77330 Federal Register / Vol. 76, No. 238 / Monday, December 12, 2011 / Rules and Regulations 

1None 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. 

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. 

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. 

Following pre-hearing procedures, an 

ALJ conducted a hearing on July 6, 8, 


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2While 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. 

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 § 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 eightythree 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 selfadministration, 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. 

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 


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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 


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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 


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3Compare 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’’). 

4At 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. 

5As 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-therecord 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. 

‘‘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. 

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-therecord 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-therecord hearing [would] serve[.]’’ 5

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 


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6Throughout 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. 

7Under 21 CFR 14.172, ‘‘[a]ny interested person 

may request, under § 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. 

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: 

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. 

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, 


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8Meda 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. 

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 

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. 

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


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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. 

10The 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. 

11According 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. 

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. 

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

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

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

TABLE 1—SELECTED PHARMACEUTICAL ED VISITS (NONMEDICAL USE): 2004–2007 FROM DAWN 

[Data output 08/02/2008] 

Selected drugs 

Estimates 

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 


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13According 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. 

14See Table 6 from the OSE ‘‘Duration of Use 

Analysis’’ for Soma (NDA 11–792) dated June 27, 

2007. 

By dividing the number of ED visits 

by the number of prescriptions, FDA 

calculated ‘‘abuse frequencies’’ for 

carisoprodol; cyclobenzaprine, a nonscheduled 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®: National, Years 2002–2007, Data Extracted April, 2008 File: VONA 2008–517 4– 

15 13

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 singledrug.5,055 21 Carisoprodol singledrug.3.870 27 Carisoprodol singledrug.1,185 12 

Carisoprodol multidrug.19,450 79 Carisprodol multi-drug 10,349 73 Carisoprodol multidrug.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. 

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 * * *. 


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15Mr. 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 

Continued 

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 FDAregulated 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 casefinding 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. 


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phenomenon among DAWN reporters either 

generally or with respect to carisoprodol. 16Mr. 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. 

17The 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. 

18Carisoprodol was scheduled as C–IV in Florida 

in July 2002, but was not tracked until 2003. GX 

6, at 18. 

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 selfreporting.’’ 16 Id. at 13. 

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

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/Guidance

ComplianceRegulatoryInformation/

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 

Year Drugs found in body Total 

occurrences 

Cause 

(% total) Present % Change from prior year 

2003 18 .......... Carisoprodol/Meprobamate ................................................... 208 45 (22) 163 ND 

2004 ............. Carisoprodol/Meprobamate ................................................... 289 81 (28) 208 39 

2005 ............. Carisoprodol/Meprobamate ................................................... 314 96 (31) 218 9 

2006 ............. Carisoprodol/Meprobamate ................................................... 313 74 (24) 239 ¥0.3 

2007 ............. Carisoprodol/Meprobamate ................................................... 337 88 (26) 249 8 

2008 ............. Carisoprodol/Meprobamate ................................................... 415 84 (20) 331 23 

Id.; see also GX 7, at 11. 

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 


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19Mr. 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. 

20As support for this assertion, Mr. Dasgupta 

cited the 2008 annual report (MX 63); however, the 

above tables do not include data for that year. 

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

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. 

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 


jlentini on DSK4TPTVN1PROD with RULES2
77342 Federal Register / Vol. 76, No. 238 / Monday, December 12, 2011 / Rules and Regulations 

21Participating state and local laboratories handle 

88% of the nation’s 1.2 million analyses of state and 

local drug cases. 

22Contrary 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. 

23Pursuant 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. 

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. 

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 statelevel 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. 

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. 

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 


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Federal Register / Vol. 76, No. 238 / Monday, December 12, 2011 / Rules and Regulations 77343 

24On 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. 

25The 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. 

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. 

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 nonmedical use of carisoprodol. This figure 

is more than eleven times the number of 

persons who have used meprobamate 

products for a non-medical purpose. 

