The Relationship Between Benzodiazepine

n- . . . . . . . . AP.«.-«. .- CNSDlugs 2010; 24 (8): 639-653KEViEW ARTICLE n72-7047/10/0008<ló39/S49.95/0

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The Relationship between BenzodiazepineUse and Traffic AccidentsA Systematic Literature Review

Beitske E. Smink} Antoine CG. Egberts,^'^ Klaas J. Lusthof,'^ Donald R.A. Uges'^'^ andJohan } . de Gier^

1 Department of Toxicology, Netherlands Forensic Institute, The Hague, the Netherlands2 Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical

Sciences, Utrecht, the Netherlands3 Department of Clinical Pharmacy, University Medical Centre, Utrecht, the Netherlands4 Department of Pharmacy, Toxicology and Forensic Medicine, University Medical Center Groningen,

Groningen, the Netherlands5 Department of Analytical Biochemistry, Groningen Research Institute for Pharmacy, University of

Groningen, Groningen, the Netherlands6 Department of Pharmacotherapy and Pharmaceutical Care, Groningen Research Institute for Pharmacy,

University of Groningen, Groningen, the Netherlands

ContentsAbstract 6391. Literature Search Methodolagy 641

1.1 Data Sources 6411.2 Study Selection 6411.3 Data Extraction 642

2. Characteristics of the Included Studies 6423. Assaciatians between Benzadiazepine Use and Accident Risk 6434. Discussion 6485. Conclusions 650

AbStrOCt In many countries, benzodiazepines are the most commonly used andmisused psychoactive medicinal drugs. Results of epidemiological studiesinvestigating the association between benzodiazepine use and traffic acci-dents seem to be inconclusive or inconsistent at first sight. However, theoutcome of epidemiological studies may be influenced by several methodo-logical factors like study design, study population, exposure measurement,outcome definitions and possible confounders.

Our objective was to conduct a systematic literature review of epidemio-logical studies that investigated the association between benzodiazepine useand traffic accidents, including related outcomes like culpability and injury oraccident severity. We searched EMBASE, PubMed and Forensic ScienceAbstracts 3/0 (FORS®) for references included in these databases at 1 June 2009

640 Smink et al.

using the term 'benzodiazepines' in combination with 'driving performance' or'accident risk' or 'traffic accident'. For inclusion in this review, the study designhad to be comparative, include road users involved in accidents and providespecific data about benzodiazepines. Sixty-six studies were included in thereview. The study populations varied from the general (driving) population,accident-involved road users with or without injury and persons admitted to ahospital to fatally injured accident-involved drivers. Exposure assessment wasperformed by using toxicologieal results, prescription data or questionnaires.The divergent study populations and comparison groups and the variety ofmethods used to express the outcome of interest hampered comparison betweenresults.

Evidence is growing that exposure to benzodiazepines is related to in-creased accident risk. The literature indicates that the greatest accident risk isassociated with the use of long half-life benzodiazepines, increasing dosageand the first few weeks of use of benzodiazepines. Clear evidence of increasedculpability associated with benzodiazepine use is scarce. More research has tobe done to elucidate the relationship between benzodiazepine use and injuryseverity.

Driving under the influence of benzo-diazepines is a topic of concern with respect totraffic safety.f In 1960, Murray'^' was the firstto report on this topic, finding about a 10-foldincrease on projected road accident statisticsin a group of 68 drivers taking methamino-diazepoxide. Since then, the association betweenbenzodiazepine use and (traffic) accidents hasbeen studied all over the world. Benzodiazepines(including benzodiazepine-like substances, suchas zolpidem and zopiclone) have been associatedwith impaired driving and increased accidentriskJ^"^ In many countries, benzodiazepines arethe most commonly used and misused psycho-active medicinal drugs.'^' For example, in theNetherlands, with a population of about 16 millioninhabitants, oxazepam and temazepam are num-bers two and three on the list of most frequentlyprescribed medicinal drugs.'^ During recent years,new legislation has been adopted in several coun-tries in order to increase traffic safety. To ourknowledge, restrictions for benzodiazepine use arecurrently included in zero tolerance laws in twoEuropean countries (Sweden and Finland).'^'^'

