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Propofol Abuse

Ethan O. Bryson, MD

Elizabeth A.M. Frost, MDMount Sinai Medical CenterNew York, New York

Propofol (2,6-diisopropylphenol) is an intravenous anestheticagent used for the rapid induction of general anesthesia and formoderate-to-deep sedation for painful or uncomfortable procedures.Despite the significant potential for abuse of this agent, recreational useof propofol was, at least until recently, primarily by medical profes-sionals. It is not classified as a controlled substance by the Unites States

Drug Enforcement agency, which might suggest little potential for drugabuse and is freely available in the hospital setting. Although propofolhas been used safely for over 20 years in this country without significantproblems of addiction and dependence surfacing, the tragic death ofpopular culture icon Michael Jackson during the summer of 2009has brought abuse of this anesthetic agent by the layperson into thespotlight (Fig. 1).

Clinical Effects

Propofol works rapidly. Within seconds after the injection of a bolusdose of propofol, the patient begins to lose consciousness. By the timethe medication has traveled from the injection site to the brain, thepatient is entering a state of general anesthesia. Depending on the dose,patients awaken 5 to 10 minutes later as the drug redistributes from theactive site in the central nervous system into the bodies lipid depots,provided any necessary supportive measures have been provided by theindividual administering the medication. A short-acting agent with little

INTERNATIONAL ANESTHESIOLOGY CLINICS

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REPRINTS: ETHAN O. BRYSON, MD, DEPARTMENT OFANESTHESIOLOGY, MOUNT SINAI MEDICAL CENTER, 1GUSTAVE LLEVY PLACE, NEW YORK, NY 10029, E-MAIL: [email protected]

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or no residual effects, the patient who has received a propofol-basedsedation anesthetic typically recovers feeling well and rested. Patients

have reported a broad spectrum of feelings after propofol administra-tion ranging from a general feeling of well being to elation, euphoria,and sexual disinhibition.1

Propofol is known to enhance the chloride current at the g-aminobutyric acid type-A receptor,2 and may also interfere with thefunction of the N-methyl-D-aspartate receptor as well.3 As with mostdrugs of abuse, it is not surprising to find that propofol also enhancesthe levels of dopamine in the areas of the brain associated with reward.Either through direct release of dopamine from presynaptic nerve

terminals4 or inhibition of dopamine reuptake5 increased levels ofdopamine in the reward circuitry of the mesocorticolimbic system serveto reinforce the behaviors associated with obtaining and injectingpropofol. For most people, this is not a conscious issue as they are likelyunaware of the particular agent with which they were anesthetized, andwould be unlikely to be able to obtain it if they were.

On account of its favorable pharmacokinetic profile, propofol hasbecome the induction agent of choice for most general anesthetics in theUnited States. The extent to which this drug is used became evident

when a critical shortage of the agent occurred in the fall of 2009.Suddenly faced with limited supplies of propofol because of problemswith 2 of the 3 major manufacturing facilities, hospitals throughout theworld quickly found out that the main alternative to a propofolinduction of general anesthesia, thiopental, was also in short supply,primarily because of reduced demand had significantly reducedproduction. Despite its ubiquitous presence in current medical practice,however, the actual incidence of documented cases of propofol abuse isvery small.

Incidence and Prevalence of Abuse

The potential abuse liability of propofol was investigated in 1993 byZancy et al6 who conducted a discrete-choice study in humans. Healthy

Figure 1. Chemical structure of propofol (2,6-diisopropylphenol). Image from http://commons.wikimedia.org/wiki/File:Propofol.svg (Accessed on 27 June, 2010).

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volunteer subjects with a generally light history of lifetime substance useand no history of abuse or treatment for addiction were exposed toplacebo, intralipid, or propofol and then given a choice of what agentthey would prefer to have during a subsequent session. In this study,users either chose propofol because they preferred the subjective effectsof the drug such as feeling spaced out or high or chose placebo

because they disliked the dizziness and confusion associated withpropofol administration. The authors concluded that, for some people,propofol may be rewarding even in individuals without a history ofsubstance abuse and that further abuse liability testing was indicated.

Given the pharmacologic actions of propofol, it is not surprising thatcases of abuse began to be reported in the medical literature soon afterthe drug was introduced into clinical practice. As expected, almost allcases involved medical personnel with access to the agent. In 1992,Follette and Farley7 published the first case of propofol dependence,involving an anesthesiologist who reportedly self-administered 100 mgof propofol 10 to 15 times per day. What is most concerning about thisreport is the frequency with which this addict was injecting thismedication. The volume of propofol required to maintain such usewould be difficult to obtain without becoming detected if it were acontrolled substance and in fact, an editorial accompanying this casereport questioned whether or not propofol deserved to be included inthe access-restricted system, if not advanced to controlled substancestatus all together.8 Despite this early concern, many hospitals still placeno more restriction on access to propofol than to other uncontrolledmedications commonly found in the anesthesia carts in any operatingroom.