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] 

Drugs 2004 

# (%) 

2005 

# (%) 

2006 

# (%) 

2007 

# (%) 

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 b) 13,172 (5.3) 

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® ..................................................................................................... 2,616 (1.1) 2,525 (1.0) 2,840 (1.2) 2,709 (1.1) 

Flexeril® ................................................................................................... 1,968 (0.8) 1,891 (0.8) 2,405 (1.0) 2,438 (1.0) 

1 Includes Equanil®, meprobamate, and Miltown®, 2 Includes Flexeril® and Soma®, bdifference 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 selfreporting 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 


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77344 Federal Register / Vol. 76, No. 238 / Monday, December 12, 2011 / Rules and Regulations 

27The complete list of FDA References 1–58 is 

attached as Appendix B. 

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. 

(FDA Reference 1).27 However, the 

specific mechanisms of action of 

carisoprodol are not completely 

understood (2, 3). 

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 placebocontrolled 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 [3H]- 

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 a1b2 GABAAR. 

GX 6, at 6. GABA-gated currents were 

potentiated by micromolar carisoprodol 

(EC50 = 89 mM)). Id. At millimolar 

concentrations, currents began to be 

inhibited, and rebound currents were 

apparent upon termination of drug 

administration. Id. 

According to FDA, this barbituratelike trend was consistent with a 

previous description of carisoprodol 

effects on human a1b2y2 GABAAR 

function, demonstrating that 

carisoprodol, like barbiturates, does not 

require the y subunit for its activity. Id. 

at 6–7. Carisoprodol directly activated 

human a1b2y2 GABAAR, producing 

inward currents in a concentrationdependent manner (EC50 = 410 mM). 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 GABAa 

receptor, this does not establish that 

carisoprodol has barbiturate-like 

activity, but merely that it, like many 

other drugs including other noncontrolled CNS depressants, has an 

affinity to attach to a GABAa 

receptor[].’’ Id. at 3. Dr. Jasinski then 

explained that ‘‘while barbiturates as a 

class have an affinity for GABAa 

receptors, not all drugs that have affinity 

for GABAa receptors have barbituratelike 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. 

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, prenarcotic 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 


jlentini on DSK4TPTVN1PROD with RULES2
Federal Register / Vol. 76, No. 238 / Monday, December 12, 2011 / Rules and Regulations 77345 

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. 

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 electrocortical 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. 

With respect to the selfadministration 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 


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30See current label information for carisoprodol 

(Soma) (http://www.fda∼gov/cder/foil1abe1l2007/ 

0_11792s0411bl.pdf). 

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). 

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. Anticholinergic 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 longterm 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 morphinestabilized 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 sedativelike effects, as opposed to opiate-like 

effects.’’ Id. 


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31While the patients ‘‘were unaware of the nature 

and schedule of medication,’’ the observers were 

not. Fraser, at 3. 

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.’’ 

Continued 

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. 

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 ‘‘barbituratelike 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


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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. 

33According 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. 

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 (lmethylethyl) 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 °C and it has low 

water solubility (30 mg/100 ml at 25 °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 mg/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 mg/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 


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34Where 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. 

35Nearly twice as many persons reported nonmedical use of carisoprodol than reported nonmedical use of cyclobenzaprine, another muscle 

relaxant which is unscheduled. GX 6, at 17. 

36The data for the years 2004 through 2008 show 

that carisoprodol was present in between 289 and 

415 cases each year. GX 6, at 18. 

Poison Centers’ data from 1998–2003, a 

rate similar to that reported in RADARS 

(27). 

rate similar to that reported in RADARS 

(27). 

TABLE 8—ESTIMATED NONMEDICAL-USE CARISOPRODOL ED VISITS FROM DAWN 2006 BY AGE AND MOST COMMON

DRUG COMBINATIONS 34

Carisoprodol 

Age 

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 

NSDUH data for the years 2004 

through 2007 show that in each year, 

more than 100,000 twelve to seventeenyear 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. 

