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Craving dominates propofol addiction of an affected physician.

Propofol is a very commonly used intravenous anesthetic for general anesthesia worldwide. Because of its good tolerability and compatibility, it is also very often used for short sedations in endoscopies and cardioversions and for long-term sedations in intensive care units (Angelini, Ketzler & Coursin 2001; Fulton & Sorkin 1995). In addition, propofol is used for rapid opiate detoxification either to attain deep (Kienbaum et al. 2000) or light sedation (Seoane et al. 1997). This is relevant if one considers that in the case of light sedation some of these patients with a history of addiction are exposed in a conscious-sedation manner (Rodrigo & Jonsson 1989) in which they may remember some of the experience.

In the U.S., propofol received considerable public attention because its apparent involvement in the death of Michael Jackson and the subsequent prosecution of the physician who administered it to him (Megarbane 2010). Since the 1990s, detailed clinical reports of propofol-dependent medical or medical-technical personnel have accumulated mainly from Germany (Bonnet 2011; Koopmann et al. 2011; Bonnet, Harkener & Scherbaum 2008; Soyka & Schutz 1997; Follette & Farley 1992). Rarer are reports of abuse by lay people, who usually became dependent due to off-label prescriptions (Fritz & Niemczyk 2002; Schneider et al. 2001). Most recently, a 27-yearold male Korean was reported to visit endoscopists with growing frequency with the sole aim of receive propofol after having first received it for endoscopy at the age of 24 (Roh, Park & Kim 2011). In another case, it is speculated that the pleasant feelings of awakening from several self-experienced propofol sedations as part ofmedically indicated colonoscopies induced a dependence on propofol in a German nurse (Koopmann et al. 2011). In further cases, easy access to propofol in combination with prior addictive experiences with alcohol or other drugs was assumed to be crucial to self-injection of propofol (Bonnet, Harkener & Scherbaum 2008; Fritz & Niemczyk 2002; Follette & Farley 1992; Gundel & Kuhs 1992). The case presented here, however, highlights the intense power of propofol craving even with a prior negative history of addiction.

CLINICAL CASE

A 30-year-old Caucasian physician in his last (fifth) year of residency for anesthesiology requested admission for inpatient detoxification from propofol. He came voluntarily and was not mandated by superiors or colleagues. Self-detoxifications have repeatedly failed due to an intense craving. Most powerful cues were the propofol ampoules at "easy reach."

With no prior experience with addictive substances including nicotine, the patient had tried some intravenous anesthetics two years previously. He referred to novelty-seeking as his main motive. His experience was that midazolam had the disadvantage of producing an undesirably long dizziness and fentanyl the disadvantage of aversive nausea. He injected each only one time. Propofol, however, used in the dose range of 50-100 mg IV, resulted in a few minutes of "cloudy" euphoric relaxation without subsequent dizziness. Relatively quickly, he increased the dose to a 200 mg bolus to induce sleep after work, although he had no sleep disorder. He enjoyed the effect of being "beamed away" at once ("pronapping"). He was not afraid of respiratory depression because he had never observed it in the many times he had performed sedations with propofol during cardioversions. Within a year, he increased the cumulative daily dose to 4 g; the single doses remained stable at 100-200 mg, but the number of injections increased to 20 to 40 per day. He observed no tolerance with respect to the euphoric relaxation (100 mg) or pronapping (200 mg). He often fell to the ground in these propofol sessions, but he could not remember the how the fall occurred. Since he was increasingly not able to separate self-injections from work, his colleagues became aware of him because of some transient behavioral changes and lack of attention as well as fresh hematoma on his face from falls. He also increasingly neglected his own affairs and hobbies in favor of propofol misuse.

At admission, the physical examination and additional diagnostics were normal except for multiple puncture marks in both insteps and in the left arm of this right-handed man and fresher and older fall-related hematomas. The psychiatric investigation revealed a slightly depressed and anxious state.

The course of the craving and withdrawal syndromes are shown day to day in Figure 1: the information from Figures 1A, B, D and E is from the period immediately before admission and was collected retrospectively. The patient had two lapses at work in the last two weeks before admission (Fig. 1B). The entire period of inpatient observation and detoxification treatment is shown in Figures 1C and 1F. No medication was necessary to treat symptoms. In response to the commonly used Benzodiazepine Withdrawal Symptom Scale (BWSQ2; Tyrer, Murphy & Riley 1990, see discussion) the patient remembered the following symptoms: feeling unreal, very sensitive to noise, very sensitive to light, muscle twitching, shaking or trembling, dizziness, feeling faint, feeling sick, feeling depressed, loss of memory, loss of appetite. These were mild to moderate in severity (6 to 16 of 40 possible points) and were waxing and waning within the first four to five days after the complete termination of his propofol sessions (Figure 1A). Not listed in the scale were anxiety, restlessness and hyperhidrosis; all were judged to be mild. Also craving was not an item in BWSQ2. Therefore, severity of craving for propofol was determined by a visual analog scale (specified in the legend of Figure 1). He reported that the craving lasted longer than the remaining withdrawal syndrome (Figures 1A and 1D) and was much more intense than these symptoms, leading to relapses and lapses, such as those shown at work in Figure 1B (200 mg propofol each).

