Fortschr Neurol Psychiatr 2004; 72(9): 503-515
DOI: 10.1055/s-2003-812459
Originalarbeit
© Georg Thieme Verlag Stuttgart · New York

Flunitrazepam und Fahrtüchtigkeit

Eine kritische Analyse relevanter StudienFlunitrazepam and Driving Ability A Critical Analysis of Relevant Studies R.  M.  Kaufmann1 , R.  Frey1 , H.  J.  Battista2 , S.  Kasper1
  • 1Klinische Abteilung für Allgemeine Psychiatrie, Universitätsklinik für Psychiatrie, Wien (Leiter: O. Univ.-Prof. Dr. Dr. h. c. S. Kasper)
  • 2Gerichtlich beeideter Sachverständiger für allgemeine Chemie, Pharmakologie und Toxikologie und Gerichtliche Medizin, Innsbruck
Further Information

Publication History

Publication Date:
30 August 2004 (online)

Zusammenfassung

Neben epidemiologischen Studien tragen vor allem experimentelle Studien dazu bei, den Einfluss von Medikamenten auf die Fahrtüchtigkeit zu erforschen. Da die Ergebnisse einer einzelnen Studie wesentlich durch das experimentelle Design determiniert sind, kann eine fundierte Einschätzung des Risikos einer Medikamenteneinnahme in Bezug auf die Fahrtüchtigkeit weder anhand einer einzelnen Studie noch anhand von Stellungnahmen, die nur wenige Studien ohne detaillierte Informationen erfassen, erfolgen. Diese Arbeit stellt eine Übersicht über veröffentlichte Studien dar, die sich direkt oder indirekt mit dem Einfluss von Flunitrazepam auf die Fahrtüchtigkeit beschäftigen, da besonders Benzodiazepine und unter ihnen speziell Flunitrazepam mit einer Beeinträchtigung der Fahrtüchtigkeit in Zusammenhang gebracht werden. Es wird versucht, besonders auf die Unterschiede hinsichtlich der verwendeten Dosierungen, experimentellen Designs und Testmethoden einzugehen. Übersichtshalber ist die Arbeit über Flunitrazepam deshalb in Akutwirkung, Residualwirkung und Wirkung nach subchronischer Applikation untergliedert. Es wurden unterschiedliche Ergebnisse berichtet, wobei aufgrund mangelnder Einheitlichkeit der Studien keine statistische Analyse im Sinne einer Metaanalyse durchgeführt wurde.

Abstract

Major contributions to the investigation of the influence of drugs on driving ability come from experimental studies as apart from epidemiological studies. Regarding experimental studies, the results of a single study are essentially determined by the experimental design. An established assessment of the risk of a drug in regard to driving ability should not be based on either a single study or on synopses, which record only a few studies without detailed information. This article presents an overview of published studies that directly or indirectly deal with the influence of flunitrazepam on driving ability. Benzodiazepines in particular, and amongst these especially flunitrazepam are brought into connection with the impairment of driving ability. This approach emphasises differences regarding the dosages used, the experimental designs and the methods of testing. For reasons of clarity the article on flunitrazepam is subdivided into the topics of acute effects, residual effects, and effects after subchronic application. Different results are reported. A statistical analysis in terms of a metaanalysis was not carried out due to a lack of standardization of the studies.