The prevalence of driving under the influenceof alcohol and illicit and medicinal drugs in realdriving populations has been described all over theworld, illustrating the scope of the

The influence of benzodiazepines on objectivemeasures in a laboratory setting, on a test drive ina simulator or operating an instrumented motorvehicle has been described in several experimentalstudies.t^"^''^' In general, the aim of the experi-mental studies is to study the acute effects or theresidual effects, after intake of a single dose orafter multiple doses. To predict the influence ofbenzodiazepines on driving performance in realtraffic situations, the outcome of these experi-mental tests should be related to driving ability.Because circumstances in the laboratory settingdiffer from real traffic situations, studies in areal driving population are needed to support thefindings of the experimental studies. On the otherhand, experimental studies are needed to eluci-date the associations found in epidemiologicalstudies.

Results of epidemiologieal studies related tothe association between benzodiazepine use andaccidents seem to be inconclusive or inconsistentat first sight. However, the outcome of epide-miological studies may be influenced by severalmethodological factors like study design, studypopulation, exposure measurement, outcomedefinition and possible confounders.f'^''^'

The objective of this article is to conduct asystematic literature review of epidemiological

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Benzodiazepine Use and Traffic Accidents 641

studies that investigated the association betweenbenzodiazepine use and traffic accidents, includ-ing related outcomes like culpability and injuryor accident severity. Although impairment is nota primary outcome of interest, it is expected to bea predictor of a traffic accident and was thereforeincluded in this article. A review of descriptivestudies, a review of experimental studies, a com-parison between epidemiological and experi-mental studies, and a comparison of the additionaleffects of benzodiazepines with the effects of otherdrugs are beyond the scope of this article.

1. Literature Search Methodology

1.1 Data Sources

Data sources used for the review of the litera-ture were EMBASE,!'^' PubMedt^*" and ForensicScience Abstracts 3/0 (FORS®).P'l EMBASEprovides biomédical and pharmacological litera-ture. More than 11 million EMBASE recordsfrom 1974 to the present and more than 7 millionMEDLINE records from 1966 to the presentare available, updated every weekday with (onaverage) 1800 and 600 records, respectively.t"!PubMed is a service of the US National Libraryof Medicine and includes over 17 million citationsfrom MEDLINE and other life science journalsfor biomédical articles from the 1950s.[2oi FORS®database is a product of Forensic Science ServiceLtd., a UK government-owned company, andincludes more than 70 000 records on a range ofsubjects including drugs and toxicology, forensicbiology, forensic chemistry, forensic medicineand pathology. FORS® scans about 150 journalspublished worldwide from 1976 to the present,together with a series of abstracting and biblio-graphic services. Where relevant, some earliermaterial has also been included.t^'^

All databases were searched for references in-cluded in the database at 1 June 2009. Limits were'English' and 'humans'. The search strategy in-cluded the word 'benzodiazepines' in combina-tion with 'driving performance' or 'accident risk'or 'traffic accident'. References of the full textpublications retrieved were examined and in-cluded if relevant to the aim of our review.

1.2 Study Selection

Figure 1 shows the selection process forthe articles included in this review. In total, 1005unique literature references were retrieved.Screening of those references was performed ontitle, keywords and abstracts if available.

If the primary objective of the article was notrelated to benzodiazepines and accidents, the re-ference was excluded. Book references were alsoexcluded. Of the 1005 references, 688 referenceswere excluded because they reported about theuse of benzodiazepines in relation to falls, sleep-ing disorders, chronic pain, anaesthesia, epilepsy,eclampsia, psychiatric disorders, critical care,driving not primarily related to benzodiazepines,dementia, