DEA/OD/ODE Page 1 of 18 11/3/2010 

### Propofol
Scheduling Review Document: Eight Factor Analysis

Drug and Chemical Evaluation Section, Office of Diversion Control, Drug Enforcement Administration

September 2010

Introduction
Propofol is a short

- acting intravenous (i.v.) sedative

- hypnotic used for the induction and maintenance of general anesthesia or sedation for medical procedures. On March 18, 2008, the Drug Enforcement Administration (DEA) received a petition requesting th at 21 CFR §1308.13 be amended so that propofol be controlled as a schedule III substance under the Controlled Substance s Act (CSA)

. The basis of the petition was the reports of increase d incidences of propofol abuse during the past decade. The petitioner stated as the main argument in support of the request was that

“ Propofol is the most common intravenous anesthetic in the United States today but over the course of the decade, documented cases of abuse have been steadily increasing over the past 10 years... Unfortunately, there is also a very high mortality rate (greater than 33%) associated with this abuse .” The petitioner cited a published article which indicated that a seven

- fold decrease in the abuse of propofol occurred when access to propofol was controlled in a secured facility by the hospital pharmacy. The petitioner stated that controlling propofol as a scheduled drug would require health care professionals to strictly monitor the access and use of propofol and possibly save lives.

Pursuant to 21 U.S.C. 811(a) and (b), DEA gathered and evaluated the available data on propofol and o n July 2, 2009, DEA requested that the Department of Health and Human Services (DHHS) provide a scientific and medical evaluation of the available information and a scheduling recommendation for propofol , i n accordance with 21 U.S.C. 811(b).

On May 14, 2010, pursuant to 21 U.S.C. 811(c), the Department of Health and Human Services (DHHS) provided to the DEA a scientific and medical evaluation entitled “Basis for the Recommendation for the Control of Propofo l and Its Salts in Schedule IV of the Controlled Substances Act ” a nd a scheduling recommendation (DHHS review, 2010). Following consideration of the eight factors and findings related to the substance’s abuse potential, legitimate medical use, and depende nce liability, DHHS recommended that propofol and its salts be controlled in s chedule IV of the CSA under 21 U.S.C. 812 (b).DEA/OD/ODE Page 2 of 18 11/3/2010

The CSA requires DEA to determine whether the DHHS’ scientific and medical evaluation and scheduling recommendation and all othe r relevant data constitute substantial evidence that the substance should be scheduled (21 U.S.C. 811(b)). This document contains an explanation of the relevant data that DEA considered. Pursuant to 21 U.S.C. 811(c), the Attorney General reviews the fact s and all relevant data. This document is a review of the relevant data, law enforcement information and a determination to place propofol and its salts into s chedule IV of the CSA.

Factor 1. Actual or Relative Potential for Abuse

Propofol was approved in 1989 under the commercial name Diprivan ® as an ultra

- short i.v. anesthetic. Diprivan ® is an injectable emulsion (10 mg/ m L ). There are three approved generic versions. Two veterinar y versions, Rapinovet and PropoF lo /PropoVet
, were approved for marketing in 1999 and 2000, respectively. Though propofol is not controlled under the CSA, the labels for its products include a section entitled Drug Abuse and Dependence due to the occurrences of diversion and abuse of propofol among health care professionals.

T he motivation for abuse of propofol is generally for its sedative and relaxing properties and induction of euphoric effects. There have also been reports that propofol’s ability to induce sexual illusions and disinhibition co ntributes to its appeal as a drug of abuse ( Brandner et al., 1997 ; Fritz and Niemczyk, 2002; Kranioti et al., 2007; Roussin et al., 2007 ). Anecdotal reports of propofol abuse rs describe their experiences as “pleasant,” “euphoric,” and “relaxing” (Wilson

e t al., 2010).
It has been shown that the risk of misusing or abusing drugs is higher among healthcare professionals compared to the general population. The major factor contributing to the increased risk of drug misuse or abuse among healthcare professi onals is th at they can eas ily access drugs which have significant abuse potential in medical facilities (Bell et al., 1999).
According to the DHHS review (2010)
, health care professionals who have access to propofol and are trained to administer i.v. drugs are at risk of abusing propofol. It has been shown that for many cases involving propofol abuse, the abuse was only detected upon the death of the abuser s . Th erefore, it can be assumed that there are more instances of propofol abuse than are being reported DHHS provided data from FDA’s Adverse Events Reporting System (AERS), and it was searched to identify domestic cases of abuse, dependence, and overdose asso ciated with propofol, from date of the drug approval to August 27, 2009. There were 26 cases of propofol diversion and abuse reported; ten of these cases resulted in death. In 25 of the cases (96%), the abusers were health care providers or in training to become a health care professional.DEA/OD/ODE Page 3 of 18 11/3/2010

In a survey of 126 acade mic anesthesiology programs, 18 percent reported diversion or abuse of propofol

. Of the 25 individuals reported to have abused propofol, seven (28 %) had died due to propofol abuse. The indiv iduals who died were affiliated with health care facilities in which there were no pharmacy or security mechanism s to control access to propofol (Wischmeyer et al., 2007)

.
In a study conducted by Bell et al.
, (1999), 2,500 actively practicing Certified Re gistered Nurse Anesthetists (CRNAs) were surveyed to determine the prevalence of misuse of controlled drugs and other licit drugs with drug abuse potential. Out of the 2,500 participants, 167 (11 percent) of the respondents indicated that they had a histo ry of or were currently misusing of controlled and non

- controlled substances. Propofol was reported to be the fourth most preferred drug to misuse among this population. The respondents indicated that they highly preferred propofol due to its easy access ibility and its non

- control status under the CSA
There have been published case reports of individuals who became depended on propofol. The reports indicated that the individuals expressed a “craving” for propofol, causing them to compulsively self

