Propofol Abuse

Ethan O. Bryson, MD Elizabeth A.M. Frost, MD

Mount Sinai Medical Center New York, New York

Propofol (2,6-diisopropylphenol) is an intravenous anesthetic agent used for the rapid induction of general anesthesia and for moderate-to-deep sedation for painful or uncomfortable procedures. Despite the signicant potential for abuse of this agent, recreational use of propofol was, at least until recently, primarily by medical professionals. It is not classied as a controlled substance by the Unites States Drug Enforcement agency, which might suggest little potential for drug abuse and is freely available in the hospital setting. Although propofol has been used safely for over 20 years in this country without signicant problems of addiction and dependence surfacing, the tragic death of popular culture icon Michael Jackson during the summer of 2009 has brought abuse of this anesthetic agent by the layperson into the spotlight (Fig. 1).

Clinical Effects

Propofol works rapidly. Within seconds after the injection of a bolus dose of propofol, the patient begins to lose consciousness. By the time the medication has traveled from the injection site to the brain, the patient is entering a state of general anesthesia. Depending on the dose, patients awaken 5 to 10 minutes later as the drug redistributes from the active site in the central nervous system into the bodies lipid depots, provided any necessary supportive measures have been provided by the individual administering the medication. A short-acting agent with little
REPRINTS: ETHAN O. BRYSON, MD, DEPARTMENT OF ANESTHESIOLOGY, MOUNT SINAI MEDICAL CENTER, 1GUSTAVE L LEVY PLACE, NEW YORK, NY 10029, E-MAIL: ETHAN.BRYSON@MOUNTSINAI.ORG
INTERNATIONAL ANESTHESIOLOGY CLINICS Volume 49, Number 1, 173180 r 2011, Lippincott Williams & Wilkins

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

or no residual effects, the patient who has received a propofol-based sedation anesthetic typically recovers feeling well and rested. Patients have reported a broad spectrum of feelings after propofol administration 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 gaminobutyric acid type-A receptor,2 and may also interfere with the function of the N-methyl-D-aspartate receptor as well.3 As with most drugs of abuse, it is not surprising to nd that propofol also enhances the 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 of dopamine in the reward circuitry of the mesocorticolimbic system serve to reinforce the behaviors associated with obtaining and injecting propofol. For most people, this is not a conscious issue as they are likely unaware of the particular agent with which they were anesthetized, and would be unlikely to be able to obtain it if they were. On account of its favorable pharmacokinetic prole, propofol has become the induction agent of choice for most general anesthetics in the United 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 problems with 2 of the 3 major manufacturing facilities, hospitals throughout the world quickly found out that the main alternative to a propofol induction of general anesthesia, thiopental, was also in short supply, primarily because of reduced demand had signicantly reduced production. Despite its ubiquitous presence in current medical practice, however, the actual incidence of documented cases of propofol abuse is very small.

Incidence and Prevalence of Abuse

The potential abuse liability of propofol was investigated in 1993 by Zancy et al6 who conducted a discrete-choice study in humans. Healthy
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volunteer subjects with a generally light history of lifetime substance use and no history of abuse or treatment for addiction were exposed to placebo, intralipid, or propofol and then given a choice of what agent they would prefer to have during a subsequent session. In this study, users either chose propofol because they preferred the subjective effects of the drug such as feeling spaced out or high or chose placebo because they disliked the dizziness and confusion associated with propofol administration. The authors concluded that, for some people, propofol may be rewarding even in individuals without a history of substance abuse and that further abuse liability testing was indicated. Given the pharmacologic actions of propofol, it is not surprising that cases of abuse began to be reported in the medical literature soon after the drug was introduced into clinical practice. As expected, almost all cases involved medical personnel with access to the agent. In 1992, Follette and Farley7 published the rst case of propofol dependence, involving an anesthesiologist who reportedly self-administered 100 mg of propofol 10 to 15 times per day. What is most concerning about this report is the frequency with which this addict was injecting this medication. The volume of propofol required to maintain such use would be difcult to obtain without becoming detected if it were a controlled substance and in fact, an editorial accompanying this case report questioned whether or not propofol deserved to be included in the access-restricted system, if not advanced to controlled substance status all together.8 Despite this early concern, many hospitals still place no more restriction on access to propofol than to other uncontrolled medications commonly found in the anesthesia carts in any operating room. Several more cases of propofol abuse in medical personnel were reported between 1992 and 2002. In one instance, a female anesthesiologist reportedly self-administered propofol and died.9 Analysis at the scene and toxicology reports indicated blood and liver concentrations were 2.4 mg/mL and 0.56 mg/g, respectively, supporting the conclusion that the death was a consequence of propofol self-administration at therapeutic doses from a person who used the drug on a chronic basis. The rst reported case of propofol dependency in a layperson was in 2002.10 This individual was rst exposed to propofol as a treatment for tension headaches administered by an anesthesiologist. No details surrounding the nature of the treatment, such as dose of propofol used, bolus or length of infusion, number of treatments, or treatment success or failure are presented in the report, only the statement that he received several treatment sessions. Presumably, he was able to identify the substance as propofol as he was subsequently able to obtain more for personal use from various veterinarians. His case came to the attention of medical professionals when his wife found him unconscious and 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 The measured blood propofol level was 4.3 mg/mL. Given there was neither history of abuse nor signs of it at autopsy, attention focused on a male nurse acquaintance who worked in a surgical intensive care unit and presumably had access to propofol and the equipment necessary to administer it. A recent systematic review of the literature identied 45 articles relevant to evaluation of the evidence of the abuse potential of propofol.12 The articles describe the several biochemical and pharmacokinetic mechanisms of action of the agent that lend themselves to its abuse, and the physical and psychological effects that make it attractive as a recreational drug. Current evidence also supports the possibility of tolerance to and also withdrawal from propofol and its abuse potential. On the basis of their review and analysis, the authors recommend that not only the United States Drug Enforcement Administration but also other international agencies should consider regulating propofol as a controlled substance. Of note is that fospropofol (Fig. 2), a water-soluble formulation of propofol also approved for induction of anesthesia, has been placed by the Deputy Administrator of the Drug Enforcement Administration into Schedule IV of the Controlled Substance act as of 2009.13 Fospropofol is metabolized in the liver by alkaline phosphatase to propofol. As such, blood levels of propofol after an equipotent injection of fospropofol reach lower peak levels and the clinical effect is longer.