TABLE 9—NSDUH—NONMEDICAL USE OF CARISOPRODOL (SOMA®) AND OTHER DRUGS IN LIFETIME, BY AGE GROUP

[Numbers in thousands (%), 2004–2007] 

Age Groups 2004 

#(%) 

2005 

#(%) 

2006 

#(%) 

2007 

#(%) 

Carisoprodol (Soma®) 

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®) 

Ages 12–17 .............................................................................................. 34a (0.1a) 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®) 

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 a) 2,252 (6.9) 

Ages 26 or Older ..................................................................................... 11,794 (6.4) 11,913 (6.4) 12,024 a (6.4 b) 10,606 (5.6) 

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® meprobamate, and Miltown®. 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. 

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. 


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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 postmarketing 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 postmarketing 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. 


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The human data showing abuse are 

reinforced by recent animal selfadministration 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 twentyseven 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 


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37According 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. 

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 yaminobutyric 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° 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 sixmonth 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 nonresponsive 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 mg/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. 

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 


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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. 

39According 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. 

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 ‘‘suboptimal 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

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 selfmedicated. 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 significantwithin-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. 

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 


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40As 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. 

41As 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. 

42With 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. 

43 In both its brief and its exceptions, Meda notes 

that ‘‘DEA did not present any witnesses from FDA 

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

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

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-marketingadverse 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 postmarketing-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: 

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


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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 membersupported 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. 

45While 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. 

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 nonmedical 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

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: 

(A) The drug * * * has a low potential for 

abuse relative to the drugs or other 

substances in schedule III. 


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46As 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. 

(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 

GABAa receptor and elicits barbituratelike effects. Likewise, in a drugdiscrimination 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. 

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 


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Federal Register / Vol. 76, No. 238 / Monday, December 12, 2011 / Rules and Regulations 77357 

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. 

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: 

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 


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77358 Federal Register / Vol. 76, No. 238 / Monday, December 12, 2011 / Rules and Regulations 

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. 

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 nonregistrants 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

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 foreignbased 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 

■ 1. The authority citation for part 1308 

continues to read as follows: 

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

unless otherwise noted. 

■ 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: 

§ 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 


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STATES IN WHICH CARISOPRODOL IS A

CONTROLLED SUBSTANCE AND

THEIR POPULATION—Continued 

State Population 

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 Nisopropyl-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. 

(14) Siddiqi M, Jennings CA. A near-fatal 

overdose of carisoprodol (SOMA): case 

report. J Toxicol Clin Toxicol. 2004; 

42:239–40. 

(15) Sikdar S, Basu D, Malhotra AK, Varma 

VK, Mattoo SK. Carisoprodol abuse: a 

report from India. Acta Psychiatr Scand. 

1993; 88:302–3. 

(16) Hussain H, Usman A, Butt M. 

Carisoprodol-induced amnestic state and 

nocturnal blackouts. Australian and New 

Zealand Journal of Psychiatry. 

2008;42:909–11. 

(17) Adams HR, Kerzee T, Morehead CD. 

Carisoprodol-related death in a child. J 

Forensic Sci. 1975; 20:200–202. 

(18) Green OI, Caravati EM. Coma in a 

toddler from low-dose carisoprodol. J 

Tox Clin Toxicol. 2001; 39:503. 

(19) Bramness JG, Morland J, Sorlid HK, 

Rudberg N, Jacobsen D. Carisoprodol 

intoxications and serotonergic features. 

Clin Toxicol (Phila). 2005; 43:39–45. 

(20) Goldberg D. Carisoprodol toxicity. Mil 

Med. 1969; 134:597–601. 

(21) Fraser HF, Essig CF, Wolbach Jr AB. 

Evaluation of Carisoprodol and 

Phenyramidol for Addictiveness. Bull on 

Narcotics. 1961; 1–5. 