- inj ect daily

. They were abusing propofol for its relaxing and euphoric effects (Schneider et al., 2001; Soyka and Schutz, 1997 ; Bonnet et al., 2008; Follette and Farley, 1992; Fritz and Niemczyk, 2002 ).
Zacny et al. (1992) examined the effect of subanesthetic doses of propofol on mood, subjective effects, and psychomotor and physiological performance in healthy volunteers with a history of recreational drug use

. This was a prospective, randomized, placebo contro lled, and double blind study. Healthy volunteers ( n =10 ) were administered either a placebo (Intralipid ® )

or a loading dose of propofol and then infused with propofol at a given dose (0.5

– 2.0 mg/kg/hr) or placebo over a 20 min period. Each subject rece ived placebo, low dose propofol (0.08 mg/kg loading dose and 0.5mg/kg/h infusion), moderate dose propofol (0.16 mg/kg loading dose and 1 mg/kg/h infusion), and high dose propofol (0.32 mg/kg loading dose and 2 mg/kg/h infusion) in four sessions spaced one week apart

. Before, during, and after the 20 min infusion, volunteers completed mood inventories ( D rug effects/ L iking questionnaire), including the Addiction Research Center Inventory; memory (i.e., immediate and delayed recall of words); and psychomotor tests (Digit Symbol Substitution test , DSST ). Propofol did produce mood altering effects dose

- dependently , but the effect was transient and the mood returned to baseline one hour after administration. The report of subjective effects also increased dose

- dependently. Fifty percent of the volunteers reported “liking” the effects of propofol on a Visual Analogue Scale (VAS scale) ; thus, the authors stated that propofol may have a potential for abuse

.
Zacny et al. (1993 a) conducted a double

- blind and rand omized study with human healthy volunteers (n=1 0 ) with a history of recreational drug use . The purpose of the study was to assess the rewarding effects of propofol using a discrete

- trials choice procedure

. To assess subjective effects, the VAS and the Dr ug Effects/Liking questionnaires were used. Memory or short and delayed recall was also tested using lists of words and p sychomotor performance was testedDEA/OD/ODE Page 4 of 18 11/3/2010

using the DSST. B olus i.v. subanesthetic doses of propofol 0.6 mg/kg and the placebo control ( Intralipid ® ) w ere administered in a blind fashion twice to each subject. For the following three sessions, the subjects choice which drug, identified by a color code, they wanted to receive. Propofol was chosen by s ix of the subjects

. During the sessio ns, propofol choosers reported acute pleasant effects with no unpleasant residual effects

. The authors concluded that propo fol may be rewarding to non

- drug abusers, thus having abuse potential

. Zacny et al. (1993 b ) assess ed the abuse potential of propofol in healthy human subjects (n=1 0 ). Using a randomized, double

- blind, crossover method, the subjects were injected i.v. with subanesthetic doses of propofol (0.2

- 0.6 mg/kg) or placebo. The following was assessed before the injection and up to 1 h post

- injection: mood (including drug liking), memory, and psychomotor performance. Propofol induced memory impairment negatively i mpacted psychomotor performance, these effects were acute . It also altered mood, 10 of 20 VAS mood ratings. Five of the sub

jects (50 percent) said that if they participated in another study that they would choose 0.6 mg/kg propofol over the placebo. The authors concluded that propofol has the potential for abuse and/or diversion, particularly with hospital personnel.

General ly, the studies demonstrated that propofol dose

- dependently increased the reporting by the subject feeling “high,” relative to the placebo. In one study, when subjects were given a choice of either receiving i.v. propofol or placebo, about half of the sub jects chose propofol over placebo. These studies demonstrate that propofol produces a reward effect in humans and the pattern is characteristic of the abuse potential of drugs in schedule IV. Subjects, who were previous drug users, reported an increase i n sedation and “liking” scores

. Several clinical case reports regarding propofol’s actual physical dependency and addiction are also reported in the published scientific literatures ( Au et al., 1990; Follette and Farley, 1992; Tobias, 2000 ; Cawley et al., 2003 )

. There was a report of propofol withdrawal upon discontinuation of administration in a 10

- month

- old girl. The girl had been administered propofol for 2 weeks to provide sedation while she was mechanical ly ventilat ed . Upon cessation of adminis tration of propofol, the patient exhibited “generalized twitching and jitteriness.” The symptoms disappeared over a 3

- day period (Tobias, 2000).

Au et al. (1990) reported a case of a 41

- year

- old man who required propofol for sedation after emergency su rgery. He was administered propofol and papaveretum for five days, and administration was discontinued once he was extubated. Over the next few hours, he became confused, exhibit ed tremors, and had hallucinations. Ten hours later, he experienced several short grand mal seizures, which subsided with the administration of diazepam. Propofol and papaveretum infusions w ere administered to the patient , and over the next 48 h, he was gradually weaned off of the drugs without any sign s of a withdrawal syndrome

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Cawley et al. (2003) published a case report of a burn patient who required propofol administration for sedation. He was administered an infusion of propofol (10 mg/ml) at 5 g/kg/min beginning on his 35 th day of treatment, in conjunction with valpro ic acid and fluoxetine to treat the patient ’s bipolar disease. After 79 days of continuous infusion of propofol, the infusion rate rang ed from 5

- 35 g/kg/min , the infusion dose was weaned over a four day period from 25 g/kg/min for 64 h to 10 g/kg/min for the next 16 h, to finally 5 g/kg/min for another 16 h. The patient demonstrated signs o f abrupt agitation, tremors, tachycardia , tachypnea, and hyperpyrexia 6 h after the administration of propofol had been stopped. In order to improve the patient’s co mfort, the propofol infusion ( 5 g/kg/min ) was administered again, which result ed in an abru pt reduction of the tachycardia, tachypnea, and hyperpyrexia. Since the symptoms were resolved with administration o f propofol, it was suspected that the patient experienced an acute propofol withdrawal reaction. A second attempt to wean him off of the propofol was done the following day; the dose was reduced to 2.5 g/kg/min . He experienced withdrawal symptoms 39 h a fter the drop in dose. The dose was increased back to 5 micrograms/kg/min. Four day s later, the propofol dose was decreased by increments of 0.25 g/kg/min . The incremental reduction was well

- tolerated by the patient, the final infusion dose was 4.5 g/kg/min. No withdrawal symptoms were observed over a seven day period. The weaning off of propofol had to be stopped because the patient’s health was deteriorating due complications from the burn injury. The patient died after being in the hospital for 1 24 days.

