Einschätzung des Abhängigkeitsrisikos von Propofol

Zusammenfassung

In einer Befragung von amerikanischem und deutschem medizinischen Personal wurde das Injektions-Hypnotikum Propofol als eines der am häufigsten missbrauchten Anästhetika genannt. Mithilfe einer MEDLINE, EMBASE, Scopus, Cochrane und Internet-Recherche wurden Daten gesucht, die eine Einschätzung des Abhängigkeitsrisikos von Propofol erlauben. Die klinische Einschätzung für Hypnotika erfolgt üblicherweise anhand der Skala nach Griffith und Johnson. Hiernach ist das relative Abhängigkeitsrisiko (Abhängigkeitspotenzial/Toxizität) von Propofol verglichen mit Phenobarbital eher mäßig ausgeprägt. Das Abhängigkeitspotenzial ist etwas geringer als das von Lorazepam und Cannabis (nicht hypnotisches Referendum) und liegt etwa im Bereich dessen von Triazolam oder Zopiclon. Die wenigen bisher publizierten klinischen Fallberichte (n = 8) stammen hauptsächlich aus Deutschland und beschreiben ausgeprägte psychische (Craving, Kontrollverlust, Verhaltenseinengung auf Konsum und Beschaffung) und wenig körperliche Abhängigkeitsmerkmale (Entzugssyndrom, Toleranz). Durchschnittlich waren in den Kasuistiken 4,25 von 6 Abhängigkeitskriterien nach ICD-10 erfüllt. Der Konsum von Propofol ist hauptsächlich auf Mediziner oder medizinnahe Berufe begrenzt. Auf den hiesigen Schwarzmärkten ist Propofol noch nicht angekommen. Ein oraler Konsum scheint nicht vorzukommen oder unattraktiv zu sein. Die Attraktivität der Rauschwirkung (Euphorie/Entspannung) von Propofol über den intravenösen Weg wird vermutlich unterschätzt. In diese Richtung weist die hohe Mortalitätsrate (46,2 %) in den bis heute insgesamt 78 publizierten Fällen zum Propofolkonsum. Forensische Analysen machen in erster Linie akzidentielle Atemstillstände für die Todesfälle verantwortlich. Zusammenfassend kann Propfol als eine primär psychisch abhängig machende Substanz gelten, die charakteristischerweise intravenös von Personen mit medizinischen Berufen konsumiert wird. Aufgrund seines offenbar sehr engen Sicherheitsraums zwischen Vergnügen und Tod besitzt Propofol eine außerordentliche Gefährlichkeit, welche in der Skala von Griffith und Johnson leider nur unzureichend abgebildet werden kann.

Abstract

In a survey of American and German medical personnel, the injectable hypnotic propofol was identified as one of the most frequently abused anaesthetics. With the help of MEDLINE, EMBASE, Scopus, Cochrane and internet search, data were sought that permit an assessment of propofol’s risk of addiction. The clinical evaluation for hypnotics can usually be made with the scale of Griffith and Johnson. Thereafter, the relative risk of addiction (dependence potential/toxicity) of propofol is rather moderate if compared to phenobarbital. Its addictive potential is somewhat lower than that of lorazepam and cannabis (non-hypnotic reference) approximately in the range of that of triazolam or zopiclon. The few published clinical case reports (n = 8) are mainly from Germany and describe distinct psychological (craving, loss of control, focusing of behaviour on the use and procurement of the substance) and low levels of physical features of addiction (withdrawal symptoms, tolerance). On average, in the case reports 4.25 of 6 criteria of dependence (ICD-10) were met. The consumption of propofol is mainly limited to medical or medical-related occupations. Propofol has yet not arrived on the local black markets. An oral consumption appears not to occur or to be unattractive. The incentive of propofol’s ”high” (euphoria/relaxation) via the intravenous route is probably underestimated. This is supported by a high mortality rate (46.2 %) in the 78 reports on the consumption of propofol up to date. Forensic analyses consider mainly accidental respiratory arrests to be responsible for the deaths. In summary, propofol is considered to be a primary mental addictive substance that is characteristically intravenously consumed by persons within the medical profession. Because of its apparently narrow safety margin between pleasure and death, propofol is an extraordinary hazard which, unfortunately, is only reflected insufficiently in the scale of Griffith and Johnson.