During the inpatient detoxification, craving could be elicited in three therapeutic single-sessions by exposing the patient to his powerful cue-stimulus (an opened original ampoule filled with propofol). This craving (Figure 1C) and the accompanying withdrawal signs (Figure 1F) were measured directly after the opened ampoule was handed out for a minute to the patient in the presence of one author (U.B.). This procedure was performed only once per session. After repeated cue-exposure the craving for propofol became desensitized, that is, craving decreased to zero with the third exposure to an opened propofol ampoule (Figure 1C).

In further single-sessions we found an autonomy-dependency conflict by using Operationalized Psychodynamic Diagnostics (Arbeitskreis OPD 2000) and began to treat it by depth psychology. Throughout the last ten days of the inpatient detoxification the patient showed no relevant psychiatric symptoms and described a good sleep. There was no evidence of neurological disease such as epilepsy, which would have explained the reported falls. Moreover, in the diagnostic interview (SKID; Wittchen et al. 1996) by a trained psychologist no other psychiatric disorder was identified in addition to propofol dependence.

After the 14 days of inpatient detoxification in our unit the patient was transferred to a four-month inpatient rehabilitation treatment in a specialized substance dependence treatment facility. To the best of our knowledge, the patient completed this program regularly without lapsing or relapsing and wanted to return to work under abstinence-stabilizing outpatient psychotherapy. The patient could not be persuaded to take his future medical career outside of anesthesiology.

DISCUSSION

In this case, five of six possible criteria for dependence on hypnotics according to ICD-10 standards are met: craving for propofol, loss of control (falls and amnesia indicate more propofol was consumed than initially intended), narrowing behavior in favor of propofol misuse (neglecting private interests, social withdrawal, sick leave), withdrawal syndrome, and harmful use (multiple nontherapeutic puncture marks on the arms and insteps, hematoma from falls, attention deficits at work). In particular, the psychological dependence criteria (craving, loss of control and narrowed behavior) dominated the course. Because both propofol and benzodiazepines act primarily through the activation of GABA-A receptors (Bonnet 2011; Fulton & Sorkin 1995), we used the BWSQ2-scale for determining propofol withdrawal symptoms. The withdrawal syndrome showed markedly shorter duration than the craving (Figures 1A, 1D), which, unfortunately, is not listed within the BWASQ2. Within the first two weeks of total abstinence, craving but no further withdrawal symptoms could be elicited by exposing the patient to an opened propofol ampoule (Figures 1C, 1F). This described discrepancy between obvious and sustained psychological dependence criteria and rather low withdrawal symptoms and tolerance could also be demonstrated quantitatively (Figure 2) when summing the ICD-10 dependence criteria of all detailed case reports from surviving patients found in literature (Bonnet 2011; Koopmann et al. 2011; Roh, Park & Kim. 2011; Bonnet, Harkener & Scherbaum 2008; Fritz & Niemczyk 2002; Schneider et al. 2001;

Soyka & Schutz 1997; Follette & Farley 1992; Gundel & Kuhs 1992). The numerous forensic medical reports existing on this subject are not included, because these reports did not present valid descriptions of ICD-10 or DSM-IV dependence criteria (Bonnet 2011), which is nearly impossible to obtain postmortem.

[FIGURE 1 OMITTED]

Of note, the craving induced by open ampoules (Figure 1C) was estimated by the patient as not so intense as his craving at work directly before lapsing (Figure 1B), which demonstrates the great influence of context-variables on the severity of craving (Weiss 2005). Presumably, the ultra-rapid activation of synaptic and extrasynaptic "propofolophilic" GABA-A receptors (containing [beta]-1 and [beta]-3-subunits) in central reward and nonreward networks plays the crucial role in the differential expression of craving and remaining withdrawal symptoms, respectively (Bonnet 2011; Grasshoff et al. 2006; Krasowski et al. 1998). Animal experiments have repeatedly confirmed the rewarding properties of propofol (Bonnet 2011; Xiong et al. 2011), which may reflect one factor in the forming of the human feeling of craving (Weiss 2005). In the few animal studies reported on this subject so far, propofol showed little evidence of tolerance to its sedating effects or withdrawal signs on abrupt cessation (Ypsilantis et al. 2006; Hasan & Wooley 1999; Fassoulaki et al. 1994). Thus, these experimental results seem to reflect the human experiences with propofol: stronger craving combined with weaker withdrawal syndrome and tolerance (Bonnet 2011; Wilson, Canning & Caravati 2010; Roussin et al. 2007). Nonetheless, it could be assumed that withdrawal syndrome and tolerance appear more pronounced after prolonged infusion than bolus administration (Cawley et al. 2003; Cammarano et al. 1998; Buckley 1997),which is more likely to be the pattern in human addiction.

[FIGURE 2 OMITTED]

This ninth detailed clinical case report of propofol addiction is the fourth with a negative history of addiction before developing propofol dependence (Koopmann et al. 2011; Schneider et al. 2001; Soyka & Schutz 1997), which could be attributed to easy access to the drug (Monroe et al. 2011).

This report also stresses the extent to which daily propofol misuse can be performed: 20 to 40 self-injections per day were more than estimated on average for heroin or cocaine addicts, but were in the same magnitude of that reported from some addicted anesthesia personnel (Bell et al. 1999). Approximately one in ten anesthesia specialists will try out self-injecting anesthetics during his professional life (Luck & Hedrick 2004). Unlike in Europe, in the U.S. since 1970 the incidence of anesthetic misuse among anesthesiologists is investigated about every ten years. Accordingly, the ten-year incidence since 1970 remains stable at between 1% and 1.5% (Wischmeyer et al 2007; Booth et al. 2002). Most misusing anesthesiologists in the U.S. and Germany (more than 60%) preferred fentanyl or sufentanyl (Maier et al. 2010; Booth et al. 2002). Particularly striking, however, was an observed increase in propofol self-injecting anesthesiologists within the last ten years, from 0.02% to 0.1% (Wischmeyer et al. 2007). From these surveys, alarming mortality rates of around 38% (Maier et al. 2010; Wischmeyer et al. 2007) were calculated for propofol misusing anesthesiologists. Most forensic medical analyses suspected accidental apnea (Wilson, Canning & Caravati 2010; Roussin et al. 2007). More rarely, cardiac death seemed to have occurred (Riezzo et al 2009). Against this disadvantageous background, the U.S. is the first country planning statutory prescribing and dispensing control of propofol (the Drug Enforcement Administration is including it in Schedule IV; Federal Register 2010). Psycho-education, early identification, and intensive treatment and monitoring of addicted physicians may be more powerful in this context.

The patient could not be motivated to leave anesthesiology and planned to return to his usual work. We think that this is only possible under some accompanying precautions (randomized urine or hair propofol screens, outpatient abstinence maintainance psychotherapy over at least two years). However, there is some literature and opinion that anesthesiologists who have developed an addiction to drugs that are used in their practice should not be allowed to return to anesthesiology practice (Monroe et al. 2011; Wilson, Canning & Caravati 2010; Roussin et al. 2007). This should be rigorously enforced (starting with reporting him to the medical licensing authorities) when the patient lapses or relapses in outpatient observation and treatment. The subject of physicians addicted to anesthetics is a dark field in addiction research and requires more studies to derive appropriate behavior and treatment recommendations. For example, the measurement of propofol in urine and serum is possible in well-equipped clinical chemistry laboratories, but valid application studies in clinical and nonclinical populations are still lacking.

DOI: 10.1080/02791072.2012.684635

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Udo Bonnet M.D. (a) & Norbert Scherbaum M.D. (b)

(a) Head of Department of Psychiatry, Psychotherapy and Psychosomatics, Evangelisches Krankenhaus Castrop-Rauxel, & Professor, University of Duisburg/Essen, Germany

(b) Addiction Research Group at the Department of Psychiatry and Psychotherapy, Head of Department of Addictive Behaviour and Addiction Medicine, LVR-Hospital of Essen, & Professor, University of Duisburg/Essen, Germany

Please address correspondence to Dr. Udo Bonnet, Klinik fur Psychiatrie und Psychotherapie, Evangelisches Krankenhaus Castrop-Rauxel, Akademisches Lehrkrankenhaus der Universitat Duisburg/Essen, Grutholzallee 21, D-44577 Castrop-Rauxel, Germany; email: udo.bonnet@uni-due.de
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Title Annotation:Short Communication
Author:Bonnet, Udo; Scherbaum, Norbert
Publication:Journal of Psychoactive Drugs
Article Type:Case study
Geographic Code:4EUGE
Date:Jun 1, 2012
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