Animal self

- administration studies demonstrated the reinforcing effects of propofol in rat, mouse, and primate models. (Weerts et al

. , 1999; LeSage et al., 2000) It has been demonstrated that drugs that are self

- administered by animals also have drug abuse potential in humans (Weerts et al

. , 1999 ; Ator and Griffith, 2003 )

. Propofol has been demonstrated to have reinforcing effects comparable to methohexital, a schedule IV sedative

- hypnotic. In rats trained to self

- administer methohexital, propofol maintained a significant self

- administration, indicating that propofol has re warding properties comparable to methohexital (LeSage et al., 2000).

Weerts et al. (1999) evaluated the reinforcing effects of subanesthetic doses of propofol and methohexital in baboons using a standard cocaine ( CII ) substitution procedure. Both test dr ugs were administered i.v. In two of the three baboons, the rates of self

- injection were comparable to methohexital, but less that than the level of the cocaine

- maintained animals. The animals maintained low to high mean rates of self

- injection of subane sthetic doses of propofol
, when substituting for propofol

In rats, p ropofol induced a conditioned place preference paradigm at sub anesthetic doses (30, 60 mg/kg, intraperitoneal or i.p.) and at recovery from propofol anesthesia (100 mg/kg). Suban esthe tic doses of methohexital (10, 20, 30 mg/kg, i.p.) were used as a comparison; none of these doses induced a place preference paradigm , which is commonly observed with barbiturates

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T he authors also emphasize that the level of place preference induced by 60 mg/kg propofol was comparable to that induced by other tested drugs
, which cause d a pleasant affective state
, such as amphetamine (1.5 mg/kg) (Pain et al., 1996)

.
In summary, both the preclinic al and clinical data have demonstrated that propofol has a moderate abuse potential similar to that of other schedule IV sedative

- hypnotics, such as midazolam and methohexital , and by extension, lower than that of other sedatives in schedule III. The re inforcing effects in animals following self

- administration of propofol are predictive of human abuse. Abuse of propofol by humans has been observed, to a larger extent, in medical professionals. This is predominately due to propofol being available pri nci pally in medical facilities where it is easily accessible due to it not being stored as a controlled substance.

. Factor 2. Scientific Evidence of its Pharmacological Effects

The binding site of propofol is on the

- aminobutyric acid subtype A (GABA A ) receptor and propofol both activates the GABA A receptor and acts as a modulator by potentiating the activity of GABA at the receptor in the central nervous system (CNS) ( Pain et al., 1996; Weerts et al. ; 1999; LeSage et al., 2000 ; Hall et al., 2010 ) . O ther psychoactive drugs, e.g., barbiturates (schedule II and III) , benzodiazepines (schedule IV) , and volatile anesthetics
, also potentiate GABA at the GABA A receptors (Zacny et al., 1993b ; Weerts et al

. , 1999 )

. As a major group of post

- synaptic inhibitory membrane receptors, t he GABA A receptor is a ligand

- gated chloride channel that consists of five subunits and a central chloride channel.

Propofol has been shown to have an effect on the GABA uptake and release pre

synpatically. Propofol inh ibits the presynaptic uptake of GABA in a dose

- dependent manner in the CNS (Weerts et al., 1999). Some studies have shown that propofol either enhances on the potassium

- stimulated release or the spontaneous release of GABA. Other studies have shown that propofol does not enhance the potassium

- stimulated release of GABA (DHHS review, 2010)

. At supratherapeutic concentrations, propofol also inhibits the activity of post

- synaptic glutamate excitatory membrane receptors, such as N

- methyl

- D

- asparate (NMDA) re ceptors. Ketamine (CIII), an anesthetic with significant abuse potential, also inhibits the NMDA receptors (Roussin et al., 2007). Thus, propofol shares a similar pharmacological property with ketamine, a schedule III controlled substance, by inhibit ing t he action of NMDA at the post

- synaptic glutamate receptor (Roussin et al., 2007).

Schwieler et al. (2003) demonstrated that p ropofol dose

- dependently decrease d the firing rate and burst firing activity of nigral dopamine neurons. Small doses of p ropof ol (1

- 16 mg/kg) was administered, i.v., to rats. The effect was antagonized by pre

- treatment with CGP35348, a GABA B receptor antagonist. Pain et al. (2002) demonstrated that propofol induces bothDEA/OD/ODE Page 7 of 18 11/3/2010

decreases and increases of the extracellular dopamine concentrations in the nucleus accumbens
, depending on the dose of propofol administered. Rats were injected, i.p., with three doses of propofol, 9, 60, or 100 mg/kg, small, subanesthetic and anesthetic doses, respectively. The 9 mg/kg dose decreased the extracellular dopamine concentration in the nucleus accumbens, and the 60 and 100 mg/kg doses increased the extracellular dopamine concentrations. Each dose of propofol induced significant changes in dopamine levels, compared to basal levels. The 100 mg/kg dose also significantly increased homovanillic acid (HVA) levels
, a dopamine metabolite

. As is the case with other drugs of abuse, propofol increases the extracellular dopamine concentrations in the nucleus accumbens at sub

- and anesthetic doses ( Pain et al., 2002 )

. The reinforcing effects of propofol have been demonstrated via self

- administration studies in various animal models, in the rat, mouse, and primate s . (Weerts et al

. , 1999; LeSage et al., 2000) It has been demonstrated that drugs that are self

- administered by animals also have drug abuse potential in humans (Weerts et al

. , 1999 ; Ator and Griffith, 2003 ). Zacny et al. (1992, 1993a, 1993b) have demonstrated through clinical trials that propofol had reinforcing and rewarding effects in humans . The subjective effects were most comparable to schedule IV sedatives, e.g., methohexital.

