2007 are shown in Table 1 below. 
These data show an increase in the frequency of nonmedical use ED 
visits associated with carisoprodol. More specifically, in 2004, DAWN 
estimated that there were 14,736 ED visits related to the nonmedical 
use of carisoprodol, and that in 2007, there were 27,505 nonmedical ED 
visits related to the nonmedical use of the drug. However, according to 
SAMHSA, the increase from 2004 through 2007 did not reach statistical 
significance. GX 6, at 12. Accordingly, the data do not support a 
finding that the rate of abuse of carisoprodol is increasing.
    The data do, however, support a finding that carisoprodol is 
resulting in ED visits at a level comparable to that of diazepam, a 
benzodiazepine and schedule IV controlled substance. As Table 1 shows, 
in 2004 there were an estimated 15,619 ED visits related to 
diazepam.\12\
---------------------------------------------------------------------------

    \12\ In 2007, DAWN ED carisoprodol visits also accounted for an 
increasing percentage of the nonmedical use ED visits associated 
with skeletal muscle relaxants, increasing each year from 59 percent 
in 2004, to 70 percent in 2007.

 Table 1--Selected Pharmaceutical ED Visits (Nonmedical Use): 2004-2007
                                From DAWN
                        [Data output 08/02/2008]
------------------------------------------------------------------------
                                               Estimates
       Selected drugs        -------------------------------------------
                                 2004       2005       2006       2007
------------------------------------------------------------------------
Carisoprodol................     14,736     20,082     24,505     27,128
Cyclobenzaprine.............      6,183      7,629      7,142      6,197
Diazepam....................     15,619     18,433     19,936     19,674
------------------------------------------------------------------------


[[Page 77338]]

    By dividing the number of ED visits by the number of prescriptions, 
FDA calculated ``abuse frequencies'' for carisoprodol; cyclobenzaprine, 
a non-scheduled muscle relaxant; and diazepam, which is also prescribed 
for its muscle relaxant properties. These calculations, which are found 
in Table 2 below, show that the ``abuse frequency'' of carisoprodol is 
in the same range as diazepam and greater than that of cyclobenzaprine. 
More specifically, even in 2004, the carisoprodol rate was 15.1 ED 
visits per 10,000 prescriptions, while diazepam's rate was 12.5. By 
contrast, cyclobenzaprine, another skeletal muscle relaxant had a rate 
of 4.1 ED visits per 10,000 prescriptions. Most significantly, even in 
2004, and before the increase in the estimates of carisoprodol-related 
ED visits, carisoprodol had a greater frequency of ED related visits 
than diazepam.

    Table 2--Frequency of DAWN ED Visits (Nonmedical Use) per 10,000 Rx for Carisoprodol, Cyclobenzaprine and
                                                    Diazepam
                                                   [2004-2007]
----------------------------------------------------------------------------------------------------------------
                           Selected drugs                               2004       2005        2006       2007
----------------------------------------------------------------------------------------------------------------
Carisoprodol.......................................................       15.1       19.7        22.9       22.6
Cyclobenzaprine....................................................        4.1        4.61        4.1        3.3
Diazepam...........................................................       12.5       14.5        15.0       14.1
----------------------------------------------------------------------------------------------------------------
Data derived from proprietary SDI data. SDI Vector One[supreg]: National, Years 2002-2007, Data Extracted April,
 2008 File: VONA 2008-517 4-15 \13\
----------------------------------------------------------------------------------------------------------------

     
---------------------------------------------------------------------------

    \13\ According to FDA, SDI's Vector OneTM National 
(VONA) measures retail dispensing of prescriptions or the frequency 
with which drugs move out of retail pharmacies into the hands of 
consumers via formal prescriptions. GX 6, at 13 n.7. Information on 
the physician's specialty, the patient's age and gender, and 
estimates for the numbers of patients that are continuing or new to 
therapy are available. Id.
    The Vector OneTM database integrates prescription 
activity from a variety of sources including national retail chains, 
mass merchandisers, pharmacy benefits managers and their data 
systems, and provider groups. Id. Vector One receives over 1.8 
billion prescription claims per year, representing over 150 million 
unique patients. Id. The number of dispensed prescriptions is 
obtained from a sample of virtually all retail pharmacies throughout 
the United States, and represents approximately half of retail 
prescriptions dispensed nationwide. Id. SDI receives all 
prescriptions from approximately one-third of the stores and a 
significant sample of prescriptions from the remaining stores. Id.
---------------------------------------------------------------------------

    Carisoprodol has been reported as a primary or sole drug of abuse 
in DAWN only since 2006. According to the 2006 DAWN data, there were an 
estimated 24,505 ED visits related to carisoprodol, of which it was 
reported as the sole drug in 21 percent of the cases. This is 
consistent with the FDA's finding that the majority of the cases 
published in the scientific literature report that carisoprodol abuse 
has primarily been a component of multi-drug abuse.
    FDA reviewed DAWN data and found that the drugs most frequently 
used in combination with carisoprodol that resulted in ED visits were 
opioids (hydrocodone, oxycodone), benzodiazepines (alprazolam, 
diazepam, clonazepam), alcohol, and illicit drugs (marijuana, cocaine). 
Table 3 below sets forth the respective levels of carisoprodol ED 
visits related to single use and as a component of multi-drug use.

               Table 3--Estimated Nonmedical Use--Carisoprodol ED Visits From DAWN 2006, as Sole Drug and in Combination With Other Drugs
--------------------------------------------------------------------------------------------------------------------------------------------------------
                       All patients                                          Females only                                    Males only
--------------------------------------------------------------------------------------------------------------------------------------------------------
                Drug                    Number    Percent             Drug             Number    Percent             Drug             Number    Percent
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total Carisoprodol..................     24,505  .........  Total Carisoprodol.....     14,219         42  Total Carisoprodol.....     10,286         58
Carisoprodol single-drug............      5,055         21  Carisoprodol single-         3.870         27  Carisoprodol single-         1,185         12
                                                             drug.                                          drug.
Carisoprodol multi-drug.............     19,450         79  Carisprodol multi-drug.     10,349         73  Carisoprodol multi-drug      9,101         88
--------------------------------------------------------------------------------------------------------------------------------------------------------
Information received from SAMHSA on June 18, 2008.

    FDA also found that although carisoprodol is approved for short 
term use (3 weeks), SDI Vector One data from 2002-2006 \14\ show that 
more than 25 percent of patients used the drug for longer than one 
month, and 4.3 percent used the drug for more than 360 days. GX 6, at 
15. FDA concluded that longer term use may contribute to increased 
risks of misuse and abuse. Id.
---------------------------------------------------------------------------

    \14\ See Table 6 from the OSE ``Duration of Use Analysis'' for 
Soma (NDA 11-792) dated June 27, 2007.
---------------------------------------------------------------------------

MEDA's Evidence Regarding the DAWN Data
    Meda offered the testimony of Mr. Nabarun Dasgupta as an expert 
witness in epidemiology and pharmacoepidemiology. MX 173; Tr. 628. Mr. 
Dasgupta offered a lengthy critique of the DAWN ED data and opined that 
``the DAWN ED data are subject to constraints that limit their 
potential reliability for use in scientific research and public health 
policy.'' MX 173, at 3.
    More specifically, Mr. Dasgupta criticized the sampling methodology 
used by DAWN, noting that DAWN uses an oversample of hospitals in 
select metropolitan areas and a sample of hospitals from the rest of 
the country and that ``[t]he number of hospitals sampled is relatively 
small compared to the national estimates that are extrapolated from the 
sample.'' Id. Mr. Dasgupta noted that for the year 2007, ``207 
hospitals submitted provided data on 300,983 drug related ED visits * * 
*.

[[Page 77339]]

which resulted in a national estimate of 3,998,228 drug-related ED 
visits.'' Id. at 3-4. Mr. Dasgupta further stated that ``[t]he location 
of all hospitals participating * * * is not disclosed due to privacy 
reasons,'' and that ``the number of hospitals can change post hoc in 
the published annual report tables.'' Id. at 4. As support for the 
latter assertion, Mr. Dasgupta cited the 2005 and 2006 annual reports; 
however, only one of these (the 2006 report) was submitted for the 
record.
    Later in his testimony, Mr. Dasgupta asserted that ``[o]nce the 
cases in the participating hospitals are counted, DAWN applies 
statistical methods to extrapolate to a `national estimate,' '' and 
that each case is given ``a weight from 1 to 60 to arrive at the 
national estimates,'' and that while it is ``routine to describe how 
weights are derived,'' DAWN does not ``completely describe the 
process.'' Id. at 14. Mr. Dasgupta also explained that while such 
factors as ```non-response,' missing data, hospital size, physical 
location, whether it is an academic training hospital, and other 
factors are accounted for in the weight, * * * the method for doing 
this is not published.'' Id. Mr. Dasgupta concluded that ``the 
credibility of the national DAWN data * * * hinges on the statistical 
methods employed to analyze the sample data, but SAMHSA does not 
publicly disclose the current methods. We do not know how the weights 
of the individual hospitals are being applied, and we do not know what 
impact the extrapolations may be having on the reported national 
estimates.'' Id. Mr. Dasgupta thus opined that ``[t]he lack of 
information provided by DAWN concerning its statistical extrapolation 
methods hinders interpretation and hence limits the weight that can be 
given the DAWN national estimates.'' Id. at 14-15.
    On examination by the ALJ, Mr. Dasgupta was asked if, ``within the 
community of epidemiologists, * * * the DAWN ED national estimation 
[is] still relied upon?'' Tr. 652. Mr. Dasgupta replied that ``[t]he 
DAWN ED data are important to look at,'' and that ``others would agree 
* * * in that it sets * * * it's the data that is used for policy 
making.'' Id. Mr. Dasgupta then asserted that ``[f]rom a scientific 
perspective, it doesn't carry much weight.'' Id. However, DAWN ED does 
not purport to be anything other than an estimate, and Mr. Dasgupta's 
testimony suggests that epidemiologists still consider the estimates 
sufficiently reliable to make policy decisions.
    Moreover, Mr. Dasgupta generally did not identify what practices 
(including what level of disclosure) the field of epidemiologists 
considers to be necessary to establish the validity of a methodology 
and the statistical methods used to extrapolate the data to develop a 
national estimate. While Mr. Dasgupta's criticisms of the DAWN ED data 
may be based on the generally accepted standards of epidemiology, in 
the absence of evidence establishing those standards, there is no basis 
for concluding that his criticisms of DAWN ED data reflect those of the 
community of epidemiologists rather than his personal opinion.
    Mr. Dasgupta further asserted that the scientific validity of the 
data ``is questionable'' because it ``does not conform with the FDA's 
published guidance on Good Pharmacovigilance Practices and 
Pharmacoepidemiologic Assessments.'' MX 173, at 4-5. According to Mr. 
Dasgupta, this ``call[s] into question whether DAWN ED data should be 
used by FDA and FDA-regulated entities for post-marketing 
surveillance.'' Id. However, Mr. Dasgupta did not identify in what 
respect DAWN does not comply with the FDA's guidance. See id. Nor is it 
clear why compliance with the FDA's guidance is necessary to establish 
that the DAWN ED data, which is only an estimate, is not sufficiently 
reliable to support a finding that carisoprodol ``has a potential for 
abuse.'' 21 U.S.C. 811(a)(1)(A).
    Mr. Dasgupta's next criticism was that the reporters of DAWN ED 
data ``may identify an ED visit as a DAWN case even if the patient has 
a valid prescription for the drug(s) mentioned in the ED chart and is 
taking the drug(s) for therapeutic purposes.'' Id. at 5. Mr. Dasgupta 
noted that ``[w]hile Reporters are trained on selecting cases, no 
published studies have evaluated the consistency between Reporters or 
between hospitals, or over time.'' Id. Mr. Dasgupta also noted that 
this ``calls into question the reliability of reporting across sites, 
given the lack of published validation of the consistency between 
Reporters at different sites.'' Id.
    Mr. Dasgupta further noted that ``there has been a concerted effort 
by SAMHSA and the contractor to improve [the] selection of cases, 
[which is] aimed at identifying more ED visits for inclusion.'' Id. at 
5-6. Mr. Dasgupta stated that because there has been ``no public 
documentation of this process,'' it is not clear if ``the increases in 
cases over time is due to better case finding or due to increases in 
the underlying sociobiologic phenomena that give rise to DAWN cases.'' 
Id. at 6. According to Mr. Dasgupta, ``it is impossible to conclusively 
say what proportion of the increases in DAWN ED national estimates is 
attributable to changes in methodology versus changes in the actual 
number of DAWN cases associated with a particular drug'' and ``[t]his 
hinders any effort to interpret the meaning of time trends.'' Id.
    On examination by the ALJ, Mr. Dasgupta testified that this, i.e., 
the increase ``attributable to enhanced case-finding versus [that] 
attributable to the underlying actual abuse * * * is something that is 
routinely looked at in epidemiologic studies.'' Tr. 657. He also 
suggested that in such circumstances, ``a validation study'' would be 
done to determine how well those persons who review the case files were 
doing. Id. at 658. However, even acknowledging the validity of this 
criticism, the FDA's recommendation stated that the increase in the 
estimates of carisoprodol-related ED visits between 2004 and 2007 was 
not statistically significant.
    Mr. Dasgupta also observed that ``DAWN has acknowledged the 
difficulty in identifying cases of abuse'' because of the limitation of 
medical record documentation. Id. at 7. As Mr. Dasgupta observed, 
because DAWN defines ``nonmedical use'' to include a variety of 
scenarios beyond misuse/abuse, ``ED visits counted as `nonmedical use' 
'' by DAWN ``do not necessarily represent cases of abuse as that term 
is commonly understood,'' and as ``used for purposes of scheduling.'' 
Id. at 9-10.
    Mr. Dasgupta also noted that ``[a]lthough current medications 
unrelated to the visit are not supposed to be recorded, distinguishing 
medications that pertain to the ED visit from those that do not 
requires a complex toxicological determination,'' which hospitals may 
not conduct ``in the interest of providing expedient medical care.'' 
Id. at 10. Mr. Dasgupta stated that differences in how toxicology 
testing is conducted at different hospitals ``may influence whether a 
drug is detected,'' and that ``the simple presence of a drug in 
toxicology results is not sufficient to implicate its involvement in an 
ED visit.'' Id. at 12. He further noted that ``it is highly probable 
that to some extent the determination of the involvement of unrelated 
medications may be inherently subjective, [and may] vary between 
Reporters,'' who have different training and experience.\15\ Id. at 10.

[[Page 77340]]

However, Mr. Dasgupta then opined that ``drugs are most often 
identified by patient self-reporting,'' that ``[o]nly a small 
percentage is confirmed by toxicology tests,'' and that therefore, 
``DAWN data are subject to all of the uncertainties and potential 
misidentifications associated with self-reporting.'' \16\ Id. at 13.
---------------------------------------------------------------------------

    \15\ Mr. Dasgupta also testified that the DAWN data may be 
affected by diagnostic suspicion bias in that DAWN reporters may 
have become sensitized by news reports or other information as to 
the abuse of a particular drug, and therefore, may over-report such 
cases. MX 173, at 12. However, Mr. Dasgupta produced no evidence as 
to the existence of this phenomenon among DAWN reporters either 
generally or with respect to carisoprodol.
    \16\ Mr. Dasgupta further noted that DAWN may at times impute 
data when data is missing from certain hospitals. MX 173, at 18-19. 
While Mr. Dasgupta suggested that this practice is of ``questionable 
validity,'' id., this is not the same as saying that this practice 
is not generally accepted by experts in the field. Indeed, on 
examination by the ALJ, Mr. Dasgupta testified that ``it is valid to 
use imputation methods to fill in missing data, but it's a very, 
very sensitive issue that needs to be done carefully.'' Tr. 669. Mr. 
Dasgupta then stated that ``[t]here are three, four, maybe five 
major ways in which imputation is done in epidemiology to fill in 
missing data like these, and the choice of which of those imputation 
methods * * * can very strongly influence your results,'' that ``the 
onus is on the researcher to show that those assumptions have been 
met and that the method selected is the appropriate one,'' and that 
``if there is kind of [a] referenced imputation[,] it's odd to not 
see those kinds of descriptions on which statistical imputation 
method is used.'' Id. at 669-70. However, Respondent produced no 
evidence that the use of imputed data has affected the DAWN data for 
carisoprodol.
---------------------------------------------------------------------------

    As explained above, DAWN explicitly recognizes the limitations 
inherent in medical record documentation. Moreover, even crediting Mr. 
Dasgupta's criticisms, as even he recognized, ``[t]he DAWN ED data are 
important to look at'' and ``it's the data that is used for 
policymaking.'' Tr. 652. The DAWN ED data provide only an estimate; the 
data constitute just one of many pieces of evidence which support the 
conclusion that persons are taking carisoprodol ``in amounts sufficient 
to create a hazard to their health.''
FDA Adverse Event Reporting System (AERS) Data \17\
---------------------------------------------------------------------------

    \17\ The Adverse Event Reporting System (AERS) is a computerized 
database designed to support the FDA's postmarketing safety 
surveillance program for all approved drug and therapeutic biologic 
products. GX 6, at 15. The FDA receives adverse drug reaction 
reports from manufacturers as required by regulation. Id. Health 
care professionals and consumers send reports voluntarily through 
the MedWatch program, which become part of a database; the database 
complies with the international safety reporting guidance (ICH E2B) 
issued by the International Conference on Harmonization. Id.
---------------------------------------------------------------------------

    As noted above, FDA also reviewed the AERS data and found that 
through June 2007, there were a total of 472 reports related to 
potential carisoprodol abuse, including 48 reports identifying 
dependence and 19 identifying withdrawal syndrome. GX 6, at 15. In the 
majority of cases, multiple drugs were used, but there are 61 unique 
reports where carisoprodol was the only suspect drug. Id.
    Meda's Chief Medical Officer (CMO) provided more up-to-date data. 
In his written direct testimony, MEDA's CMO stated that ``MEDA's 
database contains a total of 731 spontaneous adverse events for 
carisoprodol from January 1979 through May 1, 2010,'' of which ``only 
83 reports included the terms abuse, dependency, or withdrawal.'' MX 
171, at 10. MEDA's CMO further noted that in the five-year period of 
2005-2009, more than 54 million prescriptions, totaling nearly four 
billion tablets of carisoprodol, were dispensed. Id. at 11.
    While the AERS data appears relatively small when compared with the 
total number of prescriptions, as explained in footnote fifteen, this 
data is obtained from health care professionals and consumers, both of 
whom voluntarily submit the reports. As FDA notes, it ``does not 
receive all adverse event reports that occur with a product'' as 
``[m]any factors can influence whether or not an event will be 
reported.'' FDA, Adverse Events Reporting System, available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/
AdverseDrugEffects/default.htm. Accordingly, ``AERS cannot be used to 
calculate the incidence of an adverse event in the U.S. population.'' 
Id. Indeed, the voluntary nature of the reports suggests that they are 
likely to under-represent the actual number of adverse events.
Florida Medical Examiners Commission Data
    In 2008, Florida's medical examiners reported 8,556 drug-related 
deaths (whether the drug was the cause of death or merely present) 
through toxicology reports submitted to the Medical Examiners 
Commission. GX 7, at 11. The presence of carisoprodol and/or its 
metabolite, meprobamate, was found in 415 deaths (5 percent of the drug 
related deaths). Id. In 84 of these deaths (20%), carisoprodol was 
determined to be the cause of death. Id. The following table lists, for 
the years 2003 through 2008, the number of deaths in which carisoprodol 
and meprobamate were found in toxicology testing and the number of 
deaths in which carisoprodol and meprobamate were found to be a cause 
of death.