(22) Backer RC, Zumwalt R, Mcfeeley P, 

Veasey S, Wohlenberg N. Carisoprodol 

concentrations from different anatomical 

sites: three overdose cases. J Anal 

Toxicol. 1990; 14:332–34. 

(23) Cravey RH, Jain NC. The identification 

of non-barbiturate hypnotics from 

biological specimens. J Chromatogr Sci. 

1974; 12:237–45. 

(24) Maes R, Hodnett N, Landesman H, 

Kananen G, Finkle B, Sunshine 1. The 

gas chromatographic determination of 

selected sedatives (ethchlorvynol, 

paraldehyde, meprobamate, and 

carisoprodol) in biological material. J 

Forensic Sci. 1969; 14:235–54. 

(25) Lillsunde P, Korte T. Comprehensive 

Drug Screening in Urine Using SolidPhase Extraction and Combined TIc and 

Gc/Ms Identification. Journal of 

Analytical Toxicology. 1991; 15:71–81. 

(26) Forrester MB. Carisoprodol abuse in 

Texas, 1998–2003. J Med Toxicol. 2006; 

2:8–13. 

(27) Senay, E. C., Geller, A., Woody, G., Dart, 

R., Hughes, A., and Smith, M. Y. Patterns 

of Abuse, Dependence and Misuse of 

Prescription Opioid Analgesics, 

Benzodiazepines and Carisoprodol in 

7792 Calls to Poison Control Centers 

(PCC) between 6/29/03 and 4/03/04. The 

College on Problems of Drug Dependence 

Conference. Orlando, FL. June, 2005. Ref 

Type: Abstract 

(28) Winek CL, Wahba WW, Balzer TW. Drug 

and chemical blood-level data 2001. 

Forensic Science International. 2001; 

122:107–23. 

(29) Druid H, Holmgren P. A compilation of 

fatal and control concentrations of drugs 

in postmortem femoral blood. Journal of 

Forensic Sciences. 1997; 42:79–87. 

(30) Chung H, Park M, Hahn E, Choi H, Lim 

M. Recent trends of drug abuse and drugassociated deaths in Korea. Ann NY 

Acad Sci, 2004; 1025:458–64. 

(31) Davis GG, Alexander CB. A review of 

carisoprodol deaths in Jefferson County, 

Alabama. South Med J. 1998; 91:726–30. 

(32) Baselt RC, Wright JA, Cravey RH. 

Therapeutic and toxic concentrations of 

more than 100 toxicologically significant 

drugs in blood, plasma, or serum: a 

tabulation. Clin Chem. 1975; 21:44–62. 

(33) Stead AH, Moffat AC. A collection of 

therapeutic, toxic and fatal blood drug 

concentrations in man. Hum Toxicol. 

1983; 2:437–64. 

(34) Hoiseth G, Bramness JG, Christophersen 

AS, Morland J. Carisoprodol 

intoxications: a retrospective study of 

forensic autopsy material from 1992– 

2003. Int J Legal Med. 007; 121:403–9. 

(35) Morse RM, Chua L. Carisoprodol 

dependence: a case report. Am I Drug 

Alcohol Abuse. 1918; 5:527–30. 

(36) Rust GS, Hatch R, Gums IG. Carisoprodol 

as a drug of abuse. Arch Fam Med. 1993; 

2:429–32. 

(37) Luehr JO, Meyerle KA, Larson EW. Mailorder (veterinary) drug dependence. 

JAMA. 1990; 263:657. 

(38) Littrell RA, Hayes LR, Stillner V. 

Carisoprodol (Soma): a new and cautious 

perspective on an old agent. South Med 

J. 1993; 86:753–56. 

(39) Elder NC. Abuse of skeletal muscle 

relaxants. Am Fam Physician. 1991; 

44:1223–26. 

(40) Reeves RR, Beddingfield Jl, Mack IE. 

Carisoprodol withdrawal syndrome. 

Pharmacotherapy, 2004; 24:1804–6. 