Propofol’s mechanism of action of inducti ng anesthesia is not known.

In summary , the predominant binding site of propofol is on the GABA A receptor. Propofol
, similar to other psychoactive drugs (e.g., barbiturates, and benzodiazepines) that are controlled under the CSA, act s as a modulator on the GABA A receptor ; it potentiate s the GABA activity at the receptor

.

Factor 3. The State of Current Scientific Knowledge Concerning the Substance.
Chemistry
Propofol
, or 2,6

- diisopropylphenol , ha s a molecular weight of 178.271 g/mol. The molecular formula of propofol is C 12 H 18 O. The chemical structure of propofol is below.

Propofol is slightly soluble in water and is formulated in a n oil

- in

- water emulsion that is milky

- white in appearance. The formulation has a neutral pH with a pKa in water of 11. The octanol/water partition co efficient for propofol is 6761: 1 at a pH of 6

- 8.5. Fosp ropofol, theDEA/OD/ODE Page 8 of 18 11/3/2010

water

- soluble O

- methyl

- phosphate disodium salt , a prodrug of propofol
, has been recently controlled as a s chedule IV substance under the CSA.

Pharmacokinetics
In humans, the pharmacokinetic profile of propofol is described by a three comp artment linear model, similar to that in animals, with compartment s in plasma, rapid equilibrating tissues, and slow equilibrating tissue s , mainly the adipose tissue (Iwersen

- Bergmann et al., 2001)

. Following a bolus dose of infused , i.v., p r opofol , there is a rapid equilibration between plasma and central nervous system which leads to a rapid onset of anesthesia. Plasma concentrations decline rapidly due to the distribution and metabolic clearance in almost equivalent effects. Propofol is highly protein bound and is metabolized by conjugation in the liver (Levitzsky and Vargo, 2008)

. Clinical studies show that ther e are no gender differe nces in the distribution of propofol, but there are age differences; elderly subjects achieve higher peak plasma concentrations of propofol

. I n the geriatric population, the dose of propofol required to achieve a similar anesthetic end point as that in the non

- elderly adults is lower

. The higher peak plasma concentrations of propofol in the elderly can pre

- dispos e them to adverse cardio

- respiratory effects including hypotension, apnea, airway obstruc tion, and/or arterial oxygen de

- saturation (Heuss et al., 2003)

. The metabolism of propofol occurs very rapidly after intravenous administration. Metabolized p ropofol is excrete d extensively by the kidneys with a rate reaching to almost one

third of the total body clearance (DHHS review, 2010)

. Its clearance rate exceeds hepatic blood flow and may suggest an extra

- hepatic site of elimination. Binding highly wi th plasma proteins
, propofol is extensively metabolized to glucu ronide conjugates ( Iwersen

- Bergmann et al., 2001 ; Kranioti et al., 2007 )

. According to the DHHS review (2010), t he conjugation of glucu roni de to propofol is predominantly catalyzed by the uridine diphosphate glucuronosyltr ansferase

- 1 family enzymes

. According to the DHHS review (2010), o nce the medical administration of propofol is ceased , either for maintenance of anesthesia or sedation, the plasma concentration of propofol decrease s an d subsequently, the patient awake n s rapidly

. Clinically, anesthetics are generally administered with opioids for various medical procedures, so the knowledge of the drug

- to

- drug interactions of propofol with opioids is very important for patients’ safety

. It has been demonstrated that 50

- 60 M of propofol inhibited the metabolism of alfentanil and sufentanil by 50 percent

. Since i t is very common to use these opioids concomitantly with propofol clinically
, it is imperative that anesthesiologists be aware of propofol’s effect of inhibiting the metabolism of certain opioids and increasing the half

- life of opioids (DHHS review 2010).DEA/OD/ODE Page 9 of 18 11/3/2010

In summary, the pharmacokinetic profile of propofol is identified by a three compartment linear model (similar to that in animals) with compartments in plasma, rapid equilibrating tissues, and slow equilibrating tissue s . Following a bolus dose, there is a rapid equilibration of pro po fol between plasma and central nervous system, which leads to a rapid onset of anesthesia. The p lasma concentration will decline rapidly due to the distribution and metabolic clearance in almost equivalent effects. Propofol is highly protein bound in vivo and is metabolized by conjugation in the liver. It is slowly eliminated from adipose ti ssue s . Its rate of clearance exceeds the average level of the hepatic blood flow, suggesting an extra

- hepatic site of elimination. There is an age difference in the p ro pofol metabolism, but no evidence was found to support gender differences . Under the s ame administrated dose of p r opofol, the elderly subjects may achieve a higher peak plasma concentration than the non

- elderly adults.
Factor 4. Its History and Current Pattern of Abuse
Propofol is currently marketed as a non

- controlled anesthetic in the U.S. and in other countries. The current abuse profiles of propofol indicate that propofol is principally abused by anesthesiologists and other health care professionals, e.g., nurse anesthetists and resident physicians . These professionals have access to propofol easily due to its availability in medical facilities. It has been observed that the lack of secured controls to the access of propofol in hospitals and clinics has resulted in the abuse of propofol by medical professionals (Schneider et al., 2001 ; Weetman et al