                               Table 4--Florida Medical Examiner's Data 2003-2008
----------------------------------------------------------------------------------------------------------------
                                                       Total         Cause (%                      % Change from
          Year              Drugs found in body     occurrences       total)          Present       prior year
----------------------------------------------------------------------------------------------------------------
2003 \18\...............  Carisoprodol/                      208         45 (22)             163              ND
                           Meprobamate.
2004....................  Carisoprodol/                      289         81 (28)             208              39
                           Meprobamate.
2005....................  Carisoprodol/                      314         96 (31)             218               9
                           Meprobamate.
2006....................  Carisoprodol/                      313         74 (24)             239            -0.3
                           Meprobamate.
2007....................  Carisoprodol/                      337         88 (26)             249               8
                           Meprobamate.
2008....................  Carisoprodol/                      415         84 (20)             331              23
                           Meprobamate.
----------------------------------------------------------------------------------------------------------------

Id.; see also GX 7, at 11.

    \18\ Carisoprodol was scheduled as C-IV in Florida in July 2002, 
but was not tracked until 2003. GX 6, at 18.
---------------------------------------------------------------------------

    With respect to this data, Mr. Dasgupta stated that ``[t]he 
presence of a drug in the body does not establish it as a cause of 
death'' or necessarily ``indicate drug abuse.'' MX 173, at 23. As for 
the first contention, the data recognizes as much as it differentiates 
between those instances in which toxicology testing established that 
carisoprodol/meprobamate was present in a body and those in which a 
medical examiner concluded that the ingestion of carisoprodol or 
meprobamate was a cause of death. Likewise, while a drug's presence in 
the body does not necessarily establish that the person was engaged in 
``drug abuse,'' it nonetheless is an indicator of drug abuse, 
especially where the deaths were found to be caused by an overdose.
    Mr. Dasgupta further concluded that because the data combines 
carisoprodol and meprobamate, ``it is not possible to determine * * * 
which drug * * * was a cause of death.'' Id. at 23. However, 
carisoprodol metabolizes into meprobamate, and other data in the record 
(more specifically, the NSDUH

[[Page 77341]]

data, see Table 7) indicates that more than eleven times as many 
persons have engaged in the nonmedical use of carisoprodol than have 
engaged in the nonmedical use of meprobamate. This supports the 
conclusion that the great majority of the Florida Medical Examiner 
cases in which carisoprodol/meprobamate was determined to be a cause of 
death are attributable to carisoprodol.\19\
---------------------------------------------------------------------------

    \19\ Mr. Dasgupta also raised the possibility that the Florida 
Medical Examiner data is subject to diagnostic suspicion bias. MX17, 
at 23. Again, this is simply speculation.
---------------------------------------------------------------------------

    Finally, Mr. Dasgupta asserted that the Florida data shows that 
``the proportion of total fatal overdose occurrences * * * has 
generally been decreasing annually since 2005.'' Id. at 24. However, it 
is doubtful that this change is statistically significant, and even if 
it is, the data still show that a significant and disturbing number of 
persons have died from carisoprodol overdoses and are dying each year 
in this State alone.
National Poison Data System
    Data from the National Poison Data Systems (NPDS), formerly known 
as the Toxic Exposure Surveillance System of the American Association 
of Poison Control Centers (AAPCC), show that carisoprodol products are 
involved in a number of toxic exposures (Table 5). Some of these 
carisoprodol exposures led to major adverse health outcomes (Table 6). 
For example, in 2007, carisoprodol was associated with 8,821 toxic 
exposure cases, including 3,605 cases in which it was the sole drug 
mentioned. A total of 122 of the 2,821 single exposure cases, which 
were treated in a health-care facility, had a major adverse health 
outcome.

                  Table 5--Carisoprodol Exposures Data From National Poison Data System (NPDS)
----------------------------------------------------------------------------------------------------------------
                                                     2003         2004         2005         2006         2007
----------------------------------------------------------------------------------------------------------------
Case Mentions..................................        8,248        8,765        8,613        8,187        8,821
Single Exposures...............................  ...........  ...........  ...........        3,515        3,605
----------------------------------------------------------------------------------------------------------------
Note: Single exposure data is not available prior to 2006.


    Table 6--Serious Adverse Health Outcomes in Carisoprodol Exposures Cases Who Were Treated in Health Care
                                                   Facilities
----------------------------------------------------------------------------------------------------------------
                                                     2003         2004         2005         2006         2007
----------------------------------------------------------------------------------------------------------------
Treated in Health Care Facility *..............        6,617        7,032        7,501        2,687        2,821
Deaths.........................................           28           30           18            1            1
Major Effect **................................          406          468          525          105          122
Moderate Effect ***............................        1,710        1,882        1,953          688          720
                                                ----------------------------------------------------------------
    Total......................................        2,144        2,878        2,496          794          843
----------------------------------------------------------------------------------------------------------------
* The data for 2006 and 2007 are from single exposure cases.
** Major effect: The patient exhibited signs or symptoms as a result of the exposure that were life-threatening
  or resulted in significant residual disability or disfigurement.
*** Moderate effect: The patient developed signs or symptoms as a result of the exposure that were more
  pronounced, more prolonged or more systemic in nature than minor effects.

    Regarding the NPDS data, Mr. Dasgupta acknowledged that the persons 
who answer the calls to the regional poison centers ``are nurses, 
pharmacists, and physicians who have been trained in medical toxicology 
and are instructed on the proper ways of completing case report forms 
in a systematic manner'' and that the data collection software has 
``[a]n extensive data quality assurance process.'' MX 173, at 29-30. 
Mr. Dasgupta then stated that there is the ``potential 
misidentification of the substance during the initial call to the 
poison center'' and that researchers have ``determined that, for some 
drugs, 25-30% are misclassified during the first call.'' Id. at 30. 
However, Meda did not provide this research and Mr. Dasgupta did not 
provide evidence as to what the rate of misclassification is for 
carisoprodol. He then opined that the self-reporting and (apparently 
the lack of toxicology test results) showing the ``presence and levels 
of drug * * * make it impossible to conclude that a mentioned drug was 
causally implicated in the exposure.'' Id.
    Mr. Dasgupta also maintained that ``the single exposure data 
presented by DEA combines single-entity carisoprodol and carisoprodol/
aspirin combination products.'' Id. at 31 (citing Meda Ex. 63).\20\ 
However, as the data for 2007 show, even if single entity and 
combination products should not be counted together, the amount of case 
mentions and single exposures attributable to combination products is a 
small fraction of both the case mentions (163 v. 8658) and single 
exposures (69 v. 3536) attributable to single entity products. See MX 
64, at 1020, 1026.
---------------------------------------------------------------------------

    \20\ As support for this assertion, Mr. Dasgupta cited the 2008 
annual report (MX 63); however, the above tables do not include data 
for that year.
---------------------------------------------------------------------------

    Mr. Dasgupta also criticized the use of the NPDS data because the 
intentional exposures data includes suicide attempts and accidental 
pediatric exposures. MX 173, at 34. However, the Senate Report, which 
accompanied the CSA's enactment, expressly stated that ``[m]isuse of a 
drug in suicides and attempted suicides, as well as injuries resulting 
from unsupervised use are regarded as indicative of a drug's potential 
for abuse.'' S. Rep. 91-613, 1970 U.S.C.C.A.N., at 4602. Thus, contrary 
to Mr. Dasgupta's understanding, the fact that Table 6 includes 
suicides, ``suicide attempts,'' and ``accidental pediatric exposures,'' 
see MX 173, at 34; does not reduce the data's probative value in 
assessing carisoprodol's abuse potential.
    Mr. Dasgupta criticized Table 6 because it ``purports to show 
`serious adverse health outcomes in carisoprodol exposure cases,' '' 
but ``[i]ntentional exposure cases can also include associated medical 
outcomes that are not serious.'' Id. at 32. Mr. Dasgupta further 
asserted that ``[t]he DEA Review does not present enough detail 
concerning methodology to determine

[[Page 77342]]

what type of cases were included in Table [6].'' Id.
    However, it is apparent that Table 6 simply replicates the NPDS's 
classification of carisoprodol incidents by the severity of the 
outcome. See MX 64, at 940-41, 1020, 1026 (2007 report). Moreover, even 
if single entity and combination carisoprodol products should not have 
been added together, the number of cases attributable to combination 
products is a small fraction of those attributable to single entity 
products (15 v. 705 moderate effects outcomes, 2 v. 120 major effect 
outcomes, and 0 v. 1 death). Compare id. at 1020, with id. at 1026.

2. Is there significant diversion of carisoprodol from legitimate drug 
channels?

The NFLIS Data
    Current data shows that there is significant diversion of 
carisoprodol from legitimate drug channels. Data collected by DEA 
establishes that carisoprodol has been seized from persons engaged (and 
places used) in illegal activities involving other controlled 
substances, including diazepam, marijuana, cocaine, methamphetamine, 
codeine, and hydrocodone. DEA has found carisoprodol present during the 
execution of search warrants at residences, offices, and pharmacies. 
According to data retrieved from DEA's National Forensic Lab 
Information System (NFLIS) database, which includes data on samples 
analyzed by DEA laboratories (STRIDE), as well as state and local 
forensic laboratories,\21\ since 2000, carisoprodol has consistently 
ranked in the top 25 of the drugs most frequently seized and identified 
by state and local forensic laboratories during the course of criminal 
investigations.
---------------------------------------------------------------------------

    \21\ Participating state and local laboratories handle 88% of 
the nation's 1.2 million analyses of state and local drug cases.
---------------------------------------------------------------------------

    In terms of the number of seizures, in 2008, NFLIS reported 4,291 
identifications of carisoprodol, thus ranking it above such controlled 
substances as codeine, psilocin, lorazepam, MDA, hydromorphone, and 
methylphenidate. MX 53, at 9. In 2007, NFLIS reported 4,420 
identifications of carisoprodol, thus ranking it above such controlled 
substances as phencyclidine (PCP), psilocin, buprenorphine, MDA, 
methylphenidate, ketamine, lorazepam, and hydromorphone. MX 54, at 7. 
Because the primary focus of law enforcement agencies is on 
investigating the unlawful distribution of controlled drugs, the 
incidents in which carisoprodol has been found during law enforcement 
seizures supports a finding that the drug is being abused and diverted. 
Moreover, because carisoprodol is not controlled in most States, there 
is reason to believe that many laboratories may not report those 
incidents in which they have identified a substance as carisoprodol. GX 
9, at 3.
    Mr. Dasgupta opined that the NFLIS data are of ``limited utility 
for making public health decisions.'' MX 173, at 26. While he 
acknowledged that carisoprodol has been among the top twenty-five drugs 
analyzed, Mr. Dasgupta explained that ``[t]he likelihood of a 
particular sample being analyzed is substantially affected by the 
prosecutor's perceptions of the available criminal charges, as well as 
politics, prosecutorial priorities, and bureaucratic influences.'' Id. 
at 25. Mr. Dasgupta then noted that ``[p]rosecutors in states where 
carisoprodol is a controlled substance would be more likely to submit a 
sample to NFLIS for identification,\22\ as the state-level scheduling 
would be more likely to result in a stiffer criminal penalty,'' and 
that ``[f]orensic laboratory data from these states may be an artifact 
of state-level scheduling because more suspected carisoprodol samples 
may be sent for analysis once a controlled substance criminal charge is 
potentially available in a particular state.'' Id. at 26. As Mr. 
Dasgupta noted, only seventeen States have controlled carisoprodol. Id. 
n.7.
---------------------------------------------------------------------------

    \22\ Contrary Mr. Dasgupta's understanding, drug samples are not 
submitted ``to NFLIS for identification.'' MX 173, at 26. Rather, 
NFLIS collects reports of drugs items which have been seized and 
analyzed and identified as a drug by a forensic laboratory. However, 
I agree with Mr. Dasgupta's opinion that if a criminal charge is not 
available in a State, it is less likely that evidence which looks 
like carisoprodol tablets will be sent to a lab for analysis and 
subsequently reported to the NFLIS.
---------------------------------------------------------------------------

    This argument, however, actually supports the Government's view 
that many laboratories do not report carisoprodol that is seized during 
criminal investigations, and thus the drug is being diverted at even 
greater levels than the NFLIS data suggests. According to U.S. Census 
data, of which I take official notice, the seventeen States, which have 
controlled carisoprodol, have a total population of approximately 108 
million and thus comprise only 35% of the national population.\23\ See 
Appendix A. This suggests that carisoprodol would likely rank 
substantially higher in the NFLIS data were it controlled nationally.
---------------------------------------------------------------------------

    \23\ Pursuant to 5 U.S.C. 556(e), Meda ``is entitled, on timely 
request, to an opportunity to show the contrary.'' In the event Meda 
disputes the census data, it may file a motion for reconsideration 
within fifteen days of the date of service of this rule, which shall 
begin on the date of mailing.
---------------------------------------------------------------------------

    The testimony of various officials further supports a finding that 
carisoprodol is being diverted. The Deputy Assistant Administrator of 
DEA's Office of Diversion Control testified that carisoprodol was being 
distributed in combination with narcotic drugs and benzodiazepines 
through Internet schemes in which patients were issued prescriptions by 
physicians they never saw and could simply order the drugs through a 
Web site. GX 9, at 2-3; Tr. 343-44. As several courts have recognized, 
the dispensing of controlled substances in this manner is a violation 
of 21 U.S.C. 841(a)(1). See United States v. Nelson, 383 F.3d 1227, 
1231-32 (10th Cir. 2004); United States v. Smith, 573 F.3d 639, 657-58 
(8th Cir. 2009); United States v. Fuchs, 467 F.3d 889 (5th Cir. 2006). 
The Deputy Assistant Administrator also noted that ``DEA investigations 
reveal that thousands of customers throughout the United States seek 
carisoprodol, either alone or, most frequently, in combination with 
controlled substances from pain clinics, physicians, and from illicit 
street dealers.'' GX 9, at 3.
    A Special Agent in Charge with the Tennessee Bureau of 
Investigation, who oversees drug enforcement responsibilities in 
twenty-eight of the State's counties and who was formerly Coordinator 
of the Tennessee Drug Diversion Task Force, testified that in his 
experience, ``carisoprodol has been used for non-medical purposes and 
illicitly distributed in circumstances that are similar to the non-
medical use and illicit trafficking in controlled substances such as 
oxycodone, hydrocodone, and alprazolam. Law enforcement investigations 
have revealed that many Tennesseans seek carisoprodol, either alone or, 
most frequently, in combination with controlled substances from pain 
clinics [and] physicians,'' who ``conduct little or no physical 
examination of the patients'' and who ``issue prescriptions for the 
specific drugs requested by the `patients.' '' GX 10, at 3-4. The 
official also related that carisoprodol is being sold on the street. 
Id. at 4.
    The official also testified that ``carisoprodol abuse has been 
implicated in many overdose events in Tennessee including overdose 
fatalities,'' and that reports from the State's medical examiner ``from 
2006 through 2008'' show that carisoprodol has been ``associated with 
approximately 100 deaths.'' Id. at 3, 5. This official further stated 
that ``[i]n the majority of these cases[,] carisoprodol is seen in 
combination with a `cocktail' of

[[Page 77343]]

other drugs[,]'' such as ``oxycodone or hydrocodone.'' Id. at 5.
    The Executive Director of the Ohio State Board of Pharmacy, who has 
worked as a pharmacist as well as held oversight/investigatory 
positions at the Board, testified that he has ``personally investigated 
cases involving carisoprodol,'' and that ``carisoprodol has been abused 
in the State of Ohio for more than 20 years.'' GX 8, at 3. The official 
testified that he was ``aware from [his] experience that many abusers 
of narcotics and other drugs abuse carisoprodol to mellow the effect of 
the narcotics or other drugs.'' Id.
    The official further testified that under Ohio law, pharmacies are 
required to report the dispensing of any controlled substance as well 
as carisoprodol. He then related that he had run a search of the Ohio 
prescription reporting system and found that carisoprodol ``is always 
prescribed in combination with an opiate, a benzodiazepine, or both.'' 
Id. at 4-5. Moreover, ``even though * * * the use of a muscle relaxant 
such as carisoprodol in conjunction with an opiate and a benzodiazepine 
is rarely clinically indicated,'' \24\ the official ``found that our 
top ten prescribers of this `trinity' have prescribed this combination 
[of drugs] to a range of 140 [to] 1,376 patients.'' Id. at 5. The 
official further found that ``many patients received carisoprodol from 
multiple prescribers,'' that during 2009, the top ten patients 
``received prescriptions from 8 [to] 13 different prescriptions,'' and 
that these ``patients received between 1,020 [and] 1,863 days' supply'' 
of the drug during the ``365 day period.'' Id. However, carisoprodol is 
indicated only for short-term use of up to two to three weeks, 
``because adequate evidence of effectiveness for more prolonged use has 
not been established and because acute, painful musculoskeletal 
conditions are generally of short duration.'' MX 6, at 2 (prescribing 
information). As the official concluded, these statistics provide 
evidence of improper prescribing by physicians, as well as doctor 
shopping and over-utilization by patients, and show that ``carisoprodol 
is a drug of abuse in Ohio.'' Id.
---------------------------------------------------------------------------

    \24\ On cross-examination, the official explained that both 
carisoprodol and benzodiazepines have muscle relaxant and anti-
anxiety effects, and that prescribing both drugs simultaneously ``is 
duplication of therapy,'' which is rarely warranted. Tr. 464-65.
---------------------------------------------------------------------------

3. Non-Medical Use of Carisoprodol

    Review of the currently available data and other information shows 
that individuals are taking the substance on their own initiative 
rather than on the basis of medical advice from a practitioner licensed 
by law to administer such substances. More specifically, the National 
Survey on Drug Use and Health (NSDUH) \25\ data show that from 2004 
through 2007, between 2.5 and 2.8 million persons admitted to having 
used carisoprodol for a non-medical purpose during their lifetime.\26\ 
As Table 7 below shows, in 2007, approximately 2.7 million persons have 
at some point engaged in the non-medical use of carisoprodol. This 
figure is more than eleven times the number of persons who have used 
meprobamate products for a non-medical purpose.
---------------------------------------------------------------------------

    \25\ The NSDUH is an annual survey sponsored by SAMHSA that 
obtains information on nine different categories of illicit drug 
use: use of marijuana, cocaine, heroin, hallucinogens, and 
inhalants; and the nonmedical use of prescription-type pain 
relievers, tranquilizers, stimulants, and sedatives in the civilian, 
non-institutionalized population of the United States age 12 or 
older. The survey interviews approximately 67,500 persons each year. 
The NSDUH provides yearly national and state level estimates of drug 
abuse, and includes prevalence estimates by lifetime (i.e., ever 
used), past year and past year abuse or dependence. Substance Abuse 
and Mental Health Services Administration (SAMHSA), Office of 
Applied Studies, Results from the 2007 National Survey on Drug Use 
and Health: National Findings (2008).
    \26\ ``Lifetime prevalence'' is a cumulative indicator of the 
total number of people who have ever tried drugs, including many in 
the distant past.
---------------------------------------------------------------------------

    Moreover, many reports of carisoprodol abuse have been published 
both in the United States and in other countries. These cases include 
the use of carisoprodol by itself and in combination with other drugs 
of abuse. See also infra Factor 5.

                   Table 7--NSDUH Data on Nonmedical Use of Specific Tranquilizer in Lifetime
                                      [Numbers in thousands and percentage]
----------------------------------------------------------------------------------------------------------------
                                              2004    2005    2006    2007  
                    Drugs                           (%)              (%)              (%)              (%)
----------------------------------------------------------------------------------------------------------------
Benzodiazepines.............................     18,643 (7.8)     19,686 (8.1)      19,662(8.0)     18,934 (7.6)
Valium or Diazepam..........................      14,607(6.1)     14,914 (6.1)    14,824 \b\ (6     13,172 (5.3)
                                                                                           \b\)
Meprobamate Products \1\....................        245 (0.1)        305 (0.1)        216 (0.1)        236 (0.1)
Muscle Relaxants \2\........................      3,907 (1.6)      3,773 (1.6)      4,449 (1.8)      4,274 (1.7)
Soma[supreg]................................      2,616 (1.1)      2,525 (1.0)      2,840 (1.2)      2,709 (1.1)
Flexeril[supreg]............................      1,968 (0.8)      1,891 (0.8)      2,405 (1.0)      2,438 (1.0)
----------------------------------------------------------------------------------------------------------------
\1\ Includes Equanil[supreg], meprobamate, and Miltown[supreg], \2\ Includes Flexeril[supreg] and Soma[supreg],
  \b\difference between 2006 and 2007 estimates statistically significant, p. <= 0.01. Source: SAMHSA, office of
  Applied Studies, National Survey on Drug Use and Health.

    Mr. Dasgupta acknowledged that ``NSDUH is a validated and generally 
scientifically defensible survey.'' MX 173, at 28. However, he then 
criticized the study because it relies on self-reporting and because 
the study does not specifically ask whether carisoprodol or Soma have 
been used in the ``past year'' or ``past 30 days,'' although a survey 
participant may ``spontaneously offer[]'' that he/she has used the drug 
within the respective time frame. Id. Mr. Dasgupta further noted that 
the NSDUH data show that the level of lifetime nonmedical use ``is 
essentially flat over time and not increasing.'' Id. at 29.
    Nonetheless, that the NSDUH survey has consistently shown that 
between 2.5 million and 2.8 million persons have engaged in non-medical 
use of carisoprodol is not evidence of ``isolated or occasional 
nontherapeutic'' use. S. Rep. 91-613; reprinted in 1970 U.S.C.C.A.N., 
at 4602. Rather, it is substantial evidence of ``significant use by 
individuals contrary to professional advice.'' Id. Where, as here, a 
drug has been this widely abused, DEA is not required to develop 
evidence that the rate of abuse is increasing in order to control it.

4. Carisoprodol's Pharmacological Activities Are Similar to Other Drugs 
With Known Abuse Liabilities

    According to the FDA, when originally marketed in 1959, 
carisoprodol was described as having qualitatively different kinds of 
central muscle relaxant properties than meprobamate, a schedule IV 
depressant

[[Page 77344]]

(FDA Reference 1).\27\ However, the specific mechanisms of action of 
carisoprodol are not completely understood (2, 3).
---------------------------------------------------------------------------

    \27\ The complete list of FDA References 1-58 is attached as 
Appendix B.
---------------------------------------------------------------------------

    FDA found that although carisoprodol is classified as a muscle 
relaxant, it has little direct effect on skeletal muscle. GX 6, at 5. 
According to FDA, both carisoprodol and meprobamate possess sedative 
properties and their therapeutic utility in acute painful 
musculoskeletal problems may be in part due to these sedative 
properties. Id. FDA also found that the drugs may be abused for their 
sedative properties and that in vitro studies demonstrate that 
carisoprodol elicits barbiturate-like effects. Id; See also discussion 
infra under Factor Two.
    Recent clinical reports addressing carisoprodol's abuse potential 
and its metabolic conversion to meprobamate have been published in 
scientific and medical journals. According to FDA, it was initially 
believed that carisoprodol's abuse potential was primarily related to 
its metabolic conversion to meprobamate. Id. at 6. However, new animal 
data from NIDA demonstrate that the abuse potential and pharmacology of 
carisoprodol may be independent of the metabolic pathway in humans to 
meprobamate. More specifically, FDA cited NIDA studies by Gatch, et 
al., which show that carisoprodol can be easily recognized by animals 
in drug discrimination studies as Schedule II, III or IV CNS 
depressants. (4-6). These studies are discussed more fully below under 
Factors Two (Scientific Evidence of the Drug's Pharmacological Effect) 
and Seven (Psychic or Physiological Dependence Potential).

Factor 2--The Scientific Evidence of Carisoprodol's Pharmacological 
Effect

    Carisoprodol is a centrally-acting muscle relaxant used medically 
for relief of discomfort associated with acute, painful musculoskeletal 
conditions, including spasms and spasticity. GX 6, at 6. The original 
approved therapeutic dose of carisoprodol was 350 mg three times a day, 
and at bedtime. Id. In placebo-controlled studies, carisoprodol was 
found more effective than placebo in treatment of acute musculoskeletal 
disorders (7) and less effective or not different from placebo in 
chronic disorders. In 2007, FDA approved a 250 mg tablet to be taken 
three times a day and at bedtime, for up to three weeks. GX 6, at 6.
    Although the exact mechanism of muscle relaxant action of this 
group of drugs is not known, it is believed to occur by depressing 
interneuronal cells and diminishing the facilitatory background 
activity on spinal motor neurons and by also inhibiting supraspinal 
influences, primarily in the lateral reticular area of the brain stem. 
Id. The polysynaptic reflexes are more readily depressed than 
monosynaptic reflexes. Id. These drugs produce sedation and drowsiness 
as their common side effects, which may reflect depressed neuronal 
activity essential for wakefulness, in the medial reticular ascending 
system. Id. Despite chemical structures that are unrelated, all muscle 
relaxants possess sedative properties. Id. The drugs also exhibit 
anticonvulsant activity in several animal models (3).

Receptor Binding Studies

    According to FDA, the complete binding profile of carisoprodol has 
not been characterized. One study showed that carisoprodol has 
negligible affinity for the benzodiazepine site, using [\3\H]-diazepam 
as a ligand in rat brain tissue (8).

In Vitro Studies

    The FDA concluded that the findings of in vitro studies demonstrate 
that carisoprodol elicits barbiturate-like effects. Whole-cell patch 
clamp studies were conducted to examine mechanistic similarities 
between carisoprodol and barbiturates (Schedules II, III or IV, 
depending on the particular barbiturate) using recombinant rat 
[alpha]1[beta]2 GABAAR. GX 6, at 6. GABA-gated currents were 
potentiated by micromolar carisoprodol (EC50 = 89 [mu]M)). 
Id. At millimolar concentrations, currents began to be inhibited, and 
rebound currents were apparent upon termination of drug administration. 
Id.
    According to FDA, this barbiturate-like trend was consistent with a 
previous description of carisoprodol effects on human 
[alpha]1[beta]2y2 GABAAR function, demonstrating 
that carisoprodol, like barbiturates, does not require the y subunit 
for its activity. Id. at 6-7. Carisoprodol directly activated human 
[alpha]1[beta]2y2 GABAAR, producing inward 
currents in a concentration-dependent manner (EC50 = 410 
[mu]M). Id. The amplitude of carisoprodol mediated currents 
(EC40) was reduced to 24 percent of control following 
incubation with bemegride (a barbiturate antagonist that has not been 
demonstrated to be specific for barbiturates). Id. By contrast, the 
benzodiazepine antagonist, flumazenil, had no significant effect on 
either the allosteric or direct effects of carisoprodol (9).
    MEDA challenged the FDA's reliance on this study. More 
specifically, MEDA elicited the testimony of Dr. Donald Robert 
Jasinski, who is a Professor of Medicine at the Johns Hopkins 
University School of Medicine and the Chief of the Center for Chemical 
Dependence, Johns Hopkins Bayview Medical Center. MX 172, at 1. Dr. 
Jasinski testified that even assuming that the model used in this study 
was ``sufficiently robust to establish an affinity of carisoprodol at a 
GABA[alpha] receptor, this does not establish that carisoprodol has 
barbiturate-like activity, but merely that it, like many other drugs 
including other non-controlled CNS depressants, has an affinity to 
attach to a GABA[alpha] receptor[].'' Id. at 3. Dr. Jasinski then 
explained that ``while barbiturates as a class have an affinity for 
GABA[alpha] receptors, not all drugs that have affinity for GABA[alpha] 
receptors have barbiturate-like activity and/or abuse liability 
profiles similar to the barbiturates.'' \28\ Id. at 4. Dr. Jasinski 
further opined that the finding that ``bemegride, a non-specific 
barbiturate antagonist, apparently reduced the amplit[ude] of 
carisoprodol-mediated currents by 24% [does not] indicate that 
carisoprodol will have barbiturate like effects.'' Id.
---------------------------------------------------------------------------

    \28\ Dr. Jasinski further testified that in a subsequent 
article, the authors of this study wrote that ``[a]lthough both our 
in vivo and in vitro studies are consistent with barbiturate-like 
effects of carisoprodol, we are not concluding that carisoprodol is 
acting at the barbiturate site of the receptor.'' MX 172, at 3 n.1.
---------------------------------------------------------------------------

    While Dr. Jasinski may be correct that the findings of the 
aforementioned study do not conclusively establish that carisoprodol 
has barbiturate-like effects, there is substantial other evidence in 
the record (including human studies) which supports this finding. See 
discussion under Factor Five.

Animal Pharmacology Studies

    Berger, et al. (1, 10), described the muscle relaxant and analgesic 
properties of carisoprodol in animals. Reversible paralysis of 
voluntary muscles that lasts for nearly 15 minutes occurs in most mice 
administered carisoprodol (180 mg/kg, i.p.). Paralysis was preceded by 
signs of excitement manifested by aimless running and staggering, 
hyperextension of the neck, and clonic movement of extremities. After 
administration of high doses, pre-narcotic excitement was absent. 
During paralysis, respiration and heartbeat were regular, skeletal 
muscles were relaxed, tremors and twitchings were absent, and corneal 
reflex was present. Stimulation of the sciatic nerve during paralysis 
produced prompt muscular response of the leg, indicating that the 
peripheral

[[Page 77345]]

nerve, myoneural junction, and muscle were not significantly affected 
by the drug. Depression of motor activity, as measured by loss of the 
righting reflex, occurred in 50 percent of animals after oral 
administration of 400 mg/kg of carisoprodol in mice and 750 mg/kg in 
rats.
    According to FDA, carisoprodol is a relatively poor strychnine 
antagonist in mice, which differs from other muscle relaxants such as 
mephenesin (a centrally-acting muscle relaxant that is not marketed in 
the United States). Carisoprodol depresses the electro-cortical 
activation response to electrical stimulation of the sciatic nerve, the 
midbrain reticular formation or of the diffuse thalamic system (nucleus 
centralis lateralis). Carisoprodol showed an antinociceptive action in 
response to injection of silver nitrate into joints of rats. 
Carisoprodol differs from meprobamate (Schedule IV) by not affecting 
the hippocampal seizures produced by stimulation of the fornix (10).
    More recently, the National Toxicology Program of the National 
Institutes of Environmental Health Sciences examined the toxicity of 
carisoprodol (11). Male rodents in the 200 mg/kg carisoprodol group and 
female rodents in the 100 and 800 mg/kg carisoprodol groups had 
significantly greater mean body weight gains than animals that received 
vehicle (control group). The incidence of adverse events was dose-
related, and females were more sensitive than males to the effects of 
carisoprodol. Carisoprodol induced ataxia and prostration in rats and 
mice, increases in liver weights in rats and mice, and nephropathy in 
male rats.
    In cats, carisoprodol was very effective in abolishing decerebrate 
rigidity, whereas meprobamate and mephenesin had no effect on 
spasticity. Carisoprodol appeared to be eight times more potent than 
these drugs in alleviating decerebrate spasticity (10).
    In dogs, carisoprodol (100 mg/kg p.o.) produced loss of muscle 
tone. At larger doses (200 mg/kg p.o.), signs of excitement 
characterized by tail wagging and howling were observed along with 
muscular weakness and ataxia with no tremors, convulsions or salivation 
(10).

Self-Administration Studies

    The FDA found that carisoprodol has positive reinforcing effects, 
in that rhesus monkeys maintained self administration responding that 
was greater than rates maintained by saline, although less than rates 
maintained by i.v. injections of methohexital (C-IV). GX 6, at 8. 
However, because of the limited solubility of carisoprodol, doses 
larger than 0.3 mg/kg injection could not be tested. NIDA Research 
Monograph, volume 146:423-433 (1999). This dose (0.3 mg/kg/injection) 
is lower than the doses used orally in humans. GX 6, at 8.

Drug-Discrimination Studies

    According to the FDA, ``drug discrimination studies in animals are 
believed to be predictive of subjective effects in humans and are thus 
useful in assessing the abuse potential of drugs.'' Id. Carisoprodol 
can stimulate the barbiturate site on the GABA-A receptor. In drug 
discrimination studies, pentobarbital (C-II) fully substitutes in 
carisoprodol-trained rats and bemegride fully antagonizes the 
subjective effects of carisoprodol.
    FDA also noted that another study found that in dogs tolerant and 
dependent on barbital (C-IV), oral doses of 200 mg/kg of carisoprodol 
every six hours were completely effective and equivalent to 100 mg/kg 
of barbital in preventing the appearance of abstinence phenomena (12).
    Bemegride fully blocked the discriminative stimulus effects of the 
training dose of carisoprodol (100 mg/kg p.o.), whereas the 
benzodiazepine antagonist, flumazenil, produced a moderate attenuation 
of the discriminative stimulus effects of carisoprodol across a wide 
range of doses. According to FDA, these findings suggest that 
carisoprodol may directly activate or allosterically modulate 
GABAA receptors which mediate the discriminative stimulus 
effects of carisoprodol. FDA further found that the actions of 
carisoprodol at the barbiturate site may be more relevant than actions 
at the benzodiazepine site and that certain effects of carisoprodol may 
be independent of its metabolism to meprobamate (C-IV) (9).
    Gatch, et al., (4) assessed the ability of rats to discriminate 
carisoprodol from vehicle. Rats were trained to discriminate 
carisoprodol and a carisoprodol dose-effect curve was established for 
doses from 25 to 100 mg/kg. Meprobamate (C-IV), pentobarbital (C-II/C-
III), and chlordiazepoxide (C-IV) were each tested for their ability to 
substitute for the discriminative stimulus effects of carisoprodol; 
each was found to substitute fully for the discriminative stimulus 
effects produced by 100 mg/kg of carisoprodol.
    In another study, Gatch, et al. (5), found that 5 mg/kg bemegride 
antagonized the discriminative stimulus effects produced by 100 mg/kg 
of carisoprodol in rats trained to discriminate carisoprodol and 
decreased the response rate to 79 percent of the carisoprodol control 
group. Gatch, et al. (6), also studied the effects of carisoprodol in 
the presence of Cimetidine, to determine if the effects of carisoprodol 
are produced by its active metabolite, meprobamate. Cimetidine, a P450 
enzyme inhibitor, which prevents the conversion of carisoprodol to 
meprobamate, failed to inhibit the discriminative stimulus effects 
produced by 100 mg/kg of carisoprodol in rats trained to discriminate 
carisoprodol. According to FDA, these results suggest that carisoprodol 
can produce discriminative stimulus effects directly without being 
converted into meprobamate.
    Dr. Jasinski disputed the FDA's reliance on the various animal 
studies it used to assess carisoprodol's abuse potential. MX 172, at 4-
7. While Dr. Jasinski acknowledged that ``in these studies the animals 
reflected behavior patterns with respect to carisoprodol that suggest 
patterns similar to barbiturates,'' he then opined that ``due to the 
inherent limitations of animal studies they simply do not provide an 
adequate basis to make decisions concerning abuse potential in 
humans.'' Id. at 4. Dr. Jasinski offered no further explanation as to 
what those limitations are. Moreover, at the hearing, Dr. Jasinski 
testified that it is appropriate to rely on animal studies as one 
aspect of assessing a drug's abuse potential in humans.\29\ Tr. 721.
---------------------------------------------------------------------------

    \29\ In its brief, Meda argues that animal studies ``are 
significantly less probative than human studies'' in assessing a 
drug's abuse potential. Meda Br. 25. However, Meda did not establish 
the degree to which animal studies are less probative than human 
studies and even its Expert conceded that it is appropriate to rely 
on animal studies in assessing abuse potential in humans. Tr. 721. 
While Meda cites human data--in particular, the results of recent 
clinic trials it conducted and the Fraser study--and argues that 
this data should be given greater weight than the animal studies, as 
discussed below, both studies have significant limitations.
---------------------------------------------------------------------------

