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1 CNS Drugs The Relationship between Benzodiazepine Use and Traffic Accidents A Systematic Literature Review Beitske E. Smink, et al. Supplemental Digital Content This Supplemental Digital Content contains the table referred to in the full version of this article, which can be found at Adis Data Information BV. All rights reserved.

2 First author (year of publication)* Country Study design Study population Study period Outcome Substances of interest (determinants) 'Benzodiazepine/Driving' France Case-control Injured crash involved road users (n Accident-related Ethanol, Collaborative Group (1993) total = 2852): responsible drivers (n injury, hospitalization = 1599) and non-responsible drivers yes/no and pedestrians injured (n =9 99) Exposure assessment Toxicological results (plasma) IMMORTAL R4.2 (2005) Netherlands Case-control Injured crash involved drivers admitted to a hospital (cases, n = 184) and randomly selected drivers (controls, n = 3779) Accident-related injury Ethanol,, tricyclic antidepressants, methadone, opiates, amphetamines, cannabis, cocaine Toxicological results (breath, serum,, questionnaire IMMORTAL R4.2 (2005) Norway Case-control Injured and killed drivers (cases, n = 87) and randomly selected drivers (controls, n = 410) IMMORTAL R4.2 (2005) UK Case-control Fatally injured drivers (cases, n = 22) and randomly selected drivers (controls, n = 1312) Adams JE (2003) USA Case-control Fatally injured crash involved road users (n = 255) Accident-related injury or death Fatal accidents (cases); (controls) Incidence and nature of pelvic fractures Ethanol, amphetamine,, cannabis, cocaine, ecstasy, opiates Ethanol,, codeine, other opiates, amphetamines, ecstasy, cannabis, cocaine Ethanol, cocaine, Toxicological results (breath, autopsy/blood samples, oral fluid) Toxicological results (breath, postmortem samples, oral fluid), questionnaire Ahlm K (2009) Sweden Case-control Fatally injured drivers (n = 56) and hospitalized non-fatally injured drivers (n = 144) (cases); (controls) Prevalence, crash and injury characteristics Barbone F (1998) UK Case cross-over drivers involved in a first road Accidents, severity of traffic accident, 916 ever users of injury, driver at fault Ethanol, 200 most commonly used pharmaceutical substances and illicit drugs, tricyclic antidepressants, selective serotonin-reuptake inhibitor, other psychoactive drugs, results breath test Barnas C (1992) Austria Case-control Victims of ski accidents (n = 402) Severity of injury Ethanol, Toxicological results (, questionnaire Binnie GAC (1983) UK Cohort Patients aged over 15 years of one practice (n = 410; 205 pairs of drug takers and controls) Bo O (1975) Norway Case-control Injured motor vehicle drivers (n = 74) and non-accident drivers attending routine medical check-ups (n = 204) Accidents, phenothiazines, antidepressants 1973 Accident-related injury Ethanol, diazepam plasma)

3 Bouchard J (2004) Canada Case-control Fatally injured drivers (n total = 855; cases who had been involved in prior collisions causing bodily injury n = 53, controls n = 802; cases who had been involved in prior collisions causing property damage n = 161, controls n = 694) Accidents with or Ethanol, cannabis, cocaines, without involvement in opiates, PCP,, prior collisions causing barbiturates, amphetamines bodily injury or property damage Bramness JG (2002) Norway Cross-sectional Suspected drivers under the influence of ethanol or only one benzodiazepine (n = 10,759 and 818 resp) Bramness JG (2003) Norway Cross-sectional Suspected drivers under the influence of only one benzodiazepine (n = 818) Christensen LQ (1990) Denmark Cross-sectional Drivers suspected for drug influence (n = 461) Clinical impairment Ethanol, Clinical impairment Accidents Barbiturates,, other sedatives, cyclic antidepressives, antiepileptics, neuroleptics, opioids, CNS stimulants, cannabinoids, remaining drugs Christophersen AS (1995) Norway Case-control Drivers involved in an injury accident and the Norwegian population 1993 Non-fatal accidents Ethanol, cannabinoids, amphetamines, cocaine,, and Norwegian statistics of barbiturates, opiates and sales other analgesic drugs, muscle relaxants, antiepileptics, neuroleptics, antidepressants, antihistamines Cimbura G (1982) Canada Case-control Fatally injured drivers (n = 401) and pedestrians (n = 83) Fatal accidents Ethanol, basic, neutral and acidic drugs urine and occasionally vitreous humor, stomach content, liver) Currie D (1995) UK Case-control Responsible (n = 163) and not responsible people (n = 66) involved in accidents and presenting at two hospitals 1992 Injurious accidents for which there were no evident external factors Ethanol, tricyclic antidepressants, serum)