(41) Reeves RR, Ladner ME. Carisoprodol 

withdrawal syndrome misdiagnosed as a 

psychotic disorder. Ann Clin Psychiatry. 

2008; 20:173–74. 

(42) Reeves RR, Hammer JS, Pendarvis RO. Is 

the frequency of carisoprodol 

withdrawal syndrome increasing? 

Pharmacotherapy. 2007; 27:1462–66. 

(43) Roth BA, Vinson DR, Kim S. 

Carisoprodol-induced myoclonic 

encephalopathy. J Toxicol Clin Toxicol. 

1998; 36:609–12. 

(44) Isaac P., Janecek E. Abuse Detected by 

Pharmacists’ Hotline. Canadian 

Pharmaceutical Journal. 1995; 128:5. 

(45) Bramness JG, Fum K, Engeland A, 

Skurtveit S. Carisoprodol use and abuse 

in Norway. A pharmacoepidemiological 

study. Br J Clin Pharmacol. 2007. 

(46) Reeves RR, Carter AS, Pinkofsky HB, 

Struve FA, Bennett OM. Carisoprodol 

(soma): abuse potential and physician 

unawareness. J Addict Dis. 1999; 18:51– 

56. 

(47) Bailey ON, Briggs JR. Carisoprodol: an 

unrecognized drug of abuse. Am. Clin 

Pathol. 2002; 117:396–400. 

(48) Olsen H, Koppang E, Alvan G, Morland 

J. Carisoprodol elimination in humans. 

Ther Drug Monit. 1994; 16:337–40. 

(49) Littrell RA, Sage T, Miller W. 

Meprobamate dependence secondary to 


jlentini on DSK4TPTVN1PROD with RULES2
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carisoprodol (Soma) use. Am J Drug 

Alcohol Abuse. 1993; 19:133–34. 

(50) Logan BK, Case GA, Gordon AM. 

Carisoprodol, meprobamate, and driving 

impairment. J Forensic Sci. 2000; 

45:619–23. 

(51) Bramness JO, Skurtveit S, Morland J. 

Impairment due to intake of 

carisoprodol. Drug Alcohol Depend. 

2004; 74:311–18. 

(52) Jones W, Holmgren A, Kugelberg FC. 

Concentrations of Scheduled 

Prescription Drugs in Blood of Impaired 

Drivers: Considerations for Interpreting 

the Results. Ther Drug Monit. 2007; 

29:248–60. 

(53) Beers MH, Ouslander I, Reuben DB, 

Brooks J, Beck JC. Explicit criteria for 

determining inappropriate medication 

use in nursing home residents. UCLA 

Division of Geriatric Medicine. Arch 

Intern Med. 1991; 151:1825–32. 

(54) Aparasu RR, Fliginger SE. Inappropriate 

medication prescribing for the elderly by 

office-based physicians. Ann 

Pharmacother. 1997; 31:823–29. 

(55) Roberge RJ, Lin E, Krenzelok EP. 

Flumazenil reversal of carisoprodol 

(Soma) intoxication. J Emerg Med. 2000; 

18:61–64. 

(56) WylIer TB, Korsmo G, Gadeholt G. 

Dependence on carisoprodol (Somadril)? 

A prospective withdrawal study among 

prisoners. Tidsskr Nor Laegeforen. 1991; 

111:193–95. 

(57) Rohatgi G, Rissmiller OJ, Gorman JM. 

Treatment of carisoprodol dependence: a 

case report. J Psychiatr Pract. 2005; 

11:347–52. 

(58) Reeves RR, Possible dangerous 

interaction of oxycontin and 

carisoprodol. Am Fam Physician. 2003; 

67:941–42. 

(59) Heacock C, Bauer MS. Tolerance and 

dependence risk with the use of 

carisoprodol. Am Fam Physician. 2004; 

69:1622–23. 

[FR Doc. 2011–31542 Filed 12–9–11; 8:45 am] 

BILLING CODE 4410–09–P 


jlentini on DSK4TPTVN1PROD with RULES2