Schlüsselwörter

Propofol - Abhängigkeitspotenzial - Mortalitätsrisiko

Keywords

propofol - addictive potential - mortality risk

Literatur

• 1 Angelini G, Ketzler J T, Coursin D B. Use of propofol and other nonbenzodiazepine sedatives in the intensive care unit.  Crit Care Clin. 2001;  17 863-880
• 2 Fulton B, Sorkin E M. Propofol. An overview of its pharmacology and a review of its clinical efficacy in intensive care sedation.  Drugs. 1995;  50 636-657
• 3 Roussin A, Montastruc J L, Lapeyre-Mestre M. Pharmacological and clinical evidences on the potential for abuse and dependence of propofol: a review of the literature.  Fund Clin Pharmacol. 2007;  21 459-465
• 4 Bonnet U, Harkener J, Scherbaum N. A case report of propofol-dependence in a physician.  J Psychoact Drug. 2008;  40 215-217
• 5 Wilson C, Canning P, Caravati M. The abuse potential of propofol.  Clin Toxicol. 2010;  48 165-170
• 6 Bell D M, McDonough J P, Ellison J S et al. Controlled drug misuse by certified registered nurse anaesthetists.  AANA J. 1999;  67 133-140
• 7 Maier C. Süchtige Ärzte – ein oft tödliches Tabu. 2010 http://dgai-umfrage.de/postersucht.pdf
• 8 Hartle A. The safety of propofol.  BMJ. 2009;  339 b4024
• 9 Krusz J C, Scott V, Belanger J. Intravenous propofol: unique effectiveness in treating intractable migraine.  Headache. 2000;  40 224-230
• 10 Drummond-Lewis J, Scher C. Propofol: a new treatment strategy for refractory migraine headache.  Pain Med. 2002;  3 366-369
• 11 Mendes P M, Silberstein S D, Young W B et al. Intravenous propofol in the treatment of refractory headache.  Headache. 2002;  42 638-641
• 12 Wax D, Neustein S. Propofol: a novel treatment for breaking migraine headache.  Anaesthesiology. 2007;  106 405-406
• 13 EMEA .Committee for medical products for human use. Guideline of the non-clinical investigation of the dependence potential of medical products. 2006 http://www.cpdd.vcu.edu/Pages/Index/Index_PDFs/EMEAGuidelinesOnTheNonClinicalInvestigationOfTheDependencePotentialOfMedicinalProducts.pdf
• 14 FDA .Guidance for Industry – Assessment of Abuse Potential of Drugs. 2010 http://www.cpdd.vcu.edu/Pages/Index/Index_PDFs/FDA_Draft_Guidance_Abuse_Potential_26Jan2010.pdf
• 15 Griffiths R R, Johnson M W. Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds.  J Clin Psychiatry. 2005;  66 (Suppl 9) 31-41
• 16 Dilling H, Freyberger H J. Taschenführer zur ICD-10-Klassifikation psychischer Störungen. Bern: Hans Huber Verlag; 2006
• 17 American Psychiatric Association (APA) .Diagnostic and statistical manual of mental disorders. Fourth Edition. Text Revision. DSM-IV-TR. Arlington, VA: APA; 2000
• 18 Wrighley S R, Fairfield E, Jones R M et al. Induction and recovery characteristics of desflurane in day case patients: A comparison with propofol.  Anaesthesia. 1991;  46 615-622
• 19 Devlin J W, Lau A K, Tanios M A. Propofol-associated hypertriglyceridemia and pancreatitis in the intensive care unit: an analysis of frequency and risk factors.  Pharmacotherapy. 2005;  25 1348-1352
• 20 Bradner B, Blagrove M, McCallum G et al. Dreams, images and emotions associated with propofol anaesthesia.  Anaesthesia. 1997;  52 750-755
• 21 Isander G, Vinge E. Severe neuroexcitatory symptoms after anaesthesia – with focus on propofol anaesthesia.  Acta Anaesthesiol Scand. 2000;  44 144-149
• 22 Walder B, Tramer M R, Seek M. Seizure like phenomenon and propofol: a systematic review.  Neurology. 2002;  58 1327-1332
• 23 San-juan D, Chiappa K H, Cole A J. Propofol and electroencephalogram.  Clin Neurophysiol. 2010;  121 998-1006
• 24 Lopez U, Forster A, Annoni J M et al. Near-death experience in a boy undergoing uneventful elective surgery under general anesthesia.  Paediatr Anaesth. 2006;  16 85-88