4 Drummer OH (2004) Australia Case-control Responsible (n = 2701) and not responsible (n = 509) fatally injured drivers Fatal accidents in which the driver was culpable for the crash Ethanol,, amphetamine group (e.g. cocaine), opiate group, cannabinoid group, other psychoactive drugs, miscellaneous group (nonpsychoactive drugs) Dubois S (2008) Canada Case-control Drivers aged 20 years and over involved in fatal crashes in the United States (n = ) Potentially unsafe driving actions in relation to the crash Dussault S (2002) Canada Case-control Fatally injured drivers (cases, n = 354) and randomly selected drivers (controls, n = 5931) Engeland A (2007) Norway Cohort All Norwegians aged years between April 2004 and September 2005 (3.1 million): incidence of accidents in the exposed persontime compared with unexposed person-time French DD (2005) USA Cohort Patients at a Veterans Administration hospital system taking without concomitant drug use (n = 7522) and patients taking concomitant use of and other drugs (n = 6223) (preliminary results) Fatal accidents Ethanol, cannabis, cocaine,, opiates, barbiturates, amphetamines, PCP Accidents Opiates, (tranquilizers and hypnotics), NSAIDs, antiasthmatics, penicillins, calcium receptor antagonists Injury-related medical event Concomitant use of and other drugs Toxicological results (breath, blood, Garriott JC (1977) USA Case-control All motor vehicle-associated fatalities: drivers at fault (n = 105), drivers not at fault (n = 22), passengers (n = 58), pedestrians (n = 22) Gibson JE (2009) UK Case-crossover and case-series Individuals, aged years, involved in a motor vehicle crash (n = ) Gustavsen I (2008) Norway Cohort all Norwegians aged between January 7th 2004 until September 30th 2006 (3.1 million) Fatal accidents in which the driver was at fault Alcohol and drugs Motor vehicle crashes, non- hypnotics, beta-blockers, opioids, acetaminophen/opioid compound analgesics, tricyclic antidepressants, selective serotonin reuptake inhibitors, antihistamines Accidents Zopiclone, zolpidem, flunitrazepam, nitrazepam

5 Hebert C (2007) Canada Case-crossover compared to unmatched casecontrol See Hemmelgarn B (1997): drivers involved in an injurious crash (n = 5579) and controls (n = ). For case-crossover study: controls are cases during control periods Injurious motor vehicle crashes having a long elimination (>24h) and having a short elimination ( 24h) Hemmelgarn B (1997) Canada Nested case-control drivers (aged years) involved in an injurious crash (n=5579) and controls (13 256) Injurious motor vehicle crashes having a long elimination (>24 h) and having a short elimination ( 24 h) Honkanen R (1980) Finland Case-control Injured crash involved drivers presented at emergency departments (cases, n = 201) and randomly selected drivers at petrol stations (controls, n = 325) 1977 Accident-related injury Ethanol, psychotropic drugs (e.g. ) serum), interviews Jacobson B (1983) Sweden Case-series Traffic accident victims (drivers, cyclists or pedestrians over the age of 15 years) treated at two hospitals (n = 244) Jick H (1981) USA Case-control People aged years hospitalized for injuries suffered in an automobile accident (n = 244): fault drivers (n = 93), passengers (n = 66), others (n = 85) Accidents, AIS (injury severity) Ethanol and other drugs (e.g. ) Accident-related injury Analgesics, antihistamines, sedative/minor tranquilizer drugs, hypnotics, major tranquilizers, questionnaire Kirby J (1992) USA Case-control Injured drivers aged 15 years and older admitted to a trauma service (n = 201) Kuitunen T (1994) Finland Cross-sectional Drivers suspected to be driving under the influence of alcohol and/or drugs (n = 327) 1988 Incidence, ISS (injury severity) Ethanol, opiates, cocaine metabolite, amphetamines, barbiturates,, cannabinoids Performance on the clinical test for drunkenness (concentration related) ethanol, Kuitunen T (1994) Finland Cross-sectional Drivers tested positive for diazepam alone (n = 130) Performance on the clinical test for drunkenness (concentration related) Diazepam (acute and chronic use) Kurzthaler I (2003) Austria Case-control Patients injured in a traffic accident and admitted to the trauma surgery emergency room (n = 269) 1995 Incidence, trauma (injury severity) Ethanol, Kurzthaler I (2005) Austria Case-control Non-fatal injured patients admitted to the trauma surgery emergency room (n = 1611) 1995 Accident type and trauma (injury severity) Ethanol,

6 Leveille SG (1994) USA Matched case-control Members of a large Seattle-based health maintenance organization over age 65 years: drivers involved in injurious crashes (n = 234) and controls (n = 447) Levy RS (1996) USA Case-control All patients admitted to the orthopaedic service aged 14 years or older (n = 766; tox analysis n = 628 (82%)) Injurious collisions, cyclic antidepressants, opioids, sedating antihistamines Injury grade Ethanol, opiates, cocaine, barbiturates, amphetamines, cannabinoids,, phencyclidine toxicological results (blood, Longo MC (2000) Australia Case-control Culpable and not culpable injured car drivers (n = 2029) and motorcycle riders (n = 250) Longo MC (2001) Australia Case-control Culpable and not culpable injured drivers, benzodiazepine positive only (n = 68) MacDonald T (1999) UK Case cross-over See Barbone 1998, hospitalized patients with trauma (risk of trauma) Accidents in which drivers are judged culpable Accidents in which drivers are judged culpable Ethanol, cannabinoids,, stimulants Accidents, injury See Barbone 1998; in addition results of a previous study (the relation between benzodiazepine use and risk of hospitalization) MacPherson RD (1984) Australia Case-control Drivers subjected to evidential breath analysis with (n = 5011) and without (n = 9813) crash involvement McGwin G (2000) USA Population based casecontrol study Drivers aged 65 years and older: atfault drivers involved in crashes (n = 244), not at-fault drivers involved in crashes (n = 182) and drivers not involved in crashes (n = 475) Accidents 13 groups (e.g. analgesics, CNS depressant drugs, including a drug negative group) 1996 Accidents Medical condition, medications Breath analysis, self-reported "tablets, drugs, insulin or medicine" Telephone interviews Meulemans A (1998) Belgium Case-control Drivers, aged at least 14 years, involved in a traffic accident on a public road and entering by direct admission one of the selected emergency departments Missen A (1978) New Zealand Case-series Hospitalized drivers, fatally injured drivers, apprehended drivers with low blood alcohol levels, selected drivers (n = 1500) Prevalence, type of accidents and kind of injuries, characteristics of the victims Ethanol, amphetamines, barbiturates,, cannabinoids, cocaine, opiates, methadone, propoxyphene 3 year period Driving impairment Ethanol, diazepam and its major metabolite (Ndesmethyldiazepam)

7 Movig K (2004) Netherlands Case-control Injured drivers admitted to the emergency room of a hospital (cases, n = 110) and randomly selected drivers (controls, n = 816) Accident-related injury Ethanol, amphetamines, barbiturates,, cannabis, methadone, opiates, tricyclic antidepressants Toxicological results (serum, urine, breath) Mura P (2003) France Case-control Drivers involved in a non-fatal accident admitted to an emergency department (cases, n = 900) and patients attending the same emergency units for a non-traumatic reason (controls, n = 900) Non-fatal accident related injury Ethanol, cannabinoids, opiates, cocaine, metabolites, amphetamines, psychoactive therapeutic drugs Murray N (1960) USA Cohort Drivers taking methaminodiazepoxide (Librium) [n = 68] Unknown Unpredicted sideeffects (e.g. increased Methaminodiazepoxide road accident frequency in a period of 90 days) Not described Neutel CI (1995) Canada Cohort Adults over 20 years, included in the Saskatchewan Health Database: patients who filled prescriptions for a (n= ) and controls (n=97 862) Neutel CI (1995) Canada cohort Adults over 20 years, included in the Saskatchewan Health Database: patients who filled prescriptions for a (n= ) and controls (n=97 862) traffic accident injuries benzodiazepine hypnotics (triazolam, flurazepam) and benzodiazepine anxiolytics (oxazepam, lorazepam, diazepam) medical event, e.g. benzodiazepine hypnotics traffic accident injuries (triazolam, flurazepam) and benzodiazepine anxiolytics (oxazepam, lorazepam, diazepam) prescription data (first prescription in 6 months) prescription data Neutel CI (1998) Canada cohort Adults aged over 20 years, included in the Saskatchewan Health Database: new users cohort (n = ), repeat users cohort (n = ), combined controls (n = ) Injurious traffic accidents (age, benzodiazepine halflife, first-time/longterm related) Benzodiazepine hypnotics (triazolam, flurazepam) and benzodiazepine anxiolytics (oxazepam, lorazepam, diazepam) Oster G (1987) USA Cohort Benzodiazepine users (n = 7271) and nonusers (65 439) aged not over 65 years Oster G (1990) USA Cohort Benzodiazepine tranquillizer users (n = 4554) and users of drugs other than (n = ) 1986 Accidental injury requiring medical attention Accidental injury requiring medical attention Claims for Benzodiazepine tranquillizers Pharmacy claims