Several more cases of propofol abuse in medical personnel werereported between 1992 and 2002. In one instance, a female anesthe-siologist reportedly self-administered propofol and died.9Analysis at thescene and toxicology reports indicated blood and liver concentrationswere 2.4mg/mL and 0.56 mg/g, respectively, supporting the conclusionthat the death was a consequence of propofol self-administration attherapeutic doses from a person who used the drug on a chronic basis.The first reported case of propofol dependency in a layperson was in2002.10 This individual was first exposed to propofol as a treatment fortension headaches administered by an anesthesiologist. No detailssurrounding the nature of the treatment, such as dose of propofolused, bolus or length of infusion, number of treatments, or treatmentsuccess or failure are presented in the report, only the statement that hereceived several treatment sessions. Presumably, he was able toidentify the substance as propofol as he was subsequently able to obtainmore for personal use from various veterinarians. His case came to theattention of medical professionals when his wife found him unconsciousand cyanotic after an accidental overdose. Yet another recent case of a

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young woman found dead in her home of apparent propofol toxicity,questioned whether her death was because of abuse or homicide.11 Themeasured blood propofol level was 4.3 mg/mL. Given there was neitherhistory of abuse nor signs of it at autopsy, attention focused on a malenurse acquaintance who worked in a surgical intensive care unit andpresumably had access to propofol and the equipment necessary toadminister it.

A recent systematic review of the literature identified 45 articlesrelevant to evaluation of the evidence of the abuse potential ofpropofol.12 The articles describe the several biochemical and pharma-cokinetic mechanisms of action of the agent that lend themselves to itsabuse, and the physical and psychological effects that make it attractiveas a recreational drug. Current evidence also supports the possibility oftolerance to and also withdrawal from propofol and its abuse potential.On the basis of their review and analysis, the authors recommend thatnot only the United States Drug Enforcement Administration but alsoother international agencies should consider regulating propofol as acontrolled substance. Of note is that fospropofol (Fig. 2), a water-solubleformulation of propofol also approved for induction of anesthesia, has

been placed by the Deputy Administrator of the Drug EnforcementAdministration into Schedule IV of the Controlled Substance act as of2009.13 Fospropofol is metabolized in the liver by alkaline phosphataseto propofol. As such, blood levels of propofol after an equipotentinjection of fospropofol reach lower peak levels and the clinical effect islonger.

Figure 2. Chemical structure of fospropofol [dihydrogen (2,6-diisopropylphenoxy) methylphosphate]. Note the addition of the methyl phosphate group to the propofol base structure thatallows this drug to be stored and administered in an aqueous solution. Image from http://en.wikipedia.org/wiki/File:Fospropofol.svg (Accessed on 27 June, 2010).



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Management of the Propofol Addict

As a result of the rapid redistribution of this agent whenadministered as a bolus, the patient who has been abusing propofoland presents for surgery or a procedure requiring anesthesia will likelypresent no problems associated with acute intoxication. However, in thecase of rapid self-administration in the absence of respiratory assistanceor control of blood pressure, the patient may present with cardiac arrestor with anoxic brain injury. Trauma related to falls after bolusadministration may complicate the initial presentation but it is unlikelythat any of the propofol administered remains in clinically relevantconcentrations by the time emergency personnel arrive to administercare.

In the case of the chronic abuser of propofol, the same issues thatarise with any form of chronic intravenous drug use are applicable to thepropofol addict. Infection with human immunodeficiency virus,hepatitis C, and other blood-borne diseases should be assumed untilproven otherwise and standard universal precautions observed at alltimes. As well, chronic aspiration during repeated periods of apnea andloss of protected airway reflexes may lead to pneumonia or pneumonitisand may complicate anesthetic management.

High doses of propofol administered in the medical setting havebeen associated with sudden death,14 a phenomenon now calledpropofol infusion syndrome. The mechanism of sudden death in thechronic propofol abuser is related to the production of increased serumlevels of tumor necrosis factor a and interleukin-10 resulting in diffuseareas of myocardial band necrosis.15 These patients are particularlysusceptible for developing malignant arrhythmias, the first indicator ofwhich may be the development of ST-segment elevation in leads V1 toV3, which has been reported in the case of a chronic propofol abuser.16

Propofol infusion syndrome has also been described in a patient withrespiratory failure and sepsis.17 She had been maintained on a propofolinfusion for 7 days when a morbilliform rash developed on her upper

body. Multiple laboratory abnormalities were found including elevatedlevels of alanine transferase, aspartate transaminase, amylase, lipase,creatinine kinase, and triglycerides. Electrocardiograms (ECG) showedtachycardia. Computed tomography of the abdomen showed hepato-megaly, with fatty infiltration of the liver but a normal pancreas. Thepatient was treated with phenobarbital maintenance therapy. Labora-tory values returned to normal within 72 hours after discontinuation ofpropofol and the rash disappeared.