• 25 Downs J W, Young P E, Durning S J. Psychogenic coma following upper endoscopy: a case report and review of the literature.  Mil Med. 2008;  173 509-512
• 26 Bhakta P, Mishra P, Tawfic Q A. Psycho-mimetic manifestations following propofol in day care surgery – case reports.  Mid East J Anesthesiol. 2010;  20 599-601
• 27 Wappler F. Das Propofol-Infusions-Syndrom. Klinik, Pathophysiologie und Therapie einer seltenen Komplikation.  Deutsch Ärztebl. 2006;  103 A705-A710
• 28 Devlin J W, Mallow-Corbett S, Riker R R. Adverse drug events associated with the use of analgetics, sedatives and antipsychotics in the intensive care unit.  Crit Care Med. 2010;  38 (Suppl 6) S231-S243
• 29 Finsterer J. Treatment of mitochondrial disorders.  Eur J Paediatr Neurol. 2010;  14 29-44
• 30 Erdil F, Demirbilek S, Begec Z et al. Effects of propofol or etomidate on QT interval during electroconvulsive therapy.  J ECT. 2009;  25 174-177
• 31 Bauer J, Hageman I, Dam H et al. Comparison of propofol and thiopental as anesthetic agents for electroconvulsive therapy: a randomized, blinded comparison of seizure duration, stimulus charge, clinical effect, and cognitive side effects.  J ECT. 2009;  25 85-90
• 32 O’Reardon J P, Takieddine N et al. Propofol for the management of emergence agitation after electroconvulsive therapy: review of a case series.  J ECT. 2006;  22 247-252
• 33 Kienbaum P, Scherbaum N, Thurauf N et al. Acute detoxification of opioid-addicted patients with naloxone during propofol or methohexital anesthesia: a comparison of withdrawal symptoms, neuroendocrine, metabolic, and cardiovascular patterns.  Crit Care Med. 2000;  28 969-976
• 34 McCowan C, Marik P. Refractory delirium tremens treated with propofol: a case series.  Crit Care Med. 2000;  28 1781-1784
• 35 Meierkord H, Boon P, Engelsen B et al. European Federation of Neurological Societies. EFNS guideline on the management of status epilepticus in adults.  Eur J Neurol. 2010;  17 348-55
• 36 Zacney J P, Lichtor J L, Thompson W et al. Propofol at subanaesthetic doses may have abuse potential in healthy volunteers.  Anaesth Analg. 1993;  77 544-552
• 37 Gündel H, Kuhs H. Kasuistische Mitteilung über neuntägigen Propofol-Missbrauch.  Anasthesiol Intensivmed Notfallmed Schmerzther. 1992;  27 181-182
• 38 Krasowski M D, Koltchine V V, Rick C E et al. Propofol and other intravenous anaesthetics have sites of action on the γ-aminobutyric acid type A receptor distinct from that for isoflurane.  Mol Phamacology. 1988;  53 530-38
• 39 Grasshoff C, Rudolph U, Antkowiak B. Molecular and systemic mechanisms of general anaesthesia: the „multi-site and multiple mechanisms” concept.  Curr Opin Anaesthesiol. 2005;  18 386-391
• 40 Kasugai Y, Swinny J D, Roberts D B et al. Quantitative localisation of synaptic and extrasynaptic GABA-A receptor subunits on hippocampal pyramidal cells by freeze-fracture replica immunolabelling.  Eur J Neurosci. 2010;  32 1868-1888
• 41 Bai D, Pennefather P S, MacDonald J F et al. The general anaesthetic propofol slows deactivation and desensitization of GABA-A receptors.  J Neurosci. 1999;  19 10 635-10 646
• 42 John E R, Prichep L S. The anesthetic cascade: A theory of how anesthesia suppresses consciousness.  Anaesthesiology. 2005;  102 447-471
• 43 Pain L, Gobaille S, Schleef C et al. In vivo dopamine measurements in the nucleus accumbens after nonanaesthetic and anaesthetic doses of propofol in rats.  Anaesthesiology. 1999;  90 191-196
• 44 Li K Y, Xiao C, Xiong M et al. Nanomolar propofol stimulates glutamate transmission to dopamine neurons: a possible mechanism of abuse potential.  J Pharmacol Exp Therap. 2008;  325 165-174