Figure 2. Chemical structure of fospropofol [dihydrogen (2,6-diisopropylphenoxy) methyl phosphate]. Note the addition of the methyl phosphate group to the propofol base structure that allows 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 when administered as a bolus, the patient who has been abusing propofol and presents for surgery or a procedure requiring anesthesia will likely present no problems associated with acute intoxication. However, in the case of rapid self-administration in the absence of respiratory assistance or control of blood pressure, the patient may present with cardiac arrest or with anoxic brain injury. Trauma related to falls after bolus administration may complicate the initial presentation but it is unlikely that any of the propofol administered remains in clinically relevant concentrations by the time emergency personnel arrive to administer care. In the case of the chronic abuser of propofol, the same issues that arise with any form of chronic intravenous drug use are applicable to the propofol addict. Infection with human immunodeciency virus, hepatitis C, and other blood-borne diseases should be assumed until proven otherwise and standard universal precautions observed at all times. As well, chronic aspiration during repeated periods of apnea and loss of protected airway reexes may lead to pneumonia or pneumonitis and may complicate anesthetic management. High doses of propofol administered in the medical setting have been associated with sudden death,14 a phenomenon now called propofol infusion syndrome. The mechanism of sudden death in the chronic propofol abuser is related to the production of increased serum levels of tumor necrosis factor a and interleukin-10 resulting in diffuse areas of myocardial band necrosis.15 These patients are particularly susceptible for developing malignant arrhythmias, the rst indicator of which may be the development of ST-segment elevation in leads V1 to V3, which has been reported in the case of a chronic propofol abuser.16 Propofol infusion syndrome has also been described in a patient with respiratory failure and sepsis.17 She had been maintained on a propofol infusion for 7 days when a morbilliform rash developed on her upper body. Multiple laboratory abnormalities were found including elevated levels of alanine transferase, aspartate transaminase, amylase, lipase, creatinine kinase, and triglycerides. Electrocardiograms (ECG) showed tachycardia. Computed tomography of the abdomen showed hepatomegaly, with fatty inltration of the liver but a normal pancreas. The patient was treated with phenobarbital maintenance therapy. Laboratory values returned to normal within 72 hours after discontinuation of propofol and the rash disappeared. During the provision of anesthetic care to the patient known to be a chronic propofol abuser, serious consideration should be given to the use 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. Troublesome electrocardiographic ndings suggestive of increased risk for sudden death in the chronic propofol abuser. Note the coved type ST elevation, J-point elevation, gradually descending ST segment, and negative T-waves in the anterior precordial leads. Image adapted from http:// lifeinthefastlane.com/2009/09/what-is-brugada-syndrome/ (Accessed on 24 July, 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 further cardiac evaluation (typical features in V1 to 3). If this pattern is present on the preoperative ECG, induction of anesthesia with propofol may result in extreme hypotension, metabolic acidosis, prolonged QT interval, idioventricular rhythms, and ventricular brillation. In the case of an emergent need to provide anesthesia, it is prudent to place external debrillation pads on the chest and back before induction and avoid propofol altogether.

Conclusions

The issue of why more people do not become addicted to anesthetic agents despite the incredible number of exposures each day is likely multifactorial. In order for a patient to become addicted to an anesthetic agent, the individual must have both the ability to identify the agent they received, which most people are unable to do, and gain access to the agent, which most people cannot. The majority of patients are unable to identify the agents with which they were anesthetized, even if they nd the effects pleasurable, and thus do not even know what agent to ask for on the street. Given the recent nationwide publicity afforded propofol after the death of Michael Jackson, it would not be surprising to see a dramatic increase in the number of nonmedical personnel seeking access 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 receptor distinct from that for isourane. Mol Pharmacol. 1998;53:530538. 3. Kingston S, Mao L, Yang L, et al. Propofol inhibits phosphorylation of N-methylD-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 nucleus accumbens 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 to the 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 have abuse 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, or murder? 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 nal rule. 14. Stelow EB, Johari VP, Smity SA, et al. Propofol associated rhabdomyolysis with cardiac involvement in adults: chemical and anatomic ndings. Clin Chem. 2000; 46:577581. 15. Vernooy K, Delhaas T, Cremer OL, et al. Electrocardiographic changes predicting sudden 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 in a chronic propofol abuser. Clin Toxicol. 2009;47:358363. 17. Orsini J, Ndakami A, Chen J, et al. Propofol infusion syndrome: a case report and literature review. Am J Health Syst Pharm. 2009;66:908915.

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