Literatur

  • 1 Woods J H, Winger G. Abuse liability of Flunitrazepam.  J Clin Psychopharmacol. 1997;  17 (Suppl. 2) 1S-57S
  • 2 Busto U, Bendayan R, Sellers E M. Clinical pharmacokinetics of non-opiate abused drugs.  Clin Pharmacokinet. 1989;  16 1-26
  • 3 Jochemsen R, Breimer D D. Pharmacokinetics of benzodiazepines: metabolic pathways and plasma level profiles.  Curr Med Res Opin. 1984;  8 60-79
  • 4 Owen R T, Tyrer P. Benzodiazepine dependence: a review of the evidence.  Drugs. 1983;  25 385-398
  • 5 Farré M, Terán M T, Camí J. A comparison of the acute behavioural effects of flunitrazepam and triazolam in healthy volunteers.  Psychopharmacology. 1996;  125 1-12
  • 6 Farré M, Terán M T, Roset P N, Mas M, Torrens M, Camí J. Abuse liability of flunitrazepam among methadone-maintained patients.  Psychopharmacology. 1998;  140 486-495
  • 7 Keup W. Flunitrazepam (Rohypnol) - führend beim Missbrauch unter den Benzodiazepin-Derivaten.  Sucht. 1992;  38 3-6
  • 8 Barnas C, Rossmann M, Rössler H, Reimer Y, Fleischhacker W W. Benzodiazepines and other psychotropic drugs abused by patients in a methadone maintenance program: familiarity and preference.  J Clin Psychopharmacol. 1992;  12 397-402
  • 9 Navaratnam V, Foong K. Adjunctive drug use among Opiate addicts.  Curr Med Res Opin. 1990;  11 611-619
  • 10 San L, Tato J, Torrens M, Castillo C, Farré M, Cami J. Flunitrazepam consumption among Heroin addicts admitted for inpatient detoxification.  Drug Alcohol Depend. 1993;  32 281-286
  • 11 Calhoum S R, Wesson D R, Galloway G P, Smith D E. Abuse of Flunitrazepam (Rohypnol) and other benzodiazepines in Austin and South Texas.  J Psychoact Drugs. 1996;  28 183-189
  • 12 Krüger H P, Schulz E, Magerl H. Medikamenten- und Drogennachweis bei verkehrsunauffälligen Fahrern, Roadside Survey. Berichte der Bundesanstalt für Straßenwesen, Mensch und Sicherheit. 1996: Heft M 60
  • 13 Augsburger M, Rivier L. Drugs and alcohol among suspected impaired drivers in Canton de Vaud (Switzerland).  Forensic Sci Int. 1997;  85 95-104
  • 14 Lillesunde P, Korte T, Michelson L, Portman M, Pikkarainen J. Drugs usage of drivers suspected of driving under the influence of alcohol and/or drugs. A study of one week's samples in 1979 and 1993 in Finland.  Forensic Sci Int. 1996;  77 119-129
  • 15 Skurtveit S, Christophersen A S, Morland J. Female drivers suspected for drunken or drugged driving.  Forensic Sci Int. 1995;  75 139-148
  • 16 Barbone F, McMahon A D, Davey P G, Morris A D, Reid I C, McDevitt D G, MacDonald T M. Association of road-traffic accidents with Benzodiazepine use.  Lancet. 1998;  353 1331-1336
  • 17 Currie D, Hashemi K, Fothergill J, Findlay A, Harris A, Hindmarch I. The use of antidepressants and benzodiazepines in the perpetrators and victims of accidents.  Occup Med (Lond). 1995;  45 323-325
  • 18 Neutel C I. Risk of traffic accident injury after a prescription for a benzodiazepine.  Ann Epidemiol. 1995;  5 239-244
  • 19 Fortenberry J C, Brown D B, Shevlin L T. Analysis of drug involvement in traffic fatalities in Alabama.  Am J Drug Alcohol Abuse. 1986;  12 257-267
  • 20 Gjerde H, Beylich K M, Morland J. Incidence of alcohol and drugs in fatally injured car drivers in Norway.  Accid Anal Prev. 1993;  25 479-483
  • 21 Mercer G W, Jeffery W K. Alcohol, drugs, and impairment in fatal traffic accidents in British Columbia.  Accid Anal Prev. 1995;  27 335-343
  • 22 Druid H, Holmgren P, Ahlner J. Flunitrazepam: an evaluation of use, abuse and toxicity.  Forensic Sci Int. 2001;  122 136-141
  • 23 Honkanen R, Ertama L, Linnoila M, Alha A, Lukkaria I, Karlsson M, Kiviluoto O, Puro M. Role of drugs in traffic accidents.  Br Med J. 1980;  281 1309-1312
  • 24 Thomas R E. Benzodiazepine use and motor vehicle accidents: Systematic review of reported association.  Can Fam Physican. 1998;  44 799-808
  • 25 Bocca M L, Le Doze F, Etard O, Pottier M, L'Hoste J, Denise P. Residual effects of zolpidem 10 mg and zopiclone 7.5 mg versus flunitrazepam 1 mg and placebo on driving performance and ocular saccades.  Psychopharmacology. 1999;  143 373-379
  • 26 Gerhard U, Linnenbrink N, Georghiadou C, Hobi V. Vigilanzmindernde Effekte zweier pflanzlicher Schlafmittel.  Schweizer Rundschau für Medizin (Praxis). 1996;  85 473-481
  • 27 Harrison C, Subhan Z, Hindmarch I. Residual effects of zopiclone and benzodiazepine hypnotics on psychomotor performance related to car driving.  Drugs Exp Clin Res. 1985;  XI 823-829
  • 28 Vermeeren A, O'Hanlon J F, DeClerk A C, Kho L. Acute effects of zolpidem and flunitrazepam on sleep, memory and driving performance, compared to those of partial sleep deprivation and placebo.  Acta Ther. 1995;  21 47-64
  • 29 Hindmarch I. Psychomotor function and psychoactive drugs.  Br J Clin Pharmacol. 1980;  10 189-209
  • 30 Curran H V. Benzodiazepines, memory and mood: a review.  Psychopharmacology. 1991;  105 1-8
  • 31 Bond A J, Lader M H. Residual effects of flunitrazepam.  Br J Clin Pharmacol. 1975;  2 143-150
  • 32 Saletu B, Grünberger J, Taeuber K, Nitsche V. Relation between pharmacodynamic and -kinetics: EEG and psychometric studies with cinolazepam and nomifensine. In: Hermann. EEG in Drug Research. Stuttgart, New York: Gustav Fischer 1982: 89-111
  • 33 Griffiths A N, Marshall R W, Richens A. Saccadic eye movement analysis as a measure of drug effects on human performance.  Br J Clin Pharmacol. 1984;  18 73S-82S
  • 34 Staak M, Hobi V, Berghaus G. Testverfahren zur Überprüfung des Einflusses von Arzneimitteln auf die Verkehrssicherheit - Medizinischer Schwerpunkt. In: Dilling J, Friedel B. 8305/2,. Bergisch Gladbach, Bundesanstalt für Straßenwesen. Forschungsberichte der BASt - Unfallforschung. 1988: 1-195
  • 35 Berghaus G. Persönliche Mitteilung. 1998
  • 36 Kasper S, Volz H P. Psychiatrie compact. Stuttgart, New York: Georg Thieme Verlag 2003
  • 37 Allain H, Patat A, Lieury A, Le Coz F, Janus C, Ménard G, Gandon J M. Comparative study of the effects of zopiclone (7.5 mg), zolpidem, flunitrazepam and a placebo on nocturnal cognitive performance in healthy subjects, in relation to pharmacokinetics.  Eur Psychiatry. 1995;  10 (Suppl 3) 129s-135s
  • 38 Bareggi S R, Ferini-Strambi L, Pirola R, Smirne S. Impairment of memory and plasma flunitrazepam levels.  Psychopharmacology. 1998;  140 157-163
  • 39 Ingum J, Bjørklund R, Bjørnboe A, Christophersen A, Dahlin E, Mørland J. Relationship between drug plasma concentrations and psychomotor performance after single doses of ethanol and benzodiazepines.  Psychopharmacology. 1992;  107 11-17
  • 40 Smirne S, Ferini-Strambi L, Pirola R, Tancredi O, Franceschi M, Pinto P, Bareggi S R. Effects of flunitrazepam on cognitive functions.  Psychopharmacology. 1989;  98 251-256
  • 41 Wickstrom E, Godtlibsen O B. The effects of quazepam, triazolam, flunitrazepam and placebo, alone and in combination with ethanol, on day-time sleep, memory, mood and performance.  Hum Psychopharmacol. 1988;  3 101-110
  • 42 Linnoila M, Erwin C W, Brendle A, Logue P. Effects of alcohol and flunitrazepam on mood and performance in healthy young men.  J Clin Pharmacol. 1981;  21 430-435
  • 43 Kuhlmann J, Berger W, Podzuweit H, Schmidt U. The influence of valerian treatment on “reaction time, alertness and concentration” in volunteers.  Pharmacopsychiatry. 1999;  32 235-241
  • 44 Schmidt U, Brendemühl D, Ruther E. Aspects of driving after hypnotic therapy with particular reference to temazepam.  Acta Psychiatr Scand. 1986;  (Suppl 332) 112-118