. 2004 ; DHHS review, 2010 )

. In a survey of 126 academic anesthesiology programs in the U.S., 18 percent of the programs reported diversion or abuse of propofol. Of the 25 individuals reported to have abused propofol, seven (28 percent ) had died from propofol abuse. The individuals who died were affiliated with health care facilities in which there were no pharmacy or security mechanisms to control the access to propofol (Wischmeyer et al., 2007).
In a study conducted by Bell et al. (1999) , 2
, 500 actively practicing Certified Registered Nurse Anesthetists (CRNAs) were surveyed to determine the prevalence of misuse of controlled drugs and other licit drugs with drug abuse potential

. One hundred sixty

- seven (11 percent) of the re spondents indicated that they had a history of or were currently misusing of controlled and

non

- controlled substances. Propofol was reported to be the fourth most preferred drug to misuse among this surveyed population. The respondents indicated that the y highly preferred propofol due to its easy accessibility and its remarkable non

- control status under the CSA.
Though propofol is not controlled under the CSA, the labels for its products include a section entitled Drug Abuse and Dependence due to the occ urrences of diversion and abuse of propofol among health care professionals. Several databases, such as National Survey on Drug Use and Health (NSDUH), Monitoring the Future (MTF), and Treatment Episode Data Set (TEDS), were accessed to obtain information on trends and/or patterns of propofol abuse. None of the above public databases contained data on propofol

- related abuse. According to the DHHSDEA/OD/ODE Page 10 of 18 11/3/2010

review (2010), this may be due to the availability of propofol being limited to medical professionals instead of the general public

. According to the DHHS review (2010) , g enerally, propofol is abused alone, but there have been some reports of abuse of propofol in combination with other psychoactive drugs and substances , e.g., lidocaine, midazolam, and alcohol. When propofol is abused, it has been reported to be “ultra

- short acting” causing the abuser to frequently inject the propofol in order to maintain a high level of euphoria. Though propofol, when abused, is reported to be short

- acting, it has been report ed that propofol can adversely affect the abuser’s work performance
In summary, a buse of propofol has been observed to predominantly exist among medical professionals. This is due to propofol being available primarily in medical facilities. None of the above public drug abuse databases contained data on propofol

- related abuse. This might be due to the current non

- controlled status of propofol under the CSA

. T he incidences of propofol

related abuse may be monitor ed and track ed continuously through the above

- mentioned databases

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

DEA has searched the scientific literature and the S tate and F ederal forensic laboratory databases to assess the scope of propofol abuse in the United States. The forensic laboratory databases such as National Forensic Laboratory Information System (NFLIS) and System to Retrieve Information from Drug Evidence (STRID E) compile d data from F ederal, S tate and local laboratories regarding seizures of propofol from 1999

- 2009 ( Table 1 )

. The American Society of Anesthesiologists (ASA) and the American Association of Nurse Anesthetists (AANA) have recently endorsed the control of propofol under the CSA in order to prevent the occurrence of diversion and abuse among their respective professions. In June 2009, the AANA issued a position statement insisting that medical facilities which use propofol to implement standard p ractices to reduce the likelihood of diversion and abuse of propofol, e.g. storing propofol in a secured location. In October 2009, the ASA reiterated their previous position statement that the propofol should only be administered by persons trained in th e administration of general anesthesia.

Table 1

. Seizures of P ropofol from 1999

- 2009 in the United States

NFLIS (State and Local Levels ) 1999 200 0 200 1 200 2 200 3 200 4 200 5 200 6 200 7 200 8 200 9 Exhibits 1 0 0 0 5 0 1 1 1 1 4 STRIDE (Federal Level ) 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Exhibits 0 0 0 0 1 0 0 0 0 0 0DEA/OD/ODE Page 11 of 18 11/3/2010

On the F ederal, S tate and l ocal le vels, the seizures of propofol are very low, due to propofol not being available to the general public

. P ropofol is not currently controlled by either the federal government or state governments, and may not be a target or priority of law enforcement

. Therefore
, information on reported seizures and cases from federal, state and local law enforcement agencies is very limited

. As previous ly stated, m edical professionals are the predominant popula tion to abuse propofol

. According to the DHHS review (2010), in many of the published case reports about propofol abuse, the abuse of propofol was only detected upon death of the abuser. So, it is probable that there are more instances of propofol abu se, than what has been reported.

Factor 6. What, i f Any, Risk There i s t o t he Public Health
Propofol abuse is directly associated with significant adverse health effects, including death. The known major adverse effects include pancreatitis, pulmonary edema, and cardiovascular and respiratory depression. The cause of death with propofol toxicity is due to respiratory dep ression ( Roussin et al., 2007; Iwersen

- Bergmann et al., 2001; DHHS review, 2010 )

. In a survey conducted among health

- care providers and health center workers, the mortality rate among anesthesiologists abusing propofol was 28 percent , and 38 percent amo ng hospital residents also abusing propofol (Wischmeyer et al., 2007)

. There have been reports of incidences of apnea associated with the induction of anesthesia using propofol. The Food and Drug Administration (FDA)

- approved label for Diprivan ® states that seven percent of adult patients receiving 2

- 2.5 mg/kg experienced apnea for less than 30 seconds, 20 percent experienced apnea for 30

- 60 seconds, and 12 percent of patients experienced apnea for less than 60 seconds. In pediatric patients (fr om birth to 16 years of age) that received 1

- 3.6 mg/kg, 12 percent experienced apnea for less than 30 seconds, 10 percent experienced apnea for 30

- 60 seconds, and five percent experienced apnea for more than 60 seconds.

Though propofol, when abused, is r eported to be short

- acting, it has been indicated that propofol can still adversely affect the abuser’s work performance (Soyka and Schütz, 1997)

. Thus, since the populations who are abusers of propofol are predominantly medical professionals, this fact c ould potentially pose a significant risk to the health and safety of the patients under their care.
According to the DHHS review (2010), t here have been reports of the use of propofol in the carrying out of criminal activities. In one reported case, a me dical professional used propofol in the sexual assault of a patient. In another case, a nurse used propofol to murder one of his acquaintances

. There have been published cases of driving while under the influence of propofol abuse

. Within a 12 month per iod, three drivers were apprehended who were driving whileDEA/OD/ODE Page 12 of 18 11/3/2010

simultaneously self

- injecting propofol. All three individual s were males who were associated with a hospital (Odell, 1999).
In summary, propofol abuse has various adverse effects and can pot ential ly result in death of the abuser. The abuse of propofol also has been shown to negatively affect the work performance of abusers. Propofol poses a considerable threat to the public health because it can be used in the co mmission of criminal activity
, e.g. sexual assault and murder
, and it also impair an individual’s ability to safely operate a motor vehicle

. This fact also demonstrates a pattern of diversion of the prop ofol from the legitimate applications. Overall, t he risks as sociated with the abuse of propofol are similar to those associated with the abuse of other sedative hypnotics and CNS depressants, such as midazolam and me th ohexital, which are controlled in schedule IV of the CSA

. Factor 7. Its Psychic or P sychological Dependence Liability

Animal and human studies have demonstrated that propofol has remarkable physiological dependence liability. There has been a published case demonstrating that propofol has physiological dependence potential, though none of the reports directly compare the psychological dependence potential of propofol with that of other drugs. There have been reports that propofol induces psychological dependence, characterized by craving, compulsion to
constant ly self

- inject, and to continue t o use propofol in spite of adverse consequences ( Soyka and Schütz, 1997; Roussin et al., 2007). Another study reported about the abusers experiencing tolerance to the relaxing and euphoric effects during episodes of continuous self

- administration of propo fol (Schneider et al., 2001). The observed reinforcing effects in animals following self

administration of propofol are supportively predictive of human abuse potential and dependency liability.

Schneider et al. (2001) published a case report of a 25

- year

- old male patient who was diagnosed with a propofol dependence upon being admitted to the hospital. He was initially treated by an anesthesiologist with propofol to treat the symptoms associated with tension headaches. Though the propofol treatment w as effective, by the following year, the anesthesiologist refused to continue to treat the patient with propofol. Upon not being able to obtain propofol through his physician, the patient began to administer 200 mg propofol. One week prior to him being a dmitted to the hospital for his propofol dependence, he was using propofol daily, injecting 200 mg of propofol up to 10

- 15 times per day. Though the patient reported that he had not experienced any withdrawal symptoms, he did experience an intense craving for propofol, which caused him to compulsively inject propofol multiple times daily
Soyka and Schutz (199 7) reported on a case about a 31

- year

- old general practitioner, who was admitted to the hospital in order to detoxify from propofol. He had started injecting propofol ten months prior and was injecting almost daily. He had initially started injecting 50DEA/OD/ODE Page 13 of 18 11/3/2010

mg i.v,, his purpose of abusing propofol was he was to relieve boredom, to relax, and to treat symptoms associated with depression. After injecting propofol, the patient rapidly experienced a mild euphoria and relaxation
, followed by a strong sedation and loss of consciousness. He constantly craved the feelings associated with propofol abuse so he compulsively injected propofol, up to 100 times a day ; only stopping upon consuming the entire quantity he possessed on each occasion. He did not experience any withdrawal symptoms

. Bonnet et al. (2008) reported a case about a 30

- yea r

- old physician who had been admitted to the hospital due to a vehicle acc ident and during treatment developed symptoms similar to a benzodiazepine withdrawal syndrome . The subject was abusing propofol and cigarettes without

an addictio n history of benzodiazepines . The subject met the Inter national Classification of Diseases

- 10 ( ICD

- 10 ) criteria for diagnosis of dependency on sedatives whi ch includes positive psychological (craving propofol, loss of control) and physical (tolerance, withdrawal syndrome with hyperhidrosis, tachycardia, anxiety, and insom n ia) components and negative social sequelae, such as burglary to acquire propofol. His positive p hysical symptoms reduced over the three weeks of treatment while p sychological symptoms did not decrease , instead became more intense leading to negative behaviors associat ed with addiction
, e.g., burglary of propofol and job loss (Bonnet et al., 2008).

Follette and Farley (1992) published a report about an anesthesiologist in his early 30’s who had developed an addiction to propofol. At the peak of the addiction, he was i njecting a constant amount of propofol 10 to 15 times per day both at home and at work. T he compulsion and craving to abuse propofol became the principal motivators for abuse after he initially began to abuse propofol for its relaxing effects. He later enrolled in an extended

- care drug rehabilitation program after he was found unconscious in the emergency room following self

injecting 100 mg of propofol

. Fritz and Niemczyk (2002) reported a case about a patient who had been treated with propofo l by an anesthesiologist who was using propofol to treat the patient’s tension headaches. After several treatment sessions with the propofol
, the patient began to self

- inject propofol. With

a p revious history of abus ing drug s including benzodiazepines, m orphine and marijuana , he obtained propofol prescriptions from veterinarians for a false purpose of anesthetizing fish. He self