    With respect to the self-administration study involving rhesus 
monkeys, Dr. Jasinski explained that the fact that ``the monkeys 
seem[ed] to prefer carisoprodol over a saline, but less than a schedule 
IV substance, merely indicates that the * * * monkey prefers 
carisoprodol over saline'' and that ``[t]his preference could be due to 
factors unrelated to any potential for abuse in humans.'' Id. at 5.
    As for the drug-discrimination studies involving rats, Dr. Jasinski 
acknowledged that the study showed that ``pentobarbital substitutes for 
carisoprodol in rats trained to discriminate carisoprodol and that'' 
bemegride, a barbiturate antagonist, ``blocked the discriminate 
stimulus

[[Page 77346]]

effects.'' Id. Dr. Jasinski then opined that ``these data at most are 
only indicative that carisoprodol may have certain effects similar to 
those of barbiturates (e.g., they have activity at the GABA receptor 
site) and not that any such similarity translates into a similar 
potential abuse liability.'' Id. Dr. Jasinski further explained that 
``it is well known that certain drugs will substitute for drugs of 
abuse without themselves being subject to any significant drug abuse.'' 
Id.
    As for the study showing that 200 mg/kg of carisoprodol substituted 
for 100 mg/kg in dogs which are dependent on barbital, Dr. Jasinski 
noted that the authors had concluded that carisoprodol was an exception 
to the general rule that ``whenever drugs produce physiological 
dependence in which abstinence syndrome is similar, these drugs must 
possess a common mechanism of action and abuse liability profiles.'' 
Id. at 6 (citing MX 91). As Dr. Jasinski observed, based on several 
unpublished studies which showed that ``the chronic administration of 
carisoprodol in 4 divided doses of 1 gm/day for 6 months [did] not 
result in the development of physiological dependence,'' the authors 
concluded that ``[t]he fact that carisoprodol did effectively 
substitute for sodium barbital in [their] study indicates that false 
positive results are possible from the substitution evaluation of 
barbiturate-like physiological dependence capacity.'' MX 91; see also 
MX 172, at 6.
    However, as the authors made clear, their conclusion that 
carisoprodol produced a false positive was based on studies which 
showed that taking one gram per day of the drug did not cause 
physiological dependence. Thus, this study does not foreclose the 
possibility that chronic use of carisoprodol in daily doses of greater 
than one gram per day could cause physiological dependence and calls 
into question the validity of the authors' conclusion that carisoprodol 
caused a false positive when substituted for barbital.
    Accordingly, even discounting the rhesus monkey study, I find that 
substantial evidence supports the FDA's conclusion that the drug-
discrimination studies in both dogs and rats indicate that carisoprodol 
has positive reinforcing and discriminative effects similar to other 
drugs currently regulated under C-IV, including barbital, meprobamate, 
and chlordiazepoxide.

Clinical Experience and Human Studies

Pharmacodynamic Effects

    Beebe, et al. (13), reviewed the pharmacodynamic effects of 
carisoprodol. Lethargy, drowsiness, ataxia, dysmetria and fatigue are 
common side effects at therapeutic doses \30\ and in overdose (14). 
More severe CNS-related effects including confusion, amnesia and coma 
occur less frequently at therapeutic doses, but occur with overdose 
(15; 16). Respiratory depression may occur in patients with significant 
CNS depression (17; 18).
---------------------------------------------------------------------------

    \30\ See current label information for carisoprodol (Soma) 
(http://www.fda~gov/cder/foil1abe1l2007/0_11792s0411bl.pdf).
---------------------------------------------------------------------------

    The primary toxic effect with poisoning or exposure to carisoprodol 
is CNS depression and, in severe cases, coma. Euphoria, CNS 
stimulation, muscular incoordination, confusion, headache, 
hallucinations and dystonic reactions have also been reported. Anti-
cholinergic effects (tachycardia, dry, warm skin) are reported 
following carisoprodol poisoning. Fever is reported following 
carisoprodol overdose (14; 19). Both mild hypertension and mild 
hypotension are reported in conjunction with serotonin syndrome after 
carisoprodol overdose (19). Horizontal nystagmus, mydriasis, and 
blurred vision have also been reported with carisoprodol overdose (20).
    In addition to the above adverse effects, drug abuse, dependence 
and tolerance are reported following long-term use of carisoprodol. See 
infra Factor Seven.

Human Behavioral Studies

    Fraser, et al. (21), evaluated whether carisoprodol possessed 
morphine-like (C-II) or barbiturate like (C-II, C-III and C-IV) 
addictive properties in human subjects, all of whom ``were former 
opiate addicts.'' H.F. Fraser, et al., Evaluation of carisoprodol and 
phenyramidol for addictiveness, Bulletin on Narcotics 1 (Oct-Dec. 
1961). The study had three arms: the first evaluated the effect of 
single oral doses in non-addicted patients, the second evaluated the 
24-hour substitution of carisoprodol for morphine in morphine-
stabilized patients and was used to assess whether carisoprodol can 
prevent symptoms of abstinence from morphine, and the third assessed 
physical dependence following chronic administration of carisoprodol 
and abrupt discontinuation of the drug. See id.
    In the first arm of the study, single doses of carisoprodol ranging 
from 1,050 mg to 2,500 mg (three to seven times the usual dose of 350 
mg) were administered orally in capsules to fasting, non-tolerant 
opiate addicts. Id. Assessments were carried out hourly for six hours 
with the single-dose opiate questionnaire. Id.
    The study found that carisoprodol's effects were not consistent at 
doses lower than 2,000 mg. Id. at 1-2. Only one of fifteen subjects 
that received the 2,500 mg dose identified the drug as ``dope.'' Id. In 
the same dose-range group, most subjects became sleepy one or two hours 
after receiving 2,500 mg of carisoprodol, and when awakened, did not 
show as much dysarthria as would have been anticipated from an 
equivalent dose of barbiturates. Id. at 2. According to the FDA, the 
subjective and objective effects noted in this group were similar to 
those of barbiturates or alcohol and different from those of opiates. 
GX 6, at 10.
    In the second arm of the study, 3,600 to 4,800 mg of carisoprodol, 
which was divided into three equal oral doses, were substituted for 
morphine in six and three morphine-stabilized patients, respectively. 
Fraser, at 2. The study was controlled ``negatively, by substitution of 
a placebo for morphine, and positively, by continuing the customary 
dose morphine in the same subjects.'' Id. Moreover, because 
``carisoprodol seemed to be barbiturate-like in many respects, the 
study was also controlled by substituting'' an average dose of 1.11 g 
of pentobarbital for morphine, which was divided among five doses, in 
another experiment which involved eleven other subjects. Id. Following 
substitution, hourly ``[o]bservations for the intensity of abstinence 
were made * * * from the 11th through the 24th hour of abstinence.'' 
Id.
    This arm of the study concluded that ``carisoprodol partially but 
significantly suppressed symptoms of abstinence.'' Id. The study found 
that the patients receiving the 4,800 mg dose of carisoprodol ``were 
quite sedated and somewhat difficult to arouse, but showed only a 
slight degree of dysarthria and ataxia.'' Id.
    The FDA did not discuss the third arm of the study. See GX 6, at 
10. Instead, it concluded that this study was conducted before the 
advent of modem human abuse liability testing that uses validated 
measures, and that it therefore does not directly address the issue of 
the human abuse potential of carisoprodol. Id. However, the FDA further 
found that ``the study results indicate that carisoprodol has sedative-
like effects, as opposed to opiate-like effects.'' Id.

[[Page 77347]]

    Dr. Jasinski expressed his disagreement with the FDA's assessment 
of the validity of the study results, opining that ``[w]hile there have 
been enhancements in methodologies use[d] to assess abuse liability in 
intervening years, * * * the methodology used by Fraser yielded valid 
scientific results and should not be discounted based solely upon the 
fact that different methodologies would be used today.'' MX 172, at 7. 
Dr. Jasinski found it ``significant that in the Fraser study[,] the 
chronic administration of carisoprodol for a period of 18 to 54 days at 
doses that progressed from 1200 mg/day to 4800 mg/day * * * did not 
induce a characteristic barbiturate intoxication pattern,'' and that 
``the abrupt withdrawal of carisoprodol [did not] reveal any signs of 
barbiturate-like abstinence.'' Id. at 7-8. Dr. Jasinski thus opined 
that ``these data show that carisoprodol does not possess barbiturate-
like abuse liability and that in light of these data[,] it is not 
scientifically sound to reach a contrary conclusion based solely upon 
less reliable animal or in vitro data.'' Id. at 8.
    Both parties and the ALJ cited the Fraser study as being an exhibit 
in the record. See Gov. Br. at 19 (citing Meda Ex. 98); Meda Br. at 56-
57 (citing same), ALJ at 32 (] 46). However, this exhibit was not 
included in the record forwarded to this office, and a review of the 
transcripts contains no indication that Meda Exhibit 98 was ever 
entered into evidence. Because both parties and the ALJ have cited the 
Fraser study as if it were in evidence, I take official notice of it. 
Moreover, given the dispute as to significance of the study's findings, 
a discussion of the third arm is warranted.
    The third arm of the Fraser study, which was only single-
blinded,\31\ involved the administration of large doses of carisoprodol 
to five patients, with four of the patients receiving the drug for 18 
days and one receiving the drug for 54 days. Fraser, at 3. Each patient 
received an initial dose of 1,200 mg, which was increased by 200 mg 
each day for 16 days, and then by 300 mg on days 17 and 18 for a 
maximum daily dose of 4800 mg. Id. The patient who was given the drug 
for 54 days received a daily dose of 4800 mg from days 18 through 54. 
Id. Following the respective 18 and 54-day periods, the drug was 
abruptly withdrawn from the patients, who were then given placebo. Id.
---------------------------------------------------------------------------

    \31\ While the patients ``were unaware of the nature and 
schedule of medication,'' the observers were not. Fraser, at 3.
---------------------------------------------------------------------------

    The study found that with the exception of changes in the patients' 
EEG (electroencephalogram) patterns, ``the outstanding feature was a 
complete absence of any significant subjective effects even when the 
dosage was increased to 4,800 mg daily.'' Id. Continuing, the authors 
noted that ``it was not possible to differentiate carisoprodol from a 
placebo.'' Id. Moreover, following the cessation of carisoprodol, none 
of the patients showed signs of abstinence and all were unaware that 
their medication had been changed. Id.
    While the study found that the patients' EEGs showed a 
``barbiturate-like effect'' when the patients were receiving 4200 to 
4800 mg, it also found that all of the patients' EEGs had returned to 
normal within thirty-six hours of the last dose. Id. Moreover, ``[n]one 
of these patients showed focal or generalized abnormalities of the 
paroxysmal type during withdrawal, such as those seen following 
withdrawal of barbiturates.'' Id. The study thus concluded that 
``[c]hronic administration on a progressive dosage schedule did not 
induce a characteristic barbiturate intoxication pattern'' and that the 
abrupt withdrawal of the drug did not result in ``barbiturate-like 
abstinence'' symptom. Id.
    However, the authors noted that ``it remains to be seen whether 
administering carisoprodol continuously in larger doses would induce a 
chronic state of intoxication and whether abrupt withdrawal under such 
circumstance would provoke a barbiturate or meprobamate type of 
abstinence.'' Id. The authors further noted that ``[s]uch a possibility 
is suggested by the fact that carisoprodol is a congener of meprobamate 
and exhibits many barbiturate-like pharmacological effects.'' Id. at 3-
4.
    As for Dr. Jasinski's testimony that the Fraser study ``yielded 
valid scientific results,'' another of Meda's Exhibits (the FDA's Draft 
Guidance on Assessment of Abuse Potential of Drugs) states that 
``[h]uman abuse potential studies are usually double blind, double 
dummy, placebo, and positive comparator controlled, and are crossover 
designed.'' MX 12, at 14. Moreover, such studies typically involve a 
substantially greater number of patients than the Fraser study involved 
and both ``[t]he investigator and the staff who interact with subjects 
should not know the sequence of substances administered.'' Id. In 
short, the Fraser study did not meet most of these criteria. Moreover, 
it seems unlikely that scientists would draw a definitive conclusion 
from the findings with respect to the single patient who received the 
drug for 54 days.
    Meda also cites recent clinical trials it conducted in support of 
its application to market carisoprodol in 250 mg strength as evidence 
that the drug does not cause withdrawal symptoms and is not subject to 
diversion, misuse, or abuse. MX 171, at 5. MEDA's CMO maintains that 
these studies, which involved several thousand patients at hundreds of 
clinical research centers, ``provide the only evidence-based body of 
human data from which [to] evaluate the likelihood of drug diversion, 
drug seeking behavior, and withdrawal symptoms in a controlled 
setting.'' Id. at 9 (emphasis in original). According to MEDA's CMO, 
during these studies, there was no evidence of diversion and ``there 
was no evidence whatsoever of carisoprodol-induced withdrawal syndrome 
following abrupt cessation of up to two weeks of treatment.'' Id. at 
10. Meda's CMO then opined that ``[u]nlike other drugs, such as 
opioids, this suggests that if dependence occurs, it is only following 
prolonged treatment with carisoprodol.'' Id.
    As for the lack of evidence of withdrawal, diversion or drug 
seeking behavior, the short-term nature of the studies (which involved 
administration of the drug at therapeutic levels for either one or two 
weeks at most, MX 171, at 8) renders this evidence of minimal value in 
determining whether carisoprodol causes dependency. Moreover, FDA found 
that there is extensive evidence in the scientific literature 
establishing that carisoprodol can cause dependency in humans. See 
discussion under Factors Five, Six, and Seven, infra. Finally, that 
short-term administration of carisoprodol does not cause dependency is 
not dispositive because the CSA does not impose an arbitrary time frame 
for assessing whether the taking of a drug can cause dependency.\32\
---------------------------------------------------------------------------

    \32\ Dr. Jasinski also noted that in his experience as the Chief 
of the Center for Chemical Dependence at Johns Hopkins Bayview 
Medical Center, he could not ``recall a single incidence in which an 
individual has visited our center to be treated for carisoprodol 
addiction/dependence.'' MX 172, at 9. While that may be, this may 
simply reflect that different drugs are more popular with drug 
abusers in the geographic area served by Johns Hopkins.
    Dr. Jasinski also noted that according to the Treatment Episode 
Data Set, a database maintained by SAMHSA of admissions to substance 
abuse treatment centers, ``there were no mentions of carisoprodol in 
any of the TEDS reports from 2002 through 2007.'' Id. (citing MXs 31 
& 32). However, the TEDS reports do not separately list 
carisoprodol, but rather use broader categories such as ``Other non-
Benzodiazepine Tranquilizers,'' which ``[i]ncludes meprobamate, 
tranquilizers, etc.'' MX 31, at 28. Thus, admissions to treatment 
centers for carisoprodol abuse might well be reported under this 
category. Accordingly, I place no weight on this testimony.

---------------------------------------------------------------------------

[[Page 77348]]

Factor 3--The State of Current Scientific Knowledge Regarding 
Carisoprodol

    The current scientific knowledge regarding carisoprodol includes 
information about the drug's chemistry and pharmacokinetics.

Chemistry

    Chemically, Carisoprodol is (l-methylethyl) carbamic acid 2-
[[(aminocarbonyl)oxy]methyl]-2- methylpentyl ester; N-isopropyl-2-
methyl-2-propyl-l, 3-propanediol dicarbamate; isopropyl meprobamate. GX 
6, at 10. Carisoprodol is also identified by CAS number 78-44-4. 
Carisoprodol has a molecular weight of 260.33; its molecular formula is 
C12H24N204. Id.
    Carisoprodol is a bitter tasting, odorless, white crystalline 
powder. Its melting point (without decomposition) ranges from 92-94 
[deg]C and it has low water solubility (30 mg/100 ml at 25 [deg]C). Id. 
Carisoprodol is soluble in many organic solvents and practically 
insoluble in vegetable oils. Id. Carisoprodol is stable in dilute acid 
and alkali and is not altered by artificial gastric or intestinal 
juices. Id. It is a racemic compound with one asymmetric center. Id. 
Qualitative and quantitative methods for detection of carisoprodol and 
other drugs by gas chromatography/mass spectrometry (GC/MS) or thin 
layer chromatography in combination with GC/MS have been published (22-
25).

Pharmacokinetics

    The pharmacokinetics of carisoprodol have been investigated in 
several animal and human studies. At a dose of 350 mg, the mean peak 
plasma concentration (Cmax) achieved was 2.29  0.68 [mu]g/
ml; women tended to reach peak plasma concentrations earlier than men 
(1.45 vs. 2.5 hrs) and had a faster apparent oral clearance (0.772 vs. 
0.38 l/h/kg). GX 6, at 10. Carisoprodol is metabolized in the liver via 
cytochrome 2D6. Id. Meprobamate (C-IV) is one of the products of 
carisoprodol metabolism. Id. Following a single 350 mg dose of 
carisoprodol, the corresponding normalized peak concentration of 
meprobamate was 2.08  0.48 [mu]g/ml; these levels are 
approximately 25 percent those observed following a single 400 mg dose 
of meprobamate. Id. Carisoprodol is eliminated by both renal and non-
renal routes with a terminal elimination halflife of 2.44  
0.93 hr. Id. at 10-11.

Factor 4--Carisoprodol's History and Current Pattern of Abuse

    In 1959, carisoprodol was introduced into the U.S. market as a 
single-agent drug, and in 1960, as a combination product with aspirin. 
Id. at 11. In 1983, carisoprodol was marketed in combination with 
aspirin and codeine. Id. Numerous generic products have been introduced 
into the U.S. market. Id. Carisoprodol is also marketed worldwide under 
various trade names including Artifar, Carisoma, Carisoprodol 
Sintesina, Listaflex, Mio Relax, Sanoma, Soma, Somadril, and Somflam. 
Id.
    In assessing carisoprodol's history and current pattern of abuse, 
DEA and FDA relied on multiple data sources. As discussed above, these 
include DAWN, NSDUH, AERS, and Florida Medical Examiners Commission 
Data. In addition, reports from the scientific literature were 
reviewed.