  • 45 Sicard B A, Trocherie S, Moreau J, Vieillefond H, Court L A. Evaluation of zolpidem on alertness and psychomotor abilities among aviation ground personnel and pilots.  Aviat Space Environ Med. 1993;  64 371-375
  • 46 Stanley R O, Tiller J WG, Adrian J. The psychomotor effects of single and repeated doses of hypnotic benzodiazepines.  Int Clin Psychopharmacol. 1987;  2 317-323
  • 47 Dujardin K, Guieu J D, Leconte-Lambert C, Leconte P, Borderies P, de La Giclais B. Comparison of the effects of zolpidem and flunitrazepam on sleep structure and daytime cognitive functions: A study of untreated unsomniacs.  Pharmacopsychiatry. 1998;  31 14-18
  • 48 Rettig H C, Zuurmond W WA, Leeuwen L van. Quality of sleep and psychomotor performance after lormetazepam or flunitrazepam: a randomized and double-blind study.  J Drugtherapy Res. 1988;  13 141-144
  • 49 Bensimon G, Foret J, Warot D, Lacomblez L, Thiercelin J F, Simon P. Daytime wakefulness following a bedtime oral dose of zolpidem 20 mg, flunitrazepam 2 mg and placebo.  Br J Clin Pharmacol. 1990;  30 463-469
  • 50 Mattmann P, Loepfe M, Scheitlin T, Schmidlin D, Gerne M, Strauch I, Lehmann D, Borbély A A. Day-time residual effects and motor activity after three benzodiazepine hypnotics.  Arzneimittelforschung. 1982;  32 461-465
  • 51 Ott H. Are electroencephalographic and psychomotor measures sensitive in detecting residual sequelae of benzodiazepine hypnotics?.  Psychopharmacology. 1984;  (Suppl 1) 133-151
  • 52 Seppälä T, Nuotto E, Dreyfus J F. Drug-alcohol interactions on psychomotor skills: Zopiclone and Flunitrazepam.  Pharmacology. 1983;  27 (Suppl 2) 127-135
  • 53 Short T G, Galletly D C. Acute tolerance from benzodiazepine night sedation.  Anaesthesia. 1991;  46 929-931
  • 54 Frattola L, Maggioni M, Cesana B, Priore P. Double blind comparison of zolpidem 20 mg versus flunitrazepam 2 mg in insomniac in-patients.  Drugs Exp Clin Res. 1990;  XVI 371-376
  • 55 Hindmarch I. A repeated dose comparison of three benzodiazepine derivatives (nitrazepam, flurazepam and flunitrazepam) on subjective appraisals of sleep and measures of psychomotor performance the morning following night-time medication.  Acta Psychiatr Scand. 1977;  56 373-381
  • 56 Hindmarch I, Parrott A C, Arenillas L. A repeated dose comparison of dichloralphenazone, flunitrazepam and amylobarbitone sodium on some aspects of sleep and early morning behaviour in normal subjects.  Br J Clin Pharmacol. 1977;  4 229-233
  • 57 Hofferberth B. Saccadic eye movements as a measure of residual effects: temazepam compared with other hypnotics.  Acta Psychiatr Scand. 1986;  74 (Suppl. 332) 105-111
  • 58 Lader M, Melhuish A, Harris P. Residual effects of repeated doses of 0.5 and 1 mg flunitrazepam.  Eur J Clin Pharmacol. 1982;  23 135-140
  • 59 Charlier C J, Maes V A, Smet H C, Verrstraete A, Wennig R. Influence des médicaments sur les capacités de conduite - Etude de la littérature. In: van Den Meersschaut C. 1. Brussel, Institut Belge pour la Sécurité Routiére asbl. 1999 (IBSR)
  • 60 Kaufmann R M. Medikamente und Fahrtüchtigkeit - Klassifizierung von Benzodiazepinderivaten nach pharmakologischen und verkehrsmedizinischen Gesichtspunkten. Dissertation, Institut für Gerichtliche Medizin der Leopold-Franzens-Universität Innsbruck. 2002: 1-220
  • 61 Darcourt G, Pringuey D, Salliere D, Lavoisy J. The safety and tolerability of zolpidem - an update.  J Psychopharmacol. 1999;  13 81-93
  • 62 DeClerk A C, Bisserbe J C. Short-term safety profile of zolpidem: objective measures of cognitive effects.  Eur Psychiatry. 1997;  12 (Suppl 1) 15s-20s