• 45 Roy A W. Dopamine, learning and motivation.  Nat Rev Neurosci. 2004;  5 483-494
• 46 Robinson T E, Berridge K C. The incentive sensitization theory of addiction: some current issues.  Phil Trans R Soc B. 2008;  363 3137-3146
• 47 Keita H, Lecharny J B, Henzel D et al. Is inhibition of dopamine uptake relevant to the hypnotic action of i. v. anaesthetics?.  Br J Anaesth. 1996;  77 254-256
• 48 Patel S, Wohlfeil E R, Rademacher D J et al. The general anaesthetic propofol increases brain-N-Narachidonylethanolamine (anandamide) content and inhibits fatty acid amide hydrolase.  Br J Pharmacol. 2003;  139 1005-1013
• 49 Bonnet U, Scherbaum N. Evidenzbasierte Behandlung der Cannabisabhängigkeit. In: Backmund M, (Hrsg). Suchttherapie.. Landsberg: Ecomed; 2007: 1-28
• 50 Heinz A, Schaefer M, Higley J D et al. Neurobiological correlates of the disposition and maintenance of alcoholism.  Pharmacopsychiatry. 2003;  36 (Suppl 3) S255-S258
• 51 Ikemoto S, Wise R A. Mapping the chemical trigger zones of reward.  Neuropharmacology. 2004;  47 (Suppl 1) 190-201
• 52 Kim J Y, Lee D, Lee K C et al. Steward’s physicochemical approach in neurosurgical patients with hyperchloremic metabolic acidosis during propofol anaesthesia.  J Neurosurg Anaesthesiol. 2008;  20 1-7
• 53 Riezzo I, Centini F, Neri M et al. Brugada-like EKG pattern and myocardial effects in a chronic propofol abuser.  Clin Toxicol. 2009;  47 358-363
• 54 Uezono S, Hotta Y, Takakuwa Y et al. Acquired Carnitine Deficiency: A Clinical Model for Propofol Infusion Syndrome?.  Anesthesiology. 2005;  103 909
• 55 Adembri C, Venturi L, Tani A et al. Neuroprotective Effects of Propofol in Models of Cerebral Ischemia – Inhibition of Mitochondrial Swelling as a Possible Mechanism.  Anesthesiol. 2006;  104 80-89
• 56 Shao H, Li J, Zhou Y et al. Dose-dependent protective effect of propofol against mitochondrial dysfunction in ischaemic/reperfused rat heart: role of cardiolipin.  Brit J Pharmacol. 2008;  153 1641-1649
• 57 Kingston S, Mao L, Yang L et al. Propofol inhibits phosphorylation of N-methyl-D-aspartate subtype of glutamate receptor in cultured hippocampal neurons.  Anaesthesiology. 2006;  104 763-769
• 58 Peters C E, Korcok J, Gelb A W et al. Anesthetic concentrations of propofol protect against oxidative Stress in primary astrocyte cultures – comparison with hypothermia.  Anesthesiology. 2001;  94 313-321
• 59 Ratnakumari L, Hemmings H C. Effects of propofol on sodium channel dependent sodium influx and glutamate release in rat cerebrocortical synaptosomes.  Anaesthesiology. 1997;  86 428-439
• 60 Daskalopoulos R, Korcok J, Farhangkhgoee P et al. Propofol protection of sodium-hydrogen exchange activity sustains glutamate uptake during oxidative stress.  Anesth Analg. 2001;  93 1199-1204
• 61 Bonnet U, Wiemann M. Neuropsychopharmaka verändern den intrazellulären pH-Wert zentraler Neurone.  Fortschr Neurol Psychiat. (im Druck)
• 62 Weerts E M, Ator N A, Griffiths R R. Comparison of the intravenous reinforcing effects of propofol and methohexital in baboons.  Drug Alcohol Depend. 1999;  57 51-60
• 63 Le Sage M G, Stafford D, Glowa J R. Abuse liability of the anaesthetic propofol: self-administration of propofol in rats under fixed-ratio schedules of drug delivery.  Psychopharmacology. 2000;  153 148-154
• 64 Pain L, Oberling P, Sandner G et al. Effect of propofol on affective state as assessed by place conditioning paradigm in rats.  Anaesthesiology. 1996;  85 121-128
• 65 Hasan Z A, Wooley D E. The short-acting anesthetic propofol produces biphasic effects –depression and withdrawal rebound overshoot – on some (but not all) limbic evoked potentials in the behaving rat.  Brain Res. 1999;  818 51-64
• 66 Drummer O H. A fatality due to propofol poisoning.  J Forensic Sci. 1992;  37 1186-1189
• 67 Chao T C, Lo D S, Chui P P et al. The first fatal 2,6-di-isopropylphenol (propofol) poisoning in Singapore: a case report.  Forensic Sci Int. 1994;  66 1-7
• 68 Odell M. Propofol abuse.  Anaesth Intensive Care. 1999;  27 539
• 69 Iwersen-Bergmann S, Rösner P, Kühnau H C et al. Death after excessive propofol abuse.  Int J Legal Med. 2001;  114 248-251
• 70 Roussin A, Mirepoix M, Lassabe G et al. Death related to a recreational abuse of propofol at therapeutic range.  Br J Anaesth. 2006;  97 268
• 71 Strehler M, Preuss J, Wollersen H et al. Lethal mixed intoxication with propofol in a medical layman.  Arch Kriminol. 2006;  217 153-160
• 72 Cirimele V, Kintz P, Doray S et al. Determination of chronic abuse of the anaesthetic agents midazolam and propofol as demonstrated by hair analysis.  Int J Legal Med. 2002;  116 54-57
• 73 Kranioti E F, 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 56-58
• 74 Kirby R R, Colaw J M, Douglas M M. Death from propofol: accident, suicide, or murder?.  Anaesth Analg. 2009;  108 1182-1184
• 75 Klausz G, Róna K, Kristóf I et al. Evaluation of a fatal propofol intoxication due to self administration.  J Forensic Leg Med. 2009;  16 287-289
• 76 Gates C. Doctor died after propofol overdose. The Press; 2009 http://Stuff.co.nz/the-press/christchurch/3155797/doctor-died-after-propofol-overdose
• 77 Booth J V, Grossmann D, Moore J et al. Substance abuse among physicians: a survey of academic anaesthesiology programs.  Anaesth Analg. 2002;  95 1024-1030
• 78 Wischmeyer P E, Johnson B R, Wilson J E et al. A survey of propofol abuse in academic anesthesiology programs.  Anesth Analg. 2007;  105 1066-1071
• 79 Follette J W, Farley W J. Anaesthesiologist addicted to propofol.  Anesthesiology. 1992;  77 817-818
• 80 Soyka M, Schütz C G. Propofol dependency.  Addiction. 1997;  92 1369-1370
• 81 Schneider U, Rada D, Rollnik J D et al. Propofol dependency after treatment of tension headache.  Addict Biol. 2001;  6 263-265
• 82 Fritz G A, Niemczyk W. Propofol dependency in a lay person.  Anaesthesiology. 2002;  96 505-506
• 83 Koopmann A, der Goltz von C, Hermann D et al. Propofol addiction initiated by anaesthetic use.  Am J Psychiatry. 2011;  168 211-212
• 84 Cohen Y, Feldinger E, Ogorek D et al. Increased propofol requirement during succeeding administrations for electroconvulsive therapy.  J Clin Anesth. 2004;  16 282-285
• 85 Fassoulaki A, Farinotti R, Manz J et al. Does tolerance develop to the anaesthetic effects of propofol in rats?.  Br J Anaesth. 1994;  72 127-128
• 86 Buckley P M. Propofol in patients needing long-term sedation in intensive care: an assessment of the development of tolerance: a pilot study.  Intensive Care Med. 1997;  23 969-974
• 87 Ypsilantis P, Mikroulis D, Politou M et al. Tolerance to propofol`s sedative effect in mechanically ventilated rabbits.  Anaesth Analg. 2006;  103 359-360
• 88 Cammarano W B, Pittet J F, Weitz S et al. Acute withdrawal syndrome related to the administration of analgetic and sedative medications in adult intensive care unit patients.  Crit Care Med. 1998;  26 676-684
• 89 Saito M, Terao Y, Fukusaki M et al. Sequential use of midazolam and propofol for long-term sedation in postoperative mechanically ventilated patients.  Anaesth Analg. 2003;  96 834-838
• 90 Cawley M J, Guse T M, Laroia A et al. Propofol withdrawal syndrome in an adult patient with thermal injury.  Pharmacotherapy. 2003;  23 933-939
• 91 Münz-Wollny R. AstraZeneca, Internet-Anfrage beim Hersteller vom 8.10.2010. 