8 Ray WA (1992) USA Cohort Medicaid enrollees aged years of age who had a valid driver's licence: 2978 person-years of use and person-years of no psychoactive drug use and involvement in 495 injurious crashes Injurious crashes, cyclic antidepressants, oral opioid analgesics, antihistamines Rivara FP (1989) USA Case-control Fatally (n = 160) and nonfatally (n = 452) injured trauma victims 1986 AIS, ISS (injury severity) Ethanol, marijuana, cocaine, opiates, Rapoport MJ (2008) Canada Case-crossover Drivers with dementia aged 65 years and older (n = 8690) Motor vehicle collisions Psychotropic medication (antipsychotics, antidepressants, ) and control medications topical antifungals, topical corticosteroids) Sjogren H (1997) Sweden Case-control Fatally injured drivers (n = 111) and hospitalized injured motor vehicle drivers (n = 130) Skegg DCG (1979) UK Nested case-control Injured drivers in road accidents (n = 57) and matched controls (n = 1425) Prevalence, crash and injury characteristics Serious road accidents Ethanol, licit drugs (e.g. ) and illicit drugs Minor tranquilizers (e.g. ) and major tranquilizers (e.g. phenothiazines) Smink BE (2005) Netherlands Cross-sectional Crash involved drivers (n=993) Injury severity Ethanol, opiates, amphetamines, cocaine, methadone, cannabinoids,, barbiturates, tricyclic antidepressants Smink BE (2008) Netherlands Cross-sectional Suspected drivers under the influence of only (n = 171) Performance on field sobriety tests Smink BE (2008) Netherlands Nested case-control Injured car drivers admitted to a regional trauma center (n = 106) Injury severity Ethanol, amphetamines, barbiturates,, cannabis, cocaine, methadone, opiates, tricyclic antidepressants Stoduto G (1993) Canada Case-series Seriously nonfatally injured motor vehicle collision victims admitted to a Regional Trauma Unit (n = 854) Incidence, demographic, injury, crash characteristics Ethanol, various licit and illicit drugs (e.g. cannabinoids, cocaine,, opiates)

9 Tamblyn R (2005) Canada Cohort Persons aged 65 years and older (n = ): new users (n = ) and never users (n = ) during follow-up The first occurrence of a nonvertebral fracture, soft-tissue injury or accidentrelated hostpital admission Terhune K (1982) Report DOT HS Terhune K (1992) Report DOT HS USA Case-control Culpable and not culpable drivers injured in a motor vehicle accident and treated at a hospital (n = 497) USA Case-control Fatally injured drivers (n = 1882): responsible and responsible/contributory (n = 1503); not responsible, contributory/none, contributory (n = 371); unknown (n = 8) Vinkers DJ (2003) Netherlands Cohort Individuals aged 85 years or older: 465 person-years with use and 1339 person-years without use Wadsworth EJ (2003) UK Cohort Individuals who participated in the first phase of the Bristol Stress and Health Study (Smith et al. 2000) [n = 4673] Wadsworth EJK (2005) UK Cohort People selected at random from the 2001 electoral registers for Cardiff and Merthyr Tydfil Williams AF (1985) USA Case-series 15- to 34-year-old male fatally injured drivers (n = 440) Incidence and role in the accident (?) Incidence and role in the accident Ethanol and other drugs Major drugs of abuse and common prescription drugs (e.g. tranquilizers, sedatives) Death 1999 Accidents requiring medical attention, minor injuries and cognitive failures 2001 Accidents (e.g. road traffic accidents), injuries, cognitive failures Sleeping tablets, antidepressants Psychotropic medication (e.g. ) Questionnaire Questionnaire Fatal motor vehicle crashes in which the driver was responsible for the crash 23 drugs or drug groups * Readers are referred to the reference list of the full article (which can be found at for complete citation details of the publications listed in this table = benzodiazepines ISS = Injury Severity Score; AIS = Abbreviated Injury Scale; MAIS = Maximum Abbreviated Injury Severity; PCP = phencyclidine