During the provision of anesthetic care to the patient known to be achronic propofol abuser, serious consideration should be given to theuse of agents, alternative to propofol for induction of general anesthesia.In such a patient, a preoperative ECG should be obtained regardless of

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Figure

3.

Troublesomeelectrocardiographicfi

ndingssuggestiveofincreasedriskforsuddendeathinth

echronicpropofolabuser.No

tethecoved

typeSTelevation

,J-pointelevation,graduallyd

escendingSTsegment,andnegativeT-wavesintheanteriorprecordialleads.Imageadapted

fromhttp://

lifeinthefastlane.com/2009/09/what-is-brugada-syndrome/(Accessedon24July,

2010).



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age or cardiac history, and the presence of a Brugada-like pattern(Fig. 3) is reason enough to delay any elective case pending furthercardiac evaluation (typical features in V1 to 3). If this pattern is presenton the preoperative ECG, induction of anesthesia with propofolmay result in extreme hypotension, metabolic acidosis, prolonged QTinterval, idioventricular rhythms, and ventricular fibrillation. In the caseof an emergent need to provide anesthesia, it is prudent to placeexternal defibrillation pads on the chest and back before induction andavoid propofol altogether.

Conclusions

The issue of why more people do not become addicted to anestheticagents despite the incredible number of exposures each day is likelymultifactorial. In order for a patient to become addicted to an anestheticagent, the individual must have both the ability to identify the agent theyreceived, which most people are unable to do, and gain access to theagent, which most people cannot. The majority of patients are unable toidentify the agents with which they were anesthetized, even if they findthe effects pleasurable, and thus do not even know what agent to ask foron the street. Given the recent nationwide publicity afforded propofol

after the death of Michael Jackson, it would not be surprising to see adramatic increase in the number of nonmedical personnel seekingaccess to and becoming addicted to this drug.

References

1. Brazzalotto I. Effects of propofol. Ann Fr Anesth Reanim. 1989;8:388.2. Karowski MD, Koltchine VV, Rick CE, et al. Propofol and other intravenous

anesthetics have sites of action on the gamma-aminobutyric acid type A receptordistinct from that for isoflurane. Mol Pharmacol. 1998;53:530538.

3. Kingston S, Mao L, Yang L, et al. Propofol inhibits phosphorylation of N-methyl-D-aspartate receptor NR1 subunits in neurons. Anesthesiology. 2006;104:763769.

4. Pain L, Gobaille S, Schleef C, et al. In vivo dopamine measurements in the nucleusaccumbens after nonanesthetic and anesthetic doses of propofol in rats. Anesth Analg.2002;95:191196.

5. Keita H, Lecharny JB, Henzel D, et al. Is inhibition of dopamine uptake relevant tothe hypnotic action of iv anesthetics? Br J Anaesth. 1996;77:254256.

6. Zancy JP, Lichtor JL, Thompson W, et al. Propofol at a subanesthetic dose may haveabuse potential in healthy volunteers. Anesth Analg. 1993;77:544552.

7. Follette JW, Farley WJ. Anesthesiologist addicted to propofol. Anesthesiology. 1992;77:817818.

8. Ward CF. Substance abuse, now and for some time to come. Anesthesiology. 1992;77:619622.

9. Kranioti EF, Mavroforou A, Mylonakis P, et al. Lethal self administration of propofol(Diprivan). A case report and review of the literature. Forensic Sci Int. 2007;167:5658.

10. Fritz GA, Niemczyk WE. Propofol dependency in a lay person. Anesthesiology.2002;96:505506.

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11. Kirby RR, Colaw JM, Douglas MM. Death from propofol: accident, suicide, ormurder? Anesth Analg. 2009;108:11821184.

12. Wilson C, Canning P, Caravati EM. The abuse potential of propofol. Clin Toxicol(Phila). 2010;48:165170.

13. Fed regist. 2009 Oct 6th 74(192): 51234-6 Schedule of controlled substances;placement of fospropofol into schedule 1V final rule.14. Stelow EB, Johari VP, Smity SA, et al. Propofol associated rhabdomyolysis with

cardiac involvement in adults: chemical and anatomic findings. Clin Chem. 2000;46:577581.

15. Vernooy K, Delhaas T, Cremer OL, et al. Electrocardiographic changes predictingsudden death in propofol-related infusion syndrome. Heart Rhythm. 2006;3:131137.

16. Riezzo I, Centini F, Neri M, et al. Brugada-like EKG pattern and myocardial effects ina chronic propofol abuser. Clin Toxicol. 2009;47:358363.

17. Orsini J, Ndakami A, Chen J, et al. Propofol infusion syndrome: a case report andliterature review. Am J Health Syst Pharm. 2009;66:908915.



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