• 92 AstraZeneca, Januar 2010, Fachinformation Disoprivan® 1 %, AstraZeneca GmbH, 22 876 Wesel. 
• 93 Fechner J, Ihmsen H, Hatterscheid D et al. Pharmacokinetics and clinical pharmacodynamics of the new propofol prodrug GPI 15 715 in volunteers.  Anesthesiology. 2003;  99 303-13
• 94 National Drug Monograph .Fospropofol (Lusedra®). Jan/2011 http:// www.pbm.va.gov/DrugMonograph.aspx/Clinical%20Guidance/Drug%20Monographs/Fospropofol%20(Lusedra)%20Monograph.doc
• 95 lawmed .Propofol to become schedule IV controlled drug. Nov/2010 http://lawmedconsultant.com/1378/propofol-to-become-schedule-iv-controlled drug
• 96 Beaujouan L, Czernichow S, Pourriat J L et al. Prévalence et facteurs de risque de l’addiction aux substances psychoactives en milieu anesthésique: résultats de l’enquête nationale.  Annales Françaises d’Anesthésie et de Réanimation. 2005;  24  471-479
• 97 Luck S, Hedrick J. The alarming trend of substance abuse in anesthesia providers.  Journal of PeriAnesthesia Nursing. 2004;  19 308-311
• 98 Deutsche Beobachtungsstelle für Drogen und Drogensucht (DBBD) .2010 http://www.dbdd.de/index.php?option=com_search&Itemid=5&searchword=Propofol&submit=Suchen&searchphrase=any&ordering=newest
• 99 Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) .2010. http://www.bfarm.de/cln_103/DE/Arzneimittel/arzneimittel-node.html;jsessionid=4F8DD661E361B9D84BF0A7033E85DC9A
• 100 European Monitoring Centre for Drug and Drug Addiction (EMCDDA) .2010 http://www.emcdda.europa.eu/www/advancedsearch.cfm
• 101 Khokhar J Y, Tyndale R F. Drug metabolism within the brain changes drug response: selective manipulation of brain CYP2B alters propofol effects.  Neuropsychopharmacol. 2010;  36 692-700
• 102 Wilson J E, Kiselanova N, Stevens Q et al. A survey of inhalational anaesthetic abuse in anaesthesia training programmes.  Anaesthesia. 2008;  63 616-620
• 103 O’Malley P. Lethal outcomes. Propofol infusion syndrome and propofol abuse.  Clinical Nurse Specialist. 2010;  24 8-10
• 104 Gold M S, Melker R J, Dennis D M et al. Fentanyl abuse and dependence: further evidence for second hand exposure hypothesis.  J Addict Dis. 2006;  25 15-21
• 105 Merlo L J, Goldberger B A, Kolodner D et al. Fentanyl and propofol exposure in the operating room: sensitization hypothesis and further data.  J Addict Dis. 2008;  27 67-76
• 106 BMFG – Bundesministerium für Gesundheit .Drogen- und Suchtbericht 2009. http://www.drogenbeauftragte.de