  • 63 Lader M, Hindmarch I. Memory, psychomotor and cognitive functions after treatment with zolpidem. In: Freeman H, Puech AJ, Roth T. eds.: Zolpidem an update of its pharmacological properties and therapeutic place in the management of insomnia. Paris: Elsevier 1996: 59-71
  • 64 Unden M, Roth Schechter B. Next day effects after nighttime treatment with zolpidem: A review.  Eur Psychiatry. 1996;  11 (Suppl. 1) 21S-30S
  • 65 Greenblatt D J, Divoll M, Harmatz J S, Mac Laughlin D S, Shader R I. Kinetics and clinical effects of flurazepam in young and elderly noninsomniacs.  Clin Pharmacol Ther. 1981;  30 475-486
  • 66 Greenblatt D J, Harmatz J S, Shapiro L, Engelhardt N, Gouthro T A, Shader M D. Sensitivity to triazolam in the elderly.  N Engl J Med. 1991;  324 1691-1698
  • 67 Ray W A, Thapa P B, Shorr R I. Medications and the older driver.  Clin Geriatr Med. 1993;  9 413-438
  • 68 Roth T, Ancoli-Israel S. Daytime consequences and correlates of insomnia in the United States: results of the 1991 National Sleep Foundation Survey. II.  Sleep. 1999;  Suppl 2 S354-S358
  • 69 Ellinwood E H, Heatherly D G. Benzodiazepines, the popular tranquilizers: Dynamic of effect on driving skills.  Accid Anal Prev. 1985;  17 283-290
  • 70 Kunsman G W, Manno J E, Manno B R, Kunsman C M, Przekop M A. The use of microcomputer-based psychomotor tests for the evaluation of benzodiazepine effects on human performance: a review with emphasis on temazepam.  Br J Clin Pharmacol. 1992;  34 289-301
  • 71 Bramness J G, Skurtveit S, Mørland J. Clinical impairment of benzodiazepines-relation between benzodiazepine concentrations and impairment in apprehended drivers.  Drug Alcohol Depend. 2002;  68 131-141
  • 72 de Gier J J. Driving tests with patients.  Br J Clin Pharmacol. 1984;  18 103S-108S
  • 73 Ramaekers J G, Veggel L M van, O'Hanlon J F. A cross-study of the effects of moclobemide and brofaromine on actual driving performance.  Clin Neuropharmacol. 1994;  17 (Suppl 1) S9-S18
  • 74 Volkerts E R, Vries G de, Wiethof M, Meyer T, O'Hanlon J F. Loprazolam and flunitrazepam's residual effects upon actual driving performance. Technical Report VK 83 - 04. University of Groningen, Netherlands: Traffic Research Centre 1983
  • 75 Volkerts E R, Louwers J W, Gloerich A BM, Brookhuis K J, O'Hanlon J F. Zopiclone's residual effects upon actual driving performance versus those of nitrazepam and flunitrazepam. Technical Report VK 84 - 10. University of Groningen, Netherlands: Traffic Research Centre 1984
  • 76 Irving A, Jones W. Methods for testing impairment of driving due to drugs.  Eur J Clin Pharmacol. 1992;  43 61-66
  • 77 Stone B I. Pencil and paper tests-sensitivity to psychotropic drugs.  Br J Clin Pharmacol. 1984;  18 15S-20S
  • 78 Hindmarch I, Ott H, Roth T. Sleep, benzodiazepines and performance. “Experimental Methodologies and Research Prospects”. Heidelberg: Springer Verlag 1984
  • 79 Wittenborn J R, Flaherty C F, Hamilton L W, Schiffman R T, McGough W E. The effect of minor tranquilizers on psychomotor performance.  Psychopharmacology. 1976;  47 281-286
  • 80 Berghaus G, Staak M. Testverfahren zur Überprüfung des Einflusses von Arzneimitteleinnahme auf die Fahrsicherheit.  Beitr Gerichtl Med. 1988;  46 67-70
  • 81 Ferrara S D. Quality assurance and standardization of empirical trials on drugs and driving. Proceedings of the 12th international conference on alcohol, drugs and traffic safety. Köln 1992

Dr. Rainer Marco Kaufmann

Klinische Abteilung für Allgemeine Psychiatrie · Univ.-Klinik für Psychiatrie · Medizinische Universität Wien

Währinger Gürtel 18 - 20

1090 Wien

Österreich

Email: rainer.kaufmann@akhwien.at

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