DAWN ED Data

    As discussed above under Factor One (and as set forth in Table 
One), DAWN data suggest that there has been an increase in the 
frequency of nonmedical use ED visits associated with carisoprodol. In 
2004, DAWN estimated the number of ED visits related to nonmedical use 
of carisoprodol as 14,736; in 2007, it estimated that there were 27,128 
nonmedical ED visits related to carisoprodol. By comparison, DAWN 
estimated that in 2004, there were 15,619 ED visits related to the 
nonmedical use of diazepam, and in 2007, there were an estimated total 
of 19,674 nonmedical ED visits related to diazepam. However, according 
to SAMHSA, the increase in the number of carisoprodol visits between 
2004 and 2007 was not statistically significant. Nonetheless, even if 
there were only an estimated 14,736 ED visits related to carisoprodol, 
this is still a significant number of visits when compared with the 
number of diazepam-related visits.
    In addition, as found above under Factor One (and set forth in 
Table 2), when the number of estimated nonmedical use ED visits is 
adjusted for the number of prescriptions issued (by dividing the number 
of visits by 10,000 prescriptions), in 2007 the carisoprodol rate was 
22.6/10,000 Rx, while diazepam's rate was 14.1/10,000 Rx. By contrast, 
cyclobenzaprine, another skeletal muscle relaxant, had a rate of 3.3/
10,000 Rx.
    As also found above under Factor One, NSDUH survey data for the 
years 2004 through 2007 show that between 2.5 and 2.84 million persons 
have used carisoprodol for non-medical purposes. To be sure, the NSDUH 
data may not reflect a statistically significant increase in the number 
of persons who have used carisoprodol for a non-medical purpose. 
However, the fact that approximately 2.5 to 2.8 million persons have 
engaged in non-medical use of carisoprodol is itself significant.

Demographic and Epidemiological Factors Associated With Nonmedical Use 
of Carisoprodol

    FDA's review found that the majority of cases reported in the 
scientific literature note that carisoprodol abuse has primarily been a 
component of multi-drug abuse. GX 6, at 13. According to FDA, DAWN data 
indicates that the drugs most frequently used in combination with 
carisoprodol that resulted in ED visits were opioids (hydrocodone, 
oxycodone), benzodiazepines (alprazolam, diazepam, clonazepam), 
alcohol, and illicit drugs (marijuana, cocaine). Id. at 14.
    Beginning in 2006, carisoprodol has been reported as a primary or 
sole drug of abuse in DAWN. Additional analysis of DAWN data 
specifically addresses details of this issue for carisoprodol 
nonmedical use in 2006 (see Table 3).
    As set forth in Table 3, the DAWN 2006 data estimated that there 
were a total of 24,505 ED visits related to the nonmedical use of 
carisoprodol. Of these, 42 percent involved females and 58 percent 
males. In twenty-one percent of the cases, carisoprodol was reported as 
the sole drug, with it being the sole drug in twenty-seven percent of 
the female cases, and twelve percent of the male cases. The FDA's 
analysis concluded that these gender-based differences may suggest 
effects related to dosage and pharmacokinetic/pharmacodynamic effects 
that could influence abuse potential.
    The DAWN data also suggest that there are some age-related 
differences in the use of carisoprodol, with greater reports of single 
use among those 12-17 years old (27 percent) and those 45-54 years old 
(30 percent) than other age groups.\33\ A study by Forrester (26) found 
that adolescents accounted for 17 percent of the abuse calls related to 
carisoprodol in an analysis of Texas

[[Page 77349]]

Poison Centers' data from 1998-2003, a rate similar to that reported in 
RADARS (27).
---------------------------------------------------------------------------

    \33\ According to FDA, ``such abuse may represent a significant 
change in the pattern of abuse of carisoprodol, as abuse of 
carisoprodol without other substances and significant single drug 
use by such a large young population has not previously been 
documented in national data.'' GX 6, at 14. However, prior to 2006, 
carisoprodol was not previously reported as a sole drug in the DAWN 
ED data. Thus, it is unclear whether there has been a significant 
change in the abuse of carisoprodol by adolescents.

                  Table 8--Estimated Nonmedical-Use Carisoprodol ED Visits From DAWN 2006 by Age and Most Common Drug Combinations \34\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                  Age
                Carisoprodol                 -----------------------------------------------------------------------------------------------------------
                                                All      0-5      6-11    12-17    18-20    21-24    25-29    30-34    35-44    45-54    55-64     65+
--------------------------------------------------------------------------------------------------------------------------------------------------------
Carisoprodol-single drug....................    5,053  .......  .......      307      256      553      494      287    1,030    1,873      228       26
Carisoprodol-multi-drug.....................   19,444        0    . . .      820    1,135    2,342    2,318    2,150    5,119    4,286      752      515
                                             -----------------------------------------------------------------------------------------------------------
    Total by Age............................   24,497        0    . . .    1,127    1,391    2,895    2,812    2,437    6,149    6,159      980      541
--------------------------------------------------------------------------------------------------------------------------------------------------------

     
---------------------------------------------------------------------------

    \34\ Where age was known. Information received from SAMHSA on 
June 18, 2008. Three dots (. . .) indicate that an estimate or count 
of less than 30 or with a relative standard error greater than 50, 
has been suppressed.
---------------------------------------------------------------------------

    NSDUH data for the years 2004 through 2007 show that in each year, 
more than 100,000 twelve to seventeen-year olds reported having used 
carisoprodol for non-medical reasons. During this same timeframe, 
between 956,000 and 1,056,000 eighteen to twenty-five year olds 
reported having used carisoprodol for non-medical reasons. As the table 
below shows, these age groups reported having engaged in the non-
medical use of carisoprodol to a far greater extent than they report 
having engaged in the non-medical use of meprobamate.\35\ These figures 
were approximately thirty-three percent (in the 12-17 age group) and 
forty-two percent (in the 18-25 age group) of those persons reporting 
non-medical use of diazepam.
---------------------------------------------------------------------------

    \35\ Nearly twice as many persons reported non-medical use of 
carisoprodol than reported non-medical use of cyclobenzaprine, 
another muscle relaxant which is unscheduled. GX 6, at 17.

     Table 9--NSDUH--Nonmedical Use of Carisoprodol (Soma[supreg]) and Other Drugs in Lifetime, by Age Group
                                      [Numbers in thousands (%), 2004-2007]
----------------------------------------------------------------------------------------------------------------
                                               2004  (%)            i>(%)            i>(%)            i>(%)
----------------------------------------------------------------------------------------------------------------
                                           Carisoprodol (Soma[supreg])
----------------------------------------------------------------------------------------------------------------
Ages 12-17..................................        138 (0.5)        118 (0.5)         111(0.4)        106 (0.4)
Ages 18-25..................................        975 (3.0)      1,056 (3.3)      1,034 (3.2)        956 (2.9)
Ages 26 or Older............................      1,503 (0.8)      1,351 (0.7)      1,695 (0.9)      1,647 (0.9)
----------------------------------------------------------------------------------------------------------------
                                       Cyclobenzaprine (Flexeril[supreg])
----------------------------------------------------------------------------------------------------------------
Ages 12-17..................................   34\a\ (0.1\a\)         64 (0.3)         53 (0.2)         56 (0.2)
Ages 18-25..................................        461 (1.4)        479 (1.5)        533 (1.6)        568 (1.7)
Ages 26 or Older............................      1,473 (0.8)      1,348 (0.7)      1,819 (1.0)      1,813 (1.0)
----------------------------------------------------------------------------------------------------------------
                                            Diazepam (Valium[supreg])
----------------------------------------------------------------------------------------------------------------
Ages 12-17..................................        380 (1.5)        351 (1.4)        320 (1.3)        314 (1.2)
Ages 18-25..................................      2,434 (7.6)      2,650 (8.2)   2,480 \a\ (7.6      2,252 (6.9)
                                                                                           \a\)
Ages 26 or Older............................     11,794 (6.4)     11,913 (6.4)  12,024 \a\ (6.4     10,606 (5.6)
                                                                                           \b\)
----------------------------------------------------------------------------------------------------------------
                                            Meprobamate Products \1\
----------------------------------------------------------------------------------------------------------------
Ages 12-17..................................         34 (0.1)         22 (0.1)         24 (0.1)         18 (0.1)
Ages 18-25..................................         39 (0.1)         49 (0.2)         42 (0.1)         27 (0.1)
Ages 26 or Older............................        173 (0.1)        234 (0.1)        150 (0.1)        192 (0.1)
----------------------------------------------------------------------------------------------------------------
\1\ Includes Equanil[supreg] meprobamate, and Miltown[supreg]. \a\ Difference between year and succeeding year
  (e.g., 2004 and 2005) estimates are statistically significant, p <= 0.05. \b\ Difference between year and
  succeeding year statistically significant, p <= 0.01. Source: SAMHSA, Office of Applied Studies, National
  Survey on Drug Use and Health.

    As found above, AERS data through June 2007 contains a total of 472 
reports related to potential abuse of carisoprodol. GX 6, at 15. Of 
these, 48 reports identified dependence as the adverse event and 19 
identified withdrawal syndrome. Id. As also found above, data obtained 
from the Florida Medical Examiners Commission for the years 2004 
through 2008 identifies carisoprodol as the cause of death in between 
74 and 96 deaths each year.\36\ See Table Four above.
---------------------------------------------------------------------------

    \36\ The data for the years 2004 through 2008 show that 
carisoprodol was present in between 289 and 415 cases each year. GX 
6, at 18.
---------------------------------------------------------------------------

Scientific Literature Reports

    The FDA review concluded that there are relatively few reports in 
the scientific literature describing fatal cases of intoxication with 
carisoprodol. The FDA further found that there are inconsistencies in 
the literature with regard to what is considered a toxic concentration 
level (17, 22, 28-31). As carisoprodol is frequently abused in 
combination with other drugs, the specific contribution of carisoprodol 
to a fatality may be difficult to ascertain.

[[Page 77350]]

However, several publications have attributed therapeutic levels of 
carisoprodol at 10-40 mg/l, toxic levels at 30-50 mg/l, and a lethal 
level at 110 mg/l (31-33).
    Davis and Alexander (31) reviewed carisoprodol-related deaths in 
Jefferson County, Alabama, from January 1, 1986 to October 31, 1997. Of 
a total of 8,162 Medical Examiner cases, toxicology analysis found 24 
cases in which carisoprodol was in the decedent's blood. Blood 
carisoprodol concentrations in decedents ranged from <1 mg/l to 96.8 
mg/l, with a mean carisoprodol concentration of 16.4 mg/l and a 
standard deviation of 21.0 mg/l. In no case was carisoprodol the only 
drug detected, nor was it ever the sole cause of death. The authors 
also noted the frequent association in their series and in the DAWN 
data of carisoprodol with co-ingested respiratory depressants 
(propoxyphene, diazepam, codeine). As carisoprodol also can cause 
respiratory depression, the authors concluded that it was a probable 
contributor to the cause of death (31).
    Hoiseth, et al. (34), investigated all forensic autopsies at the 
Norwegian Institute of Public Health during the period 1992-2003 and 
found five cases which reported the median concentrations of 
carisoprodol associated with intoxication. In another 93 intoxication 
cases, levels of carisoprodol relative to the other drugs varied. When 
the number of intoxications with carisoprodol each year was divided by 
the number of defined daily doses (DDD) sold, a fatal toxicity index 
(FTI) of between 5.6 and 6.9 deaths/million DDD was obtained. The 
carisoprodol FTI was higher than data for the schedule IV CNS 
depressants diazepam (5.2), oxazepam (4.9), nitrazepam (2.8), and 
zopiclone (1.9), but lower than those for alprazolam (16.0) and 
clonazepam (16.1). The total number of cases involving carisoprodol 
increased during the time period observed, as did sales figures for the 
same period. Only a small number of deaths could be attributed to use 
of carisoprodol alone.
    In summary, multiple national and state data systems used in the 
United States provide substantial evidence that carisoprodol is being 
abused. This conclusion is corroborated by various reports published in 
the scientific literature. While carisoprodol is most often abused in 
combination with other drugs, in about 20 percent of the reports 
carisoprodol is the only drug of abuse. In addition, national survey 
data show that in excess of one million people under the age of twenty-
six have acknowledged using carisoprodol for non-medical reasons. These 
data are consistent with DEA data indicating that carisoprodol is being 
diverted.

Factor 5--The Scope, Duration, and Significance of Abuse

    According to the FDA, examination of the case reports and studies 
of abuse in the United States and other countries are useful in 
assessing the scope, duration, and significance of carisoprodol abuse. 
GX 6, at 19. Because carisoprodol has been marketed since 1959, there 
is a substantial body of post-marketing epidemiologic abuse-related 
data in the published scientific literature and from AERS. Id. at 19-
20. Drug abuse and dependency are determined by the evaluation of a 
patient's drug-seeking behavior, as evidenced by the use of multiple 
prescribers, the increased frequency of refills, the use of increasing 
doses, and reports of withdrawal symptoms when a drug is suddenly 
withdrawn. Id. at 20. Withdrawal symptoms vary and include anxiety, 
tremor, insomnia, hallucinations, and seizures. Id.
    Reports in the scientific literature document that carisoprodol can 
cause dependency (35-39) and there are cases where withdrawal symptoms 
have been reported (40-42). While the presence of other drugs of abuse 
complicates the assessment, there are reports where carisoprodol is the 
sole drug of abuse (35, 43) (see Factor 7 for further details of these 
reports).
    There are other reports in addition to those discussed under Factor 
Four. A report from India describes sixteen cases of carisoprodol 
abuse, mainly among young male polydrug abusers (15). Carisoprodol was 
purportedly taken to attenuate opioid withdrawal, but its abuse for 
pleasurable effects was also described. Carisoprodol thus gained a 
reputation among addicts for producing psychic effects. Isaac, et al. 
(44), reported a case of abuse from Canada that was recognized through 
a pharmacist hotline.
    Bramness, et al. (45), conducted a pharmacoepidemiological study on 
the use and abuse of carisoprodol in Norway. The study used the 
Norwegian Prescription Database (NorPD), which contains information on 
prescription drugs dispensed in Norway. An advantage to this database 
is that patients were followed over time. In 2004, 53,889 Norwegian 
women (2.4 percent) and 29,824 men (1.3 percent), age 18 or older, 
received carisoprodol at least once. At the time of the study, 
carisoprodol was approved in Norway for the treatment of acute low back 
pain, for short term use only (up to 1 week) at a defined daily dose 
(DDD) of 1400 mg (350 mg three times a day and at bedtime).
    The investigation included the dispensing of 3,772,154 DDDs to 
83,713 patients of 18 years of age or older. Measured parameters 
included the one year prevalence of use (i.e., the number of 
individuals who had received at least one prescription of carisoprodol 
per 100 inhabitants) and parameters for potential abuse including high 
use (high users were defined as those receiving >15 DDDs during the 
year), high intensity use (high intensity over different lengths of 
time), doctor shopping, and concomitant use of potential drugs of 
abuse. The possible drug abuse parameters for carisoprodol were 
compared to five other commonly prescribed drugs.
    Of those meeting the study's requirements, the following groups 
emerged: therapeutic users, 62 percent; pseudo-therapeutic long-term 
users of carisoprodol, 16 percent; ``pure'' carisoprodol abusers, 1 
percent; concomitant benzodiazepine abusers, 8 percent; and concomitant 
opioid abusers, 14 percent. The therapeutic users received only 12 
percent of the carisoprodol dispensed in 2004, while those considered 
primary opioid abusers received 48 percent of the total amount of 
dispensed. Eighty-nine percent of the patients received their 
carisoprodol from a single prescribing doctor, with the remainder 
having multiple prescribers. Eighty-two percent of the patients were 
defined as high users (received 15 DDDs) of carisoprodol and 14 percent 
of the patients received >=75 DDDs.
    Reports in the scientific literature indicate that relatively few 
physicians are aware of the addictive potential of the drug (39; 46; 
47). The lack of medical and public awareness regarding the abuse 
potential of carisoprodol may contribute to the abuse of the drug.
    In summary, carisoprodol's post-marketing history indicates that 
the drug can, and is, being abused, in both the United States and other 
countries. The growing evidence includes epidemiologic abuse-related 
data in the published scientific literature (e.g., Bramness) and from 
AERS, as well as data from national and state data systems that track 
drug abuse. While recent data show that carisoprodol is most commonly 
abused in combination with other drugs, DAWN data show that it is 
abused as a single drug in 20 percent of the cases. Other data (the 
NSDUH survey) show that carisoprodol is being widely abused by 
adolescents and young adults.

[[Page 77351]]

    The human data showing abuse are reinforced by recent animal self-
administration and drug-discrimination studies indicating that 
carisoprodol has positive reinforcing and discriminative effects 
similar to other drugs currently controlled under schedule IV, 
including barbital, meprobamate, and chlordiazepoxide.