- injected propofol three to four times a week with each session lasting one to two hours. He

was admitted into a treatment prog ram, but checked himself out after seven days

. Chronic administration of propofol can produce significant physical dependence and withdrawal symptoms . There have been published reports of withdrawal symptoms upon abrupt cessation of propofol administrati on after several days of treatment ( Au et al., 1990; Follette and Farley, 1992; Tobias, 2000 ; Cawley et al., 2003). The symptoms included agitation, tremors, tachycardia, tachypnea, hyperpyrexia, confusion, and hallucinations. The withdrawal symptoms improved once an administration of propofol wa s reinitiated, and the dosages were tapered overDEA/OD/ODE Page 14 of 18 11/3/2010

a two

- day period

. Howeve r, the withdraw al induced

- delusional state may last up to seven days before full recovery of mental functions

. Cawley et al. (2003) recommend ed that after a prolonged administration of propofol, the cessation of administration should be done cautiously

an d the patient should be monitored for any signs of a withdrawal syndrome

. . In summary, the pharmacological action of propofol, the published abuse potential data and case reports, collectively suggest that propofol has potential to cause psychological a nd physical dependence. Propofol’s abuse liability combining with its psychological and physical dependence are comparable to other controlled drugs in schedule IV, such as midazolam and

me th ohexital.

Factor 8. Whether the Substance is an Immediate Precursor of a Substance Already Controlled

Propofol is not an immediate precursor of any substance currently controlled under the CSA.DEA/OD/ODE Page 15 of 18 11/3/2010

Findings
After consideration of the above eight factors determinative of control of a substance (21 U.S.C. § 811(c)), and a review of the scientific and medical evaluation and scheduling recommendation provided by the DHHS, DEA finds that propofol, including its salts, isomer, salts of isomers whenever the existence of such isomers, esters, ethers, and salts is p ossible as summarized below meet the criteria for placement in s chedule IV of the CSA, under 21 U.S.C. § 812 (b)(4).

1) P ropofol has a low potential for abuse relative to the drugs or other substances in

s chedule I II

.
The binding site of propofol is on the

- aminobutyric acid subtype A (GABA A ) receptor, acting as a modulator by potentiating the GABA activity at the receptor (Pain et al., 1996 ; Weerts et al., 1999 ). Other psychoactive drugs , such as barbiturates, benzod iazepines, and volatile anesthetics, potentiate GABA at the GABA A receptors in the CNS (Zacny et al., 1993b; Weerts et al

. , 1999). GABA is the main inhibitory neurotransmitter in the CNS.

Animal self

- administration studies demonstrated the reinforcing effects induced by propofol in rat, mouse, and primate models. Propofol has been demonstrated to have reinforcing effects comparable to methohexital, a schedule IV sedative

- hypnotic. Baboons self

- administered sub

- anesthetic doses of propofol in a pattern comparable to methohexital (Weerts et al., 1999). In rats trained to self

- administer methohexital, propofol maintained self

- administration, indicating that propofol has rewarding properties comparable to o ther controlled substances, such

as methohexital (LeSage et al., 2000)

. There have been several published abuse liability studies of propofol in humans in which the reinforcement and reward effects have been demonstrated. Zacny et al. (1992, 1993a, 1993b) showed that propofol produced subjective effects most comparable to sc hedule IV sedatives, e.g., methohexital. Generally, the studies demonstrated that propofol dose

dependently increased the reporting by the subject feeling “high,” relative to the placebo. In one study, when subjects were given a choice of either receivin g i.v. propofol or placebo, about half of the subjects chose propofol over placebo. These studies demonstrate that propofol produces a reward effect in humans and the pattern is characteristic of the abuse potential of drugs in schedule IV. Subjects, who were previous drug users, reported an increase in sedation and “liking” scores.

It has b een observed that the lack of secured controls to the access of propofol in hospita ls and clinics had resulted in an increase of the abuse of propofol by health ca re professionals
, e.g., anesthesiologists, n urse anesthetists and resident physicians (Schneider et al., 2001; Weetman et al, 2004 ; DHHS review, 2010 )

.DEA/OD/ODE Page 16 of 18 11/3/2010

In a survey o f 126 academic anesthesiology programs, 18 percent reported diversion or abuse of propofol . Of the 25 individuals reported to have abused propofol, seven (28 percent) had died as a result of propofol abuse. The individuals who died were affiliated with health centers in which there was no secured pharmacy accounting system for propofol disper sion (Wischmeyer et al., 2007)

. 2) Propofol has a currently accepted medical use in treatment in the United States.
Propofol was approved, under the commercial name of Diprivan @ , in 1989
, as an ultra

short acting i.v. anesthetic. Propofol is indicated in adults for the initiation and maintenance of Monitored Anesthesia Care (MAC) sedation
, combined sedation, and regional anesthesia, and for Intensive Care Unit (ICU) sedation of intubated and mechanically ventilat ed patients. For children, propofol is indicated for induction and maintenance of general anesthesia. Propofol is also approved for use as a veterinary anesthetic.

3) Abuse of propofol may lead to limited psychological or physical dependence relative to the drugs or other substances in schedule III.
There have been reports of withdrawal symptoms following a long

- term use of propofol suggesting its physical dependence potential. The withdrawal symptoms are resolved by slowly tapering the dose of the propofol administrated, thus indicati ng the limited dependence potential. Psychic dependence potential of propofol is identified by i ntravenous drug self

- administration studies in animals and subjective effects in propofol abusers

.DEA/OD/ODE Page 17 of 18 11/3/2010

References 1. Au J, Walker WS, and Scott DH. (1990)

. Withdrawal syndrome after propofol infusion. Anaesthesia
, 45
, 741

- 2. 2. Bartter T and Gooberman LL. (1996). Rapid opiate detoxification. American Journal of Drug and Alcohol Abuse
, 22 , 489

- 495. 3. Bell, DM, McDonough JP, and Ellison JS, and Fitzhugh EC. (1999). Controlled drug misuse by certified registered nurse anesthetists. American Association of Nurse Anesthetists
, 67 , 133