Factor 6--The Risk to the Public Health

    The scientific literature and other data, including DAWN, NSDUH, 
and AERS, document the adverse health consequences of the use, misuse, 
and abuse of carisoprodol. According to the FDA, the risks of 
carisoprodol to the public health are typical of other CNS depressants 
that are controlled in the CSA. GX 6, at 21. These risks include CNS 
depression, respiratory failure, cognitive and motor impairment, 
addiction, dependence, and abuse. Id.
    Because carisoprodol metabolizes to meprobamate (C-IV), 
carisoprodol may pose similar risks to the public health as those 
exhibited by meprobamate. Olsen, et al. (48), concluded that the 
meprobamate formed during carisoprodol metabolism may contribute to the 
effects of carisoprodol. A case report of a pediatric death due to CNS 
depression and respiratory failure as a consequence of a carisoprodol 
overdose indicates that oral ingestion of carisoprodol alone could 
produce significant serum levels of both carisoprodol and meprobamate 
(17).
    Backer, et al. (22), reported three cases involving overdoses of 
carisoprodol and measured the concentration of carisoprodol and 
meprobamate in urine, vitreous humor, heart and femoral blood by GC/MS. 
In the first case, which involved a 43-year old woman, an empty bottle 
of 30 tablets of carisoprodol was found next to her. The prescription 
had been filled 3 days earlier. Only carisoprodol and meprobamate were 
detected, but the concentrations varied by anatomical site.
    Carisoprodol has been implicated in cases of impaired driving (49-
52). Logan, et al. (50), reported the analytical results from a 
Washington State Toxicology Laboratory (WSTL) review of drivers 
suspected of driving under the influence of drugs and further reviewed 
the pharmacology of the carisoprodol and meprobamate, including 
literature implicating these drugs in impaired driving. They found 104 
cases submitted to the WSTL between January 1996 and July 1998 in which 
meprobamate and/or carisoprodol was detected in the blood of drivers 
involved in accidents or arrested for impaired driving. Analytical 
toxicology, patterns of drug use, driving behaviors, and symptoms 
observed in the drivers were considered. The symptomatology and level 
of driving impairment were consistent with that of other CNS 
depressants, most notably alcohol. Reported driving behaviors included 
erratic lane travel, weaving, driving slowly, swerving, stopping in 
traffic, and hitting parked cars and other stationary objects. Drivers 
stopped by the police displayed poor balance and coordination, 
horizontal gaze nystagmus; bloodshot eyes; unsteadiness; slurred 
speech; slow responses; a tendency to doze off or fall asleep; 
difficulty standing, walking or exiting their vehicles; and 
disorientation.
    Many of these cases involved drivers who had also taken alcohol or 
other CNS active drugs, making it difficult to attribute the documented 
impairment solely to carisoprodol and meprobamate. However, in twenty-
one cases, no other drugs were detected and similar signs and symptoms 
were present. In these cases, impairment was possible at any 
concentration of these two drugs, but the most severe impairment was 
noted when the combined concentration was greater than 10 mg/L, which 
is still within the therapeutic range. The authors speculated that the 
toxicology findings in these cases resulted from recent use or overuse 
of the drug, but they also suggested that chronic use may be a factor, 
particularly in those with impaired metabolisms.
    Bramness, et al. (51), reported on 62 cases of impaired driving 
where carisoprodol and meprobamate were the only drugs identified in 
the database of the Norwegian Institute of Public Health, Division for 
Forensic Toxicology and Drug Abuse. The study found that impaired 
drivers (73 percent) had higher blood carisoprodol concentrations than 
drivers who were not impaired (27 percent), but found no difference in 
blood meprobamate concentration for all the drivers viewed together. 
However, among occasional users of carisoprodol, there was a difference 
in blood meprobamate concentration between non-impaired and impaired 
drivers. The risk of being judged impaired rose with increasing blood 
carisoprodol concentration, but not with increasing blood meprobamate 
concentration. The clinical effects of carisoprodol as measured by the 
clinical test for impairment (CTI) resembled those of benzodiazepines 
(C-IV). Additional effects included tachycardia, involuntary movements, 
hand tremor and horizontal gaze nystagmus. The authors concluded that 
carisoprodol probably has an impairing effect by itself at blood 
concentration levels greater than those observed after therapeutic 
doses.
    In 2007, Jones, et al. (52), reported the concentrations of 
scheduled prescription drugs found in blood samples from people 
arrested in Sweden during 2004 [n=7052] and 2005 [n=7759] for driving 
under the influence. In Sweden, both carisoprodol and meprobamate are 
C-IV drugs, but meprobamate is no longer registered for use. 
Carisoprodol was found in 66 specimens (0.9% of the total specimens); 
the mean concentration was 3.8 mg/l (median 2.8 mg/l and highest 11.9 
mg/l) and meprobamate in 63 (0.8%) (mean concentration 15.7 mg/l, 
median 11 mg/l, and highest 64.0 mg/l). In eight specimens, only 
meprobamate was found. In twenty-seven percent of the carisoprodol 
cases, the blood concentrations were higher than what would be expected 
for normal therapeutic use (2.5-10 mg/l), thus suggesting overdose or 
abuse of the drug. Multi-drug use was not evaluated separately.
    The FDA also noted evidence in the medical literature that the use 
of carisoprodol in the elderly and the nursing home population should 
be done with great care (53, 54). As with other CNS depressants, 
because of recognized age-related changes in drug metabolism and 
excretion and increased sedation, seniors could have an increased risk 
of adverse events including falls and auto accidents.
    The FDA further noted that the effects induced by carisoprodol are 
characteristic of CNS depressants, and include altered attention, 
coordination, reaction time, judgment, decision making and other skills 
necessary to safe driving. Consequently, individuals under the 
influence of both therapeutic and supra-therapeutic doses of 
carisoprodol present a public health risk that needs to be considered 
when carisoprodol is prescribed. Representative cases are described 
below.
    As documented in the scientific and medical literature, 
carisoprodol may produce dependence and a withdrawal syndrome 
characterized by anxiety, insomnia, and irritability. Moreover, in some 
cases, muscular pain has been described upon abrupt cessation following 
long-term use. See Factor 7.

Adverse Events Report in the Scientific Literature

    The FDA also discussed several adverse events reported in the 
scientific literature. A two-year old ingested 700 milligrams (two 350 
mg tablets) of

[[Page 77352]]

carisoprodol and became increasingly drowsy over 60 minutes with 
symptoms progressing to lethargy and hypoxia (18). The patient's level 
of consciousness declined significantly requiring respiratory 
ventilation. Following activated charcoal and supportive care, the 
patient recovered fully within 12 hours.
    Roberge, et al. (55), reported the case of a 52-year-old woman who 
presented with CNS depression and a Glasgow Coma Score of 9, secondary 
to ingestion of carisoprodol. She reportedly took her carisoprodol 
tablets in an erratic fashion (taking an estimated thirty-five extra 
350 milligram tablets over a thirteen-day period) and developed stupor 
along with confusion and garbled speech. After administration of i.v. 
flumazenil (0.2 mg IV), the patient's neurologic status normalized and 
she required no further therapy. Carisoprodol and its metabolite 
meprobamate are y-aminobutyric acid receptor indirect agonists with CNS 
chloride ion channel conduction effects similar to the benzodiazepines, 
thus making flumazenil a potentially useful antidote in toxic 
presentations.
    Siddiqi and Jennings reported the case of a near-fatal overdose 
involving a 40-year old male (14). The patient, who had a history of 
hypertension, ingested 60 carisoprodol tablets (21 grams) and an 
unknown quantity of chlordiazepoxide and temazepam. He developed a coma 
(with absent tendon and plantar reflexes), sinus tachycardia (130 bpm) 
with a prolonged QT interval, mild respiratory acidosis (pH 7.31; pCO2 
50.1 mmHg, partially compensated with artificial ventilation), fever 
(100.5[deg] F), hypertension (220/118--mmHg), and dry and warm skin. 
Following supportive care, he recovered completely without further 
sequelae.
    Reeves, et al. (40), studied the case of a 43-year-old male who 
took up to 30 or more tablets per day (a dose equal to or greater than 
10,500 mg/day) of carisoprodol for several weeks, to treat chronic back 
and shoulder pain. After the patient abruptly stopped taking 
carisoprodol, he developed anxiety, tremors, muscle twitching, 
insomnia, auditory and visual hallucinations, and bizarre behavior. The 
patient was treated with olanzapine and tapering doses of lorazepam and 
his symptoms gradually resolved. The authors suggested that this drug 
withdrawal syndrome was due to the accumulation of meprobamate, the 
active metabolite of carisoprodol.
    Bailey, et al. (47), published a retrospective analysis of drug 
screening performed for patient care during a six-month period at a 
laboratory in California. Carisoprodol was detected in the urine 
specimens of nineteen patients who became the study population; 
demographic and clinical information was then obtained by a 
retrospective review of the patients' medical records. In only one case 
was carisoprodol and/or meprobamate the sole drug(s) detected; 
benzodiazepines, opiates and cannabinoids were the other drugs most 
frequently identified.
    The most common clinical abnormality was depressed levels of 
consciousness which occurred in twelve cases; eight patients were 
lethargic, three obtunded but were responsive to pain, and one obtunded 
and was non-responsive to pain. The clinical history suggested that in 
seven cases, the drug was abused or implicated in a suicide attempt or 
gesture. In another seven cases, the drug was used primarily for 
medical purposes, and in five cases, the reason for use could not be 
determined. Additional findings were tachycardia (eight cases), 
dysarthria (seven cases), hypotension (six cases), and seizure activity 
(five cases, including the one case where no other drugs were 
identified). Approximately half of the time, the patient was 
hospitalized. In each case, supportive care alone led to recovery. 
While the authors acknowledged the potential contribution of the other 
drugs identified to the symptomatology found in these cases, they 
recommended that carisoprodol and its metabolite meprobamate be 
included in comprehensive drug screening as it had become an 
unrecognized drug of abuse in the community.
    Goldberg (20) reported that manifestations of acute carisoprodol 
toxicity were due chiefly to stimulation and depression of the CNS. 
Drowsiness, dizziness, headache, diplopia, and vertigo predominated. 
Impaired coordination, nystagmus on lateral gaze, and an altered state 
of consciousness were prominent findings. Acute symptomatology was 
present at carisoprodol levels above 33 [mu]g/ml, which lasted from 
eight to fifteen hours. Gastric lavage and supportive measures are the 
accepted methods of treating acute carisoprodol overdose.

Meda's Factor Six Evidence

    Meda contends that scheduling carisoprodol ``will have a negative 
impact on patient care.'' MX 174, at 4. According to Meda, some 
physicians will stop writing prescriptions for the drug and use other 
non-scheduled muscle relaxants due to ``concerns that their prescribing 
may be second guessed by government regulators or law enforcement 
personnel.'' Id. According to one of Meda's Experts, he had 
``personally asked a number of physicians if they would use 
carisoprodol if scheduled, and many indicated they would not.'' Id.
    As support for this contention, Meda also submitted two bar charts 
which show the percentage decrease in the number of carisoprodol 
prescriptions in Indiana, Nevada, Texas, and Louisiana after the drug 
was scheduled in these States. MX 21. More specifically, the charts 
show that in Indiana and Nevada, the amount of prescriptions decreased 
by approximately five percent following scheduling, and that in Texas 
and Louisiana, the amount of prescribing decreased by approximately two 
to three percent and four percent respectively.\37\ However, in the 
first quarter of 2010, the number of prescriptions in Louisiana had 
actually increased over the baseline level. Id.
---------------------------------------------------------------------------

    \37\ According to the chart, Indiana scheduled carisoprodol on 
July 1, 2004, and Nevada on July 14, 2004. MX 21. However, Meda's 
chart shows prescribing levels only through the fourth quarter of 
2005, at which time the reduction in prescribing levels in both 
States had begun to decrease. Id.
---------------------------------------------------------------------------

    Meda's evidence does not establish that scheduling carisoprodol 
will harm patients. As for the testimony of Meda's Expert that many 
physicians had told him that they would not prescribe carisoprodol and 
his conclusion that ``a not insubstantial number would'' stop 
prescribing, Meda's Expert produced no evidence to establish that his 
conclusion was based on a statistically valid sample. More 
specifically, Meda's Expert offered no evidence as to how many 
physicians he had asked, what their specialties were, how the questions 
were phrased, and how many had said they would stop prescribing the 
drug.
    Likewise, the data showing a decrease in the amount of 
prescriptions following the scheduling of the drug in the above States 
do not support Meda's argument, because it assumes that the baseline 
level of prescribing reflects legitimate prescriptions. However, the 
evidence in this record clearly establishes that carisoprodol is being 
diverted; thus, to the extent the baseline level of prescribing 
includes illegitimate prescriptions, the decrease in prescriptions may 
reflect nothing more than doctors recognizing that certain patients are 
seeking carisoprodol for non-medical reasons, and are therefore being 
more cautious in evaluating their patients and declining to prescribe 
the drug to drug-seeking patients. The decrease may also reflect that 
doctors who have knowingly prescribed the drug for non-medical reasons 
have ceased this activity because the

[[Page 77353]]

scheduling of the drug creates additional consequences for prescribing 
it without a medical purpose. Also, even if some doctors may have 
chosen to prescribe non-controlled muscle relaxants instead of 
carisoprodol after the drug was scheduled, this alone does not 
establish that patients have been harmed or that they have received 
``sub-optimal treatment.'' MX 174, at 5. In any event, as long as 
doctors follow accepted standards of medical practice in evaluating 
their patients and establish a legitimate medical purpose for 
prescribing carisoprodol to their patients, they have nothing to fear 
from DEA. Furthermore, doctors are expected to use their best 
professional judgment in determining which of various drugs they should 
prescribe to properly treat their patients.\38\
---------------------------------------------------------------------------

    \38\ In its brief, Meda cites an article which states that 
``[d]espite concerns about the potential risk of abuse from 
carisoprodol because of its metabolism to meprobamate, the available 
literature provides no data regarding the comparative risk of abuse 
and addiction from skeletal muscle relaxants.'' Meda Br. at 48 
(citing Meda Ex. 83, Chou, et al., Comparative Efficacy and Safety 
of Skeletal Muscle Relaxants for Spasticity and Musculoskeletal 
Conditions: A Systematic Review, 28 J. of Pain & Symptom Mgmt. 140, 
167 (2004)). The CSA does not, however, require that the Agency (or 
the Secretary) conduct a comparative analysis of the abuse/addiction 
risk of the drugs in a therapeutic category in order to schedule a 
particular drug.
---------------------------------------------------------------------------

    I thus find unavailing Meda's contention that scheduling 
carisoprodol will create a risk to public health. To the contrary, the 
record contains substantial evidence establishing that the abuse of 
carisoprodol poses a substantial risk to those persons who abuse the 
drug, as well as others. See also Factor Four.

Factor 7--Its Psychic or Physiological Dependence Potential

    According to FDA, the term psychic dependence is not in current use 
and refers to impaired control over drug use, such as craving. This 
term was introduced in the late 1950's by the World Health Organization 
Expert Committee on Addiction-Producing Drugs, as one of the factors 
that, in conjunction with physical dependence, defined the addiction 
phenomena (Savage et al., 2003). FDA further explained that physical or 
physiological dependence is a form of physiologic adaptation to the 
continuous presence of certain drugs in the body. GX 6, at 24.
    Tolerance and physical dependence examine the responses to repeated 
administration of a drug. Id. at 25. An assessment of tolerance or 
physical dependence is needed as part of the safety assessment of a 
drug and is a factor considered in scheduling. Id.
    Tolerance is the need for increasing doses of a drug to maintain a 
defined effect, such as analgesia, in the absence of disease 
progression or other external factors. Id. Physical dependence is a 
state of adaptation manifested by a drug class-specific withdrawal 
syndrome produced by abrupt cessation, rapid dose reduction, decreasing 
blood level of the drug and/or administration of an antagonist. See 
American Academy of Pain Medicine, American Pain Society and American 
Society of Addiction Medicine Consensus Document (2001). Tolerance is a 
state of adaptation in which exposure to a drug induces changes that 
result in a diminution of one or more of the drug's effects over time. 
Id.
    The FDA found that early animal drug dependence studies 
demonstrated that carisoprodol has a similar dependence liability to 
barbital, a schedule IV CNS depressant. Id. (citing FDA Reference 12). 
In dogs tolerant and dependent on barbital, 200 mg/kg p.o. of 
carisoprodol every six hours was completely effective and equivalent to 
100 mg/kg of barbital in preventing the appearance of abstinence 
phenomena. Id.
    Wyller, et al. (56), studied the occurrence of abstinence symptoms 
during carisoprodol withdrawal in humans. In this study, carisoprodol 
was gradually withdrawn over a two-week period in nine male prisoners 
who had been taking the drug in daily doses ranging from 700 mg to 
2,100 mg for at least 9 months. Patients were assessed clinically 
during the withdrawal period. Most of the patients reported mental 
distress, such as anxiety, insomnia, and irritability. Cranial and 
muscular pain and vegetative symptoms were also frequently reported. 
Most of the symptoms observed were transient, with neither seizures nor 
psychotic reactions being reported.
    Rohatgi, et al. (57), reported the treatment of a case of 
carisoprodol dependence involving a 46-year old male who self-treated 
his anxiety when his doctor stopped his narcotic prescriptions. The 
patient purchased carisoprodol over the internet and self-medicated. 
The patient was admitted to a treatment center and withdrawn from 
carisoprodol. Withdrawal symptoms included heart palpitations, 
diaphoresis, chills, stomach cramps, nausea, insomnia, restlessness, 
myalgias, arthralgias, tremors, diarrhea, severe psychomotor agitation, 
feelings of depersonalization, and anxiety with suicidal ideation. The 
patient's symptoms were managed with risperidone, clonazepam, 
mirtazapine, and fluoxetine.
    The FDA also noted that several other reports found that patients 
who abruptly stop the intake of carisoprodol may have a withdrawal 
syndrome. Reeves and Parker (58) studied changes in the occurrence of 
somatic dysfunctions in five patients during an eight-day period 
following discontinuation from large doses of carisoprodol. The results 
showed that the number of somatic dysfunctions changed significantly 
during the withdrawal period. Each patient had an increase in the 
number of somatic dysfunctions during the first three days after 
cessation of carisoprodol with a return to the baseline by the eighth 
day. This was reflected statistically in a significant-within-subjects 
effect for time. The results of supplemental analyses revealed a 
significant component of the effect and a trend for the quadratic 
component to be significant. Increases in the number of somatic 
dysfunctions during carisoprodol discontinuation support the existence 
of a carisoprodol withdrawal syndrome.
    Finally, FDA found that the development of dependence or tolerance 
is also evidenced by several published reports (35, 40, 49, 57, 59). 
Patients increased their doses to toxic levels and appeared to be 
exhibiting drug-seeking behavior. FDA further found that prolonged 
misuse of carisoprodol can lead to physical dependence and that 
patients who abruptly stop carisoprodol can develop a withdrawal 
syndrome that includes symptoms such as anxiety, insomnia, 
irritability, and worsening muscular pain (40).
    Subsequent to the FDA forwarding its evaluation to DEA, doctors at 
the Mayo Clinic published a clinical report documenting withdrawal 
symptoms in a 51-year old man who was taking up to 8400 mg per day of 
carisoprodol, which he obtained from both his physician and an internet 
pharmacy, but which he had exhausted at some point before he was 
hospitalized.\39\ GX 18, at 2. On admission, the patient ``was anxious, 
distractable, [and] disoriented,'' and exhibited ``[a] high frequency, 
postural, and kinetic tremor in [his] extremities.'' Id. at 1. While 
the patient was placed on a tapering schedule, on the third day of his 
hospitalization, ``the patient's tremor, agitation and confusion 
worsened, and he experienced visual hallucinations and myoclonic jerks 
in the extremities.'' Id. at 2.
---------------------------------------------------------------------------

    \39\ According to the case report, the doctors were not 
initially aware of the quantity of carisoprodol that the patient was 
taking and that he purchased it online. GX 18, at 2.
---------------------------------------------------------------------------

    While the doctors were able to successfully treat the patient and 
taper him off of the drug, they concluded that ``[t]his case 
demonstrates adverse effects

[[Page 77354]]

of both carisoprodol toxicity and withdrawal.'' Id. More specifically, 
the authors noted that ``[t]he abrupt discontinuation of high-dose 
carisoprodol may result in withdrawal symptoms including anxiety, 
psychosis, tremors, myoclonus, ataxia, and seizures.'' Id. The authors 
also opined that ``[t]his withdrawal syndrome is likely under-
recognized.'' Id.
    Regarding the individual case reports, Dr. Jasinski opined that 
care should be taken in evaluating the significance of them because the 
subjects may have taken the drug for therapeutic reasons ``or for non-
therapeutic uses unrelated to any abuse liability,'' such as to commit 
suicide. MX 172, at 9. Dr. Jasinski further opined that the individual 
case reports should be considered in light of the facts that ``all 
drugs produce untoward effects if taken at doses significantly above 
the recommended therapeutic dose,'' that a patient's having anxiety 
upon discontinuation of carisoprodol ``could very well be a function of 
the interruption of effective treatment of their discomfort or pain,'' 
or that the ``the untoward effect reported with carisoprodol'' could 
``have been caused by other substances which the patient was'' taking 
concurrently. Id. at 9-10.
    As for Dr. Jasinski's suggestion that individual case reports 
should be given less weight because the patient may have taken the drug 
for therapeutic reasons, whether a patient initially took a drug to 
treat a legitimate medical condition is not relevant in assessing 
whether the drug causes dependence. Indeed, many patients who have 
become addicted to controlled substances started taking them to treat a 
legitimate medical condition.\40\
---------------------------------------------------------------------------

    \40\ As for Dr. Jasinski's contention that the individual case 
reports should be given less weight because the person may have 
taken carisoprodol to commit suicide, I need not decide whether such 
evidence is probative of whether a drug has dependence liability. 
However, as explained above, the Senate Report expressly stated that 
the Agency can consider such evidence ``as indicative of a drug's 
potential for abuse.'' S. Rep. 91-6134, reprinted in 1970 
U.S.C.C.A.N., at 4602.
---------------------------------------------------------------------------

    Moreover, while it is undoubtedly true that all drugs have 
``untoward effects if taken at doses significantly above the 
recommended therapeutic dose,'' the evidence establishes that patients 
engage in drug-seeking behavior and that the abrupt withdrawal of 
carisoprodol produces a withdrawal syndrome that includes a variety of 
symptoms such as anxiety, insomnia, irritability, tremors, and muscle 
pain. Contrary to Dr. Jasinski's contention that the anxiety 
experienced by these patients may have been caused by the interruption 
of effective treatment of their pain and may not be ``evidence of any 
physical dependence,'' the symptoms which have been documented upon the 
abrupt cessation of the drug are far more extensive than anxiety.

    Furthermore, several of the case reports involved patients who had 
taken carisoprodol for extensive periods. The prescribing information 
for carisoprodol states, however, that the drug ``should only be used 
for short periods (up to two or three weeks) because adequate evidence 
of effectiveness for more prolonged use has not been established.'' MX 
6, at 2. Thus, it does not seem likely that the patients' reported 
anxiety upon the cessation of the drug was due to ``the interruption of 
effective treatment of their discomfort or pain.'' MX 172, at 10.\41\
---------------------------------------------------------------------------

    \41\ As for the contention that in two of the case reports, 
``the untoward effect reported with carisoprodol would appear to 
have been caused by other substances the patient had taken 
concurrently,'' Dr. Jasinski identified these reports only by their 
exhibit numbers and the publication they appeared in. See MX at 172, 
at 10 (citing MXs 110 & 161). However, neither of these exhibits was 
entered into evidence. I thus cannot evaluate the validity of Dr. 
Jasinski's contention.
---------------------------------------------------------------------------

    Finally, in October 2009, based on new safety information, the FDA 
required that Meda make several changes to the approved label. The 
first of these involved the insertion of a sentence into section 5.2 
(entitled ``Drug Dependence, Withdrawal, and Abuse'') that ``there have 
been post-marketing-adverse event reports of SOMA associated abuse when 
used without other drugs with abuse potential.'' MX 30, at 5. Thus, 
this section of the label now states:

    In the postmarketing experience with SOMA, cases of dependence, 
withdrawal, and abuse have been reported with prolonged use. Most 
cases of dependence, withdrawal, and abuse occurred in patients who 
have had a history of addiction or who used SOMA in combination with 
other drugs with abuse potential. However, there have been post-
marketing-adverse event reports of SOMA associated abuse when used 
without other drugs with abuse potential. Withdrawal symptoms have 
been reported following abrupt cessation after prolonged use. To 
reduce the chance of SOMA dependence, withdrawal, or abuse, SOMA 
should be used with caution in addiction-prone patients and in 
patients taking other CNS depressants including alcohol, and SOMA 
should not be used more than two to three weeks for the relief of 
acute musculoskeletal discomfort.
    Soma, and one of its metabolites, meprobamate (a controlled 
substance), may cause dependence.

MX 6, at 2.\42\ The FDA also required that Meda change the label to 
include the following statement:

    \42\ With the exception of the third sentence (``However, there 
have been post-marketing adverse reports of SOMA-associated abuse 
when used without other drugs with abuse potential.]''), this 
portion of the label repeats verbatim the 2007 label. See MX 25, at 
5.
---------------------------------------------------------------------------

    SOMA is not a controlled substance * * *.
    Discontinuation of carisoprodol in animals or in humans after 
chronic administration can produce withdrawal signs, and there are 
published case reports of human carisoprodol dependence.
    In vitro studies demonstrate that carisoprodol elicits 
barbiturate-like effects. Animal behavior studies indicate that 
carisoprodol produces rewarding effects. Monkeys self administer 
carisoprodol. Drug discrimination studies using rats indicate that 
carisoprodol has positive reinforcing and discriminative effects 
similar to barbital, meprobamate, and chlordiazepoxide.

    See MX 30, at 8; MX 6, at 3. While Meda initially objected to the 
proposed changes, it eventually agreed to them. MX 30, at 1.

    I therefore conclude that substantial evidence supports a finding 
that carisoprodol has dependence liability similar to that of barbital, 
a schedule IV CNS depressant.

Factor 8--Whether the Substance Is an Immediate Precursor of a 
Substance Already Controlled

    Carisoprodol metabolizes to meprobamate, a schedule IV controlled 
substance. However, the FDA found that carisoprodol is not an immediate 
precursor of meprobamate or any other controlled substance. GX 6, at 
26.

Conclusions of Law

    Under 21 U.S.C. 811(a)(1)(a), to ``add'' a drug to one of the 
schedules of controlled substances, the Agency must first find that 
carisoprodol ``has a potential for abuse.'' If such a finding is 
supported by the record, the Agency must then make the ``findings 
prescribed by subsection 812 of this title for the schedule in which 
such drug is to be placed.'' 21 U.S.C.811(a)(1)(B). Having considered 
all eight of the section 811(c) factors, I conclude that a 
preponderance of the evidence supports the conclusion that carisoprodol 
``has a potential for abuse'' such as to warrant control and that it 
should be placed in schedule IV.

The Section 811(a)(1)(a) Finding--Carisoprodol Has A Potential for 
Abuse

    A preponderance of the evidence supports the conclusion that 
carisoprodol has a potential for abuse, and indeed, is being widely 
abused.\43\

[[Page 77355]]

The NSDUH data establish that a large number of persons are taking 
carisoprodol on their own initiative rather than on the basis of a 
physician's recommendation. The NSDUH data--which Meda's Expert 
acknowledged was generally reliable--consistently show that between 2.5 
and 2.8 million persons have used carisoprodol for non-medical reasons, 
including approximately 1 million 18-25 year olds, and more than 
100,000 12-17 year olds. As explained above, given the magnitude of the 
nonmedical use of carisoprodol, the Agency is not required to show that 
the rate of abuse is increasing in order to support a finding that the 
drug has a potential for abuse such as to warrant control.\44\
---------------------------------------------------------------------------

    \43\ In both its brief and its exceptions, Meda notes that ``DEA 
did not present any witnesses from FDA to justify their findings or 
* * * provide [it with] an opportunity * * * to challenges the bases 
for such witnesses' findings.'' Meda's Exceptions at 1. It further 
argues that it has been denied a meaningful hearing because it 
``never had an opportunity to challenge the medical and scientific 
findings that formed the basis of the scheduling determination.'' 
Id. at 2. See also Meda. Br. at 22. (``DEA counsel did not call any 
HHS or FDA witness to testify and justify the scientific, medical, 
and legal basis underlying the HHS recommendations. No FDA or HHS 
witness was made available to answer questions about the numerous 
weaknesses in the data cited [by the FDA], or otherwise explain the 
FDA analysis and conclusions.'').
    As explained above, many of HHS's findings were based on 
published articles, and Meda raises no contention that any 
unpublished articles cited by HHS were not provided to it. Meda does 
not explain why additional testimony was required to explain the 
contents of the articles. Moreover, Meda's Experts testified as to 
various issues with both the Government's data sources and the FDA's 
reliance on several articles. In addition, Meda does not contend 
that it sought (and was denied) a subpoena to require the testimony 
of any FDA employees who were involved in preparing the report. I 
thus reject Meda's contention.
    \44\ In its brief, Meda also cites to admittedly anecdotal 
evidence that an analysis by RADARS of Web site postings in Erowid, 
``an online member-supported organization where individuals 
anonymously post [their] experiences with psychoactive substances, 
including prescription drugs,'' and that Skelaxin, another muscle 
relaxant, ``was among the ten most frequently mentioned prescription 
drugs [but] carisoprodol was not.'' Meda Br. 35. Contrary to Meda's 
understanding, whether Skelaxin is being abused more often than 
carisoprodol is irrelevant in assessing whether the latter has ``a 
potential for abuse'' and warrants control. 21 U.S.C. 811(a). It is 
further noted that while Meda cites the RADARS analysis as an 
exhibit, see Meda Br. 97 (citing Meda Exh. 15), the record does not 
contain this exhibit.
---------------------------------------------------------------------------

    In addition, the evidence shows that individuals are taking 
carisoprodol in amounts sufficient to create a hazard to the health and 
safety of both themselves and others. Notwithstanding the criticism of 
the DAWN data, the estimates as to the number of emergency room visits 
related to carisoprodol are comparable to those for diazepam, a 
schedule IV controlled substance.
    Next, data obtained from the Florida Medical Examiners Commission 
for the years 2004 through 2008, establish that carisoprodol (or its 
metabolite meprobamate) was the cause of death in between 74 and 96 
cases each year. It bears noting that this is but one State's data.
    Also, NPDS data for the years 2006 and 2007 show that carisoprodol 
(as a sole drug) has been involved in more than 3500 toxic exposures 
cases. Of these, between 2687 and 2821 cases were serious enough to 
require treatment in a health care facility, and in more than 100 
cases, the patient had life-threatening symptoms or a significant 
residual disability.
    Finally, while Meda notes that data from the FDA AERS system show 
that, between January 1979 and May 2001, ``only 83 reports'' have 
``included the terms abuse, dependency, or withdrawal,'' and that this 
must be compared with the total number of carisoprodol prescriptions, 
these data are compiled from reports which have been voluntarily 
submitted by consumers and health care professionals. Thus, these data 
likely substantially underreport the number of such incidents.
    The evidence further shows that there is significant diversion of 
carisoprodol from legitimate channels. First, NFLIS data show that 
carisoprodol has consistently ranked among the top twenty-five drugs 
which have been analyzed and identified by forensic laboratories 
following seizures which occurred during the course of criminal 
investigations. Moreover, because carisoprodol is controlled in only 
seventeen States, which comprise approximately thirty-five percent of 
the United States' population, and as Meda's expert recognized, the 
likelihood of a sample ``being analyzed is substantially affected by 
the prosecutor's perceptions of the available criminal charges,'' it is 
likely that the NFLIS data substantially understate the extent to which 
carisoprodol is being found during criminal investigations.
    Of particular significance, the testimonies of the DEA Deputy 
Assistant Administrator; a Tennessee Bureau of Investigation Special 
Agent in Charge, who was the former Coordinator of the Tennessee Drug 
Diversion Task Force; and the Executive Director of the Ohio State 
Board of Pharmacy; provide substantial evidence that carisoprodol is 
being unlawfully distributed, typically with narcotics and 
benzodiazepines, and is being abused. These officials testified that 
carisoprodol is being distributed by: (1) Internet pharmacies based on 
prescriptions issued by doctors who never see their patients; (2) 
doctors, who while they meet their patients, either perform no physical 
exam or a cursory physical examination; and (3) street dealing. The 
Executive Director of the Ohio Board also testified to data obtained 
through the Board's prescription monitoring program showing that 
persons are engaging in doctor shopping to obtain large quantities of 
the drug. The officials also testified to the practice of drug abusers 
using carisoprodol as part of a cocktail which includes narcotics (such 
as oxycodone and hydrocodone) and benzodiazepines.
    While carisoprodol is indicated for only short-term use of up to 
two to three weeks, prescription data for a recent five-year period 
show that more than 25 percent of patients used the drug for more than 
one month and 4.3 percent used the drug for more than 360 days. 
Similarly, Bramness, who studied carisoprodol use and abuse in Norway 
(where the drug is only approved for use of up to one week) during 
2004, found that 8 percent of the patients who obtained the drug were 
also abusing benzodiazepines and 14 percent of the patients were also 
abusing opioids. Moreover, while those patients who were using 
carisoprodol for therapeutic purposes received only 12 percent of the 
carisoprodol which was dispensed, the opioid abusers received 48 
percent. Of further note, 14 percent of the patients had received an 
amount of the drug equal to 75 daily doses or more.
    While Meda cites both the Fraser study (in particular, the third 
arm) and its recent clinical trials, both items of evidence suffer from 
significant limitations and are of limited probative value. As noted 
above, the third arm of the Fraser study, involved only five patients 
(only one of whom received the drug for 54 days), and Meda's recent 
clinical trials involved only short term use at therapeutic levels. 
Accordingly, I conclude that the record as a whole establishes that 
carisoprodol has a potential for abuse (and is being abused at such a 
level) as to warrant control. See 21 U.S.C. 811(a)(1).

The Section 812(b) Placement Findings

    The FDA recommended that carisoprodol be placed in schedule IV. 
Under 21 U.S.C. 812(b), the Attorney General is required to make the 
following findings to do so.\45\ These are:

    \45\ While Meda challenged the Government's (and FDA's) finding 
that carisoprodol has a potential for abuse such as to warrant 
control, it did not challenge the FDA's placement findings. See 
Meda's Br. at 111-14.

    (A) The drug * * * has a low potential for abuse relative to the 
drugs or other substances in schedule III.

[[Page 77356]]

    (B) The drug * * * has a currently accepted medical use in 
treatment in the United States.
    (C) Abuse of the drug * * * may lead to limited physical 
dependence or psychological dependence relative to the drugs or 
other substances in schedule III.

21 U.S.C. 812(b)(4).

    It is undisputed that carisoprodol has a currently accepted medical 
use in treatment in the United States and is FDA-approved for the 
relief of discomfort associated with acute, painful musculoskeletal 
conditions. GX 6, at 26.
    The FDA further found that carisoprodol has a low potential for 
abuse relative to schedule III controlled substances. Id. FDA found 
that carisoprodol is a CNS (central nervous system) depressant and that 
it is abused primarily in combination with other drugs of abuse 
including opioids and benzodiazepines, cocaine, and marijuana. Id. 
Carisoprodol metabolizes into meprobamate, a schedule IV controlled 
substance. Based on the DAWN ED estimates, FDA calculated an abuse 
frequency which suggests that carisoprodol is being abused at a rate 
similar to that of diazepam, a schedule IV controlled substance. See 21 
CFR 1308.14(c). In vitro studies demonstrate that carisoprodol has an 
affinity for the GABA[alpha] receptor and elicits barbiturate-like 
effects. Likewise, in a drug-discrimination study, carisoprodol was 
completely effective in preventing abstinence syndrome in dogs tolerant 
and dependent on barbital, a schedule IV controlled substance. In a 
study involving rats trained to discriminate carisoprodol, various 
controlled substances including meprobamate, pentobarbital (C-II/C-
III), and chlordiazepoxide (C-IV), substituted fully for the 
discriminative stimulus effects of carisoprodol. In a further study, 
bemegride, a barbiturate antagonist, antagonized the discriminative 
stimulus effect of carisoprodol in rats trained to discriminate the 
drug. While Meda's Expert opined that these studies do not establish 
carisoprodol's abuse liability,\46\ he acknowledged that they do 
indicate that carisoprodol may have effects similar to those of 
barbiturates.
---------------------------------------------------------------------------

    \46\ As found above, the record as a whole establishes that 
carisoprodol has a potential for abuse and is being abused. I note 
Dr. Jasinski's testimony that the animal studies do not establish 
carisoprodol's abuse liability only to provide context to his 
acknowledgement that the animal studies indicate that carisoprodol 
may have effects similar to those of barbiturates.
---------------------------------------------------------------------------

    In addition, several human studies establish that carisoprodol has 
effects similar to that of CNS depressants. Most significantly, 
Bramness, et al., found that the clinical effects of carisoprodol 
resemble those of benzodiazepines, which are schedule IV controlled 
substances. I therefore hold that substantial evidence supports the 
FDA's conclusion that carisoprodol has a low potential for abuse 
relative to the drugs or other substances in schedule III. See 
Grinspoon, 828 F.2d at 894 (upholding Agency's reliance of on studies 
which suggested that MDMA was ``related in its effects to'' other 
schedule I and II controlled substances).
    Finally, the FDA concluded that the abuse of carisoprodol may lead 
to limited physical dependence or psychological dependence relative to 
the drugs or other substances in schedule III. GX 6, at 27. In support 
of its conclusion, the FDA noted that upon the withdrawal of barbital 
from dogs dependent on it, carisoprodol prevents the abstinence 
syndrome. Id. FDA also cited case studies which show that carisoprodol 
causes psychological or physical dependence and that ``carisoprodol 
produces a withdrawal syndrome characterized by clinical depression, 
anxiety, drug craving, irritability and poor concentration.'' Id.
    The record contains substantial evidence to support the FDA's 
conclusion. Meda cites both the Fraser study and its recent clinical 
trials as evidence that carisoprodol does not cause dependence. 
However, the Fraser study expressly noted that ``it remains to be seen 
whether administering carisoprodol continuously in larger doses would 
induce'' a barbiturate-like withdrawal pattern upon discontinuation of 
the drug. Likewise, Meda's clinical trials involved administration of 
the drug for no more than two-weeks and at therapeutic levels. 
Moreover, Meda eventually agreed to change the drug label to reflect 
that ``cases of dependence [and] withdrawal * * * have been reported 
with prolonged use.'' MX 6, at 2.
    A case study by Reeves found that when a 43-year-old male, who had 
taken large doses for several weeks, stopped taking carisoprodol, he 
developed anxiety, tremors, muscle twitching, insomnia, auditory and 
visual hallucinations and engaged in bizarre behavior. In a study of 
nine male prisoners who had been taking carisoprodol in doses of 700 to 
2100 mg for at least nine months, Wyller found that when the drug was 
gradually withdrawn over a two-week period, most of the patients 
reported mental distress including anxiety, insomnia, and irritability; 
cranial and muscular pain, as well as vegetative symptoms, were also 
frequently reported. Rohatgi reported the case of a 46-year old male 
who purchased carisoprodol over the internet and self-medicated to 
treat his anxiety after his physician stopped his narcotic 
prescriptions. Upon the patient's admission to a treatment center and 
being withdrawn from the drug, the patient exhibited heart 
palpitations, diaphoresis, chills, stomach cramps, nausea, insomnia, 
restlessness, myalgias, arthralgias, tremors, diarrhea, severe 
psychomotor agitation, feelings of depersonalization, and anxiety with 
suicidal ideation. The FDA also cited five other published studies 
which evidence that persons taking carisoprodol can become physically 
dependent and engage in drug-seeking behavior.
    Finally, a case study published by physicians at the Mayo Clinic 
subsequent to the FDA's report documented the presence of withdrawal 
symptoms in a 51-year old man who had taken up to 8400 mg per day 
before he exhausted his supply (which he obtained from both his 
physician and the internet). Upon his admission, the patient ``was 
anxious, distractable, [and] disoriented,'' and exhibited ``[a] high 
frequency, postural, and kinetic tremor in [his] extremities.'' The 
patient was placed on a tapering schedule, but on the third day, his 
``tremor, agitation and confusion worsened, and he experienced visual 
hallucinations and myoclonic jerks in the extremities.'' While the 
doctors were able to successfully taper the patient off of the drug, 
they concluded that ``[t]he abrupt discontinuation of high-dose 
carisoprodol may result in withdrawal symptoms including anxiety, 
psychosis, tremors, myoclonus, ataxia, and seizures.''
    In its Exceptions, Meda argues that the ALJ unfairly and 
unjustifiably relied on this study, which the Government introduced to 
rebut Dr. Jasinski's testimony. Exceptions at 2-3. Meda objects that 
the document was offered after the ALJ had excused the last witness, 
thereby depriving it ``of any opportunity to subject the document to 
expert scrutiny.'' Id. at 2. Meda also objects that the ALJ gave this 
report ``significant weight'' and ``incorrectly elevated [it] to that 
of a `study.' '' Id. (citing ALJ 34, 85).
    However, Dr. Jasinski acknowledged that abuse of carisoprodol over 
a prolonged period could lead to limited physical or psychological 
dependence. Tr. 706-07. While Dr. Jasinski further maintained that this 
was ``not the specific issue'' and that ``[t]he specific issue [is 
whether abuse] would lead to drug seeking or * * * to a severe 
withdrawal syndrome,'' id., his view of

[[Page 77357]]

the statute is mistaken. Under subsection 812(b), a finding that abuse 
of a drug ``may lead to severe psychological or physical dependence'' 
is only required if the drug is to be placed in schedule II. 21 U.S.C. 
812(b)(2)(C). By contrast, to place a drug in schedule IV, the 
necessary finding requires only that abuse of the drug ``may lead to 
limited physical dependence or psychological dependence relative to the 
drugs * * * in schedule III.'' Id. 812(b)(4)(C).
    Even if--given Dr. Jasinski's acknowledgment that abuse of 
carisoprodol may lead to limited physical or psychological dependence--
the article does not constitute valid rebuttal, Meda cannot claim that 
its admission to the record was prejudicial. The article (which had not 
been published at the time the parties exchanged their pre-hearing 
statements) is consistent with other case studies which Dr. Jasinski 
had ample opportunity to criticize and was therefore cumulative. While 
the ALJ did mischaracterize the report as the ``Mayo Clinic data,'' ALJ 
at 101, it is just one of several clinical reports/case studies that 
supports the conclusion that prolonged abuse of carisoprodol may lead 
to limited physical or psychological dependence, as Dr. Jasinski 
acknowledged. I thus find that the abuse of carisoprodol ``may lead to 
limited physical dependence or psychological dependence relative to the 
drugs or other substances in schedule III.'' 21 U.S.C. 812(b)(4)(C). 
Accordingly, I further find that substantial evidence supports the 
FDA's recommendation that carisoprodol be placed in schedule IV.

Regulatory Requirements

    Effective January 11, 2012, \47\ carisoprodol will be placed in 
schedule IV of the Controlled Substances Act. Thereafter, any person 
who engages in the manufacture, distribution, dispensing, importing, 
exporting, as well as any person who possesses the drug will be subject 
to the provisions of the Act and DEA regulations, including the Act's 
administrative, civil, and criminal sanctions which are applicable to 
schedule IV controlled substances. These include the following:
---------------------------------------------------------------------------

    \47\ I have considered the comments of the Healthcare 
Distribution Management Association in setting the effective dates 
with respect to each of the various requirements.
---------------------------------------------------------------------------

    Registration. Any person who manufactures, distributes, dispenses, 
imports, exports, engages in research or conducts instructional 
activities or chemical analysis with carisoprodol, must be registered 
to conduct such activities in accordance with 21 CFR part 1301. Any 
person who is currently engaged in any of the above activities must 
submit an application for registration by January 11, 2012 and may 
continue their activities until DEA has approved or denied that 
application.
    Disposal of Stocks. Any person who elects not to obtain a schedule 
IV registration, or who is not entitled to such registration, must 
surrender all quantities of currently held carisoprodol in accordance 
with the procedures of 21 CFR 1307.21, on or before January 11, 2012, 
or may transfer all quantities of currently held carisoprodol to a 
person registered under the CSA and authorized to possess schedule IV 
controlled substances, on or before January 11, 2012. Any carisoprodol 
surrendered to DEA must be listed on a DEA Form 41, ``Inventory of 
Controlled Substances Surrendered for Destruction.'' DEA Form 41 may be 
obtained at http://www.deadiversion.usdoj.gov/21cfr_reports/surrend/, 
or from the nearest DEA office.
    Security. Carisoprodol will be subject to the security requirements 
applicable to controlled substances in schedules III through V 
including 21 CFR 1301.71, 1301.72(b), (c), and (d), 1301.73, 1301.74, 
1301.75(b) and (c), 1301.76, and 1301.77. The requirements of 21 CFR 
1301.71, 1301.72(d), 1301.74, 1301.75(b) and (c), and 1301.76 shall be 
applicable to carisoprodol January 11, 2012. The requirements of 21 CFR 
1301.72(b) and (c), 1301.73, and 1301.77 shall be applicable to 
carisoprodol April 10, 2012.
    Labelling and Packaging. All commercial containers of carisoprodol 
that are packaged on or after April 10, 2012 shall be labeled as C-IV 
and packaged in accordance with 21 CFR 1302.03-1302.07. Commercial 
container packaged before April 10, 2012 and not meeting the 
requirement of 21 CFR 1302.03-1302.07 may be distributed until June 11, 
2012. On or after June 11, 2012 all commercial containers of 
carisoprodol must be labeled as C-IV and comply with 21 CFR 1302.03-
1302.07.
    Inventory. Pursuant to 21 CFR 1304.03, 1304.04, and 1304.11, every 
registrant who is required to keep records and who possesses any 
quantity of carisoprodol shall take an initial inventory of all stocks 
of carisoprodol on hand on or before January 11, 2012. Thereafter, 
carisoprodol shall be included in each inventory made by the registrant 
pursuant to 21 CFR 1304.11(c).
    Records. All registrants are required to keep records pursuant to 
21 CFR 1304.03, 1304.04, 1304.21, 1304.22, and 1304.23, after January 
11, 2012.
    Prescriptions. All prescriptions for carisoprodol or prescriptions 
for products which contain carisoprodol shall comply with 21 CFR 
1306.03-1306.06, 1306.21, and 1306.22-1306.27, after January 11, 2012.
    Importation and Exportation. All importation and exportation of 
carisoprodol is subject to 21 CFR part 1312, after January 11, 2012.
    Criminal Liability. Any activity with carisoprodol not authorized 
by, or conducted in violation of, the Controlled Substances Act or the 
Controlled Substances Import and Export Act, occurring on or after 
January 11, 2012 is unlawful.

Regulatory Analyses

Executive Orders 12866 and 13563

    In accordance with 21 U.S.C. 811(a), this scheduling action is 
subject to formal rulemaking procedures done ``on the record after 
opportunity for a hearing,'' which are conducted pursuant to the 
provisions of 5 U.S.C. 556 and 557. The CSA sets forth the criteria for 
scheduling a drug or other substance. Such actions are exempt from 
review by the Office of Management and Budget pursuant to Section 
3(d)(1) of Executive Order 12866 and the principles reaffirmed in 
Executive Order 13563.

Regulatory Flexibility Act

    The Administrator hereby certifies that this rulemaking has been 
drafted in accordance with the Regulatory Flexibility Act (5 U.S.C. 
601-612), has reviewed this regulation, and by approving it certifies 
that this regulation will not have a significant economic impact on a 
substantial number of small entities.
    In considering the economic impact on small entities, the first 
question is whether a substantial number of small entities are 
affected. In this instance, the entities affected are those now selling 
carisoprodol-containing products that do not hold a DEA registration. 
DEA identified 22 firms that are manufacturing carisoprodol-containing 
products. 74 FR at 59111. Fifteen of these firms hold DEA 
registrations, leaving seven firms that sell carisoprodol and do not 
hold a registration. DEA has no information on the number of non-
registrants engaged in the distribution or importation of carisoprodol, 
but there is reason to believe that the number of such firms is well in 
excess of the seven already identified. The Small Business

[[Page 77358]]

Administration size standard for a small wholesaler of drugs is 100 
employees. It is clearly possible to operate a drug distribution firm 
with fewer than 100 employees. Therefore, a substantial number of small 
entities will be affected by this rule.
    The economic impact on non-registrants now selling carisoprodol 
will occur in two ways: The cost of registration and the cost of 
meeting the security requirements in 21 CFR part 1301. There is also a 
potential economic impact on those firms that do not currently 
distribute carisoprodol but which might wish to enter the market.
    The annual registration fee for a distributor, importer, or 
exporter is $1,147. There is some uncertainty in estimating the cost of 
meeting the security requirements, because most non-registrants already 
meet the security requirements, at least in part, for schedule III and 
IV substances. A conservative estimate assumes that every non-
registrant will have to buy a safe to store carisoprodol. A safe with a 
capacity of 13.5 cubic feet should be adequate and may be purchased for 
approximately $1,350, which, when annualized over 15 years at 7.0 
percent, results in a cost of $148 per year. Therefore, the total 
annual cost of compliance with this rule is $1,295.
    The usual standard for a significant economic impact is 1.0 percent 
of revenue. For $1,295 per year to be a significant economic impact, a 
firm's annual revenue would have to be less than $130,000. Any firm in 
the drug distribution business would need annual revenue well in excess 
of this amount to sustain itself.
    It is acknowledged that, for a small firm, there may be some 
inconvenience and expense in preparing the necessary forms to obtain 
and renew a registration. These are minor costs. There are also 
recordkeeping requirements, but these will impose little or no 
incremental cost for a firm that is already maintaining the records 
needed for a wholesale business. Accordingly, the costs of registration 
and the security requirements will not cause a significant economic 
impact.
    If a firm chooses not to register and to drop its carisoprodol 
line, the cost to the firm would exceed its earnings on its 
carisoprodol sales. The firm may also lose some customers who do not 
want to buy from a distributor that does not carry carisoprodol. A 
competent manager will recognize this cost, and in light of the small 
cost of registering, would presumably choose to drop carisoprodol from 
the firm's product line only if the firm was earning a negligible 
profit from its carisoprodol sales and dropping the product would not 
result in the loss of significant customers. Accordingly, DEA finds 
that this rule will not have a significant economic impact on a 
substantial number of small entities.\48\
---------------------------------------------------------------------------

    \48\ In the Notice of Proposed Rulemaking, DEA noted that it had 
no information regarding the number of persons who may distribute 
carisoprodol-contain products, but who do not manufacture, package, 
repackage, or relabel these products and sought comments from any 
entities that might be affected by this action. See 74 FR 59111. No 
commenter provided such information.

Executive Order 12988

    This 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 rulemaking does not preempt or modify any provision of state 
law or impose enforcement responsibilities on any state or 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.

Executive Order 13175

    This rule will not have tribal implications and will not impose 
substantial direct compliance costs on Indian tribal governments.

Paperwork Reduction Act of 1995

    This action does not impose a new collection of information under 
the Paperwork Reduction Act of 1995, 44 U.S.C. 3501-3521.

Unfunded Mandates Reform Act of 1995

    This rule will not result in the expenditure by state, local, and 
tribal governments, in the aggregate, or by the private sector, of 
$136,000,000 or more (adjusted for inflation) 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.

Congressional Review Act

    This rule is not a major rule as defined by section 804 of the 
Small Business Regulatory Enforcement Fairness Act of 1996 
(Congressional Review Act). 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, 
Reporting and recordkeeping requirements. 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 Drug Enforcement Administration pursuant to 28 CFR 
0.100, 21 CFR part 1308 is amended to read as follows:

PART 1308--SCHEDULES OF CONTROLLED SUBSTANCES

0
1. The authority citation for part 1308 continues to read as follows:

    Authority:  21 U.S.C. 811, 812, 871(b), unless otherwise noted.


0
2. Section 1308.14 is amended by redesignating paragraphs (c)(5) 
through (c)(52) as paragraphs (c)(6) through (c)(53) and adding a new 
paragraph (c)(5) to read as follows:


Sec.  1308.14  Schedule IV.

* * * * *
    (c) * * *
    (5) Carisoprodol .......8192
* * * * *

    Dated: November 18, 2011.
Michele M. Leonhart,
Administrator.

    Note: The following appendixes will not publish in the Code of 
Federal Regulations.

APPENDIX A

    States in Which Carisoprodol Is a Controlled Substance and Their
                               Population
------------------------------------------------------------------------
                         State                              Population
------------------------------------------------------------------------
Oklahoma...............................................        3,751,351
Hawaii.................................................        1,360,301
Kentucky...............................................        4,339,367
New Mexico.............................................        2,059,179
Oregon.................................................        3,831,074
Georgia................................................        9,687,653
Arkansas...............................................        2,915,918
Alabama................................................        4,779,736
West Virginia..........................................        1,852,994
Florida................................................       18,801,310
Arizona................................................        6,392,017
Indiana................................................        6,483,802
Nevada.................................................        2,700,551
Louisiana..............................................        4,533,372
Texas..................................................       25,145,561
Utah...................................................        2,763,885
Washington.............................................        6,724,540
                                                        ----------------

[[Page 77359]]

 
    Total..............................................    * 108,122,611
------------------------------------------------------------------------
Total 2010 population = 307,006,556 (source www.uscensus2010data.com).
* 35.22% of total population of United States.

APPENDIX B

FDA References

(1) Berger FM, Kletzkin M, Ludwig BJ, Margolin S, Powell LS. Unusual 
muscle relaxant and analgesic properties of N-isopropyl-2-propyl-l, 
3-propanediol dicarbamate (carisoprodol). J Pharmacol Exp Ther, 
1959; 127:66-74.
(2) Elenbaas JK. Centrally acting oral skeletal muscle relaxants. Am 
J Hosp Pharm., 1980; 37:1313-23.
(3) Raines A. Centrally Acting Muscle Relaxants. In: Pradhan SN, 
Maickel RP, Dutta SN, eds. Pharmacology In Medicine: Principles and 
Practice. Maryland: SP Press International Inc; 1986: 184-89.
(4) Gatch, M. B., Taylor, C. M., and Forster, M. J. Test of 
substitution for the discriminative stimulus effects of carisoprodol 
with meprobamate, pentobarbital, chlordiazepoxide. 4-24-2006. NIDA 
Contract NO1DA-2-8822. Ref Type: Report
(5) Gatch, M. B., Taylor, C. M., and Forster, M. J. Test for 
antagonism of the discriminative stimulus effects of carisoprodol 
with bemegride. 8-7-2006. NIDA Contract N01DA-2-8822. Ref Type: 
Report
(6) Gatch, M. B., Taylor, C. M., and Forster, M. J. Test for 
inhibition of the discriminative stimulus effects of carisoprodol 
with cimetidine. 10-9-2006. NIDA Contract N01DA-2-8822. Ref Type: 
Report
(7) Cullen AP. Carisoprodol (Soma) in Acute Back Conditions--Double-
Blind, Randomized, Placebo-Controlled Study. Current Therapeutic 
Research-Clinical and Experimental. 1976; 20:557-62.
(8) Braestrup C, Squires RF. Pharmacological characterization of 
benzodiazepine receptors in the brain. Eur J Phannacol. 1978; 
48:263-70.
(9) Gonzalez, L. A., Gatch, M. B., Taylor, C.M., Bell-Homer, C. L., 
Dillon, G.H., and Forster, M. J. Abuse liability of carisoprodol: 
Barbiturate-like activity at GABAA receptors. CPPD Annual Meeting. 
Conference on Preclinical Abuse Liability Testing: Current Methods 
and Future Challenges, 30.2006. Ref Type: Conference Proceeding
(10) Berger FM, Kletzkin M, Ludwig BJ, Margolin S. The history, 
chemistry, and pharmacology of carisoprodol. Ann N Y Acad Sci. 1960; 
86:90-107.
(11) NPT toxicity studies of carisoprodol (CAS No. 78-44-4) 
administered by Gavage to 344/N rats and B6C3Fl mice. Toxic Rep Ser. 
2000; 1-GI4.
(12) Eddy NB, Friebel H, Hahn KJ, Halbach H. Codeine and its 
alternates for pain and cough relief. 2. Alternates for pain relief. 
Bull World Health Organ. 1969; 40:1-53.
(13) Beebe FA, Barkin RL, Barkin S. A clinical and pharmacologic 
review of skeletal muscle relaxants for musculoskeletal conditions. 
Am J Ther. 2005; 12:151-71.
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