- 140. 4. Bonnet U, Harkener J and Scherbaum N. (2008). A case report of pr opofol dependence in a physician. Journal of Psychoactive Drugs
, 40 , 215

- 217. 5. Brandner B, Blagrove M, McCallum G, and Bromley LM. (1997). Dreams, images and emotions associated with propofol anaesthesia

. Anaesthesia
, 52 , 750

- 755. 6. Cawley MJ, Guse TM, Laroia A, Haith LR, and Ackerman BH. (2003)

. Propofol withdrawal syndrome in an adult patient with thermal injury. Pharmacotherapy
, 23
, 933

- 939. 7. Follette JW and Farley WJ. (1992). Anesthesiologist addicted to propofol. Anesthesiology
, 77 , 817

- 818. 8. Fritz GA and Niemczyk WE. (2002). Propofol dependency in a lay person. Anesthesiology
, 96 , 505

- 506. 9. Hall MA, Xi J, Lor C, Dai S, Pearce R, Dailey WP, and Eckenhoff RG. (2010). M

Azipropofol (AziP m ) a photoactive analogue of the intravenous general anesthetic propofol. J Med Chem
, 53 , 5667

- 5675. 10. Heuss LT, Schieper P, Drewe J, Pflimlin E, and Beglinger C. ( 2003 ). Conscious sedation with propofol in elderly patients: a prospective evaluation. Alimen t ary Pharmaco logy and Ther apeutics , 17 , 1493

- 1501. 11. Iwersen

- Bergmann S, Rösner P, Kühnau HC, Junge M, and Schmoldt A. ( 2001 ). Death after excessive propofol abuse. In ternational J ournal of Legal Med icine
, 114 , 248

- 251. 12. Kranioti EF, Mavroforou A, Mylonakis P, and Michalodimitrakis M. (2007). Lethal self

administra t ion of propofol (Diprivan): a case report and review of the literature. Forensic Science International
, 167 , 56

- 58. 13. LeSage MG, Stafford D, and Glowa JR. (2000). Abuse liability of the anesthetic propofol: self administration of propofol in rats under fixed ratios schedules of drug delivery. Psychopharmacology
, 153
, 148

- 154. 14. Levitzsky BE and Vargo JJ. ( 2008 ). Fospropofol disodium injection for the sedation of patients undergoing colonoscopy. Ther apeutics and Clinical Risk Management
, 4 , 733

- 738. 15. Odell M. (1999). Propofol abuse. Anaeshesia and Intensive Care
, 27 , 539. 16. Pain L, Oberling P, Sandner G
, and Di Scala D. (1996) . Effect of propofol on affective state as assessed by place conditioning paradigm in rats. Anesthesiology
, 85 :121

- 128.DEA/OD/ODE Page 18 of 18 11/3/2010

17. Pain L, Gobaille S, Schleef C, Aunis D, and Oberling P. (2002). In vivo dopamine measurements in the nucleus accumbens after nonanes thetic and anesthetic doses of propofol in rats. Anesthesia and Analgesia
, 95 , 915

- 919. 18. Roussin A, Montastruc J

- L, and Lapeyre

- Mestre M. (2007). Pharmacological and clinical evidences on the potential for abuse and dependence of propofol: a review of the literature. Fundamental and Clinical Pharmacology
, 21 , 459

- 46 6

. 19. Schneider U, Rada D, Ro llnik JD, Passie T, and Emrich HM. (2001). Propofol dependency after treatment of tension headache. Addiction Biology
, 6 , 263

- 265. 20. Schwieler L, Delbro DS , Engberg G
, and Erhardt S. (2003). The anesthetic agent propofol interacts with GABA B - receptors: an electrophysiological study in rats. Life Science , 72
, 2793

- 2801. 21. Soyka M and Schütz CG. (1997). Prop o fol dependency . Addiction

. 92 , 1369

- 1370. 22. Tobias JD. (2000)

. Tolerance, withdrawal, and physical dependency after long

- term sedation and analgesia of children in the pediatric intensive care unit. Crit ical Care Med icine, 28
, 2122

- 32. 23. Weerts EM, Ator NA
, and Griffiths RR. (1999). Comparison of the intravenous reinf orcing effects of propofol and methohexial in baboons. Drug and Alcohol Dependence
, 57
, 51

- 60. 24. Weetman DB, Mascardo LA, Ross MB, and Abramowitz PW. (2004). Propofol as a drug of diversion. Am erican J

ournal of Health

- Sys t em Pharm acy

. 61 , 1185

- 1186. 25. Wilson C, Canning P, and Caravati EM. (2010). The abuse of propofol. Clinical Toxicology

. 48
, 165

- 170. 26. Wischmeyer PE, Johnson BR, Wilson JE, Dingmann C , Bachman HM, Roller E, Tran ZV, and Henthorn TK. (2007). A survey of propofol abuse in academic anesth esia programs. Anesthesia and Analgesia
, 105 , 1066

- 1071. 27. Zacny JP, Lichtor JL, Coalson DW, Finn RS, Uitvlugt AM, Flemming DC, and Apfelbaum JL

. (1992). Subjective and psychomotor effects of suban esthetic doses of propofol in healthy volunteers. An esthesiology

. 76
, 696

- 702. 28. Zacny JP, Lichtor JL, Thompson W, and Apfelbaum JL (1993a). Propofol at subanaesthetic doses may have abuse potential in healthy volunteers. Anesthesia and Analgesia
, 77
, 544

- 552. 29. Zacny JP, Lichtor JL, Zaragoza JG, Coalson DW, Uitvlugt AM, Flemming DC, Binstock WB, Cutter T, and Apfelbaum JL (1993b). Assessing the behavioral effects and abuse potential of propofol bolus injections in healthy volunteers. Drug and Alcohol Dependence
, 32

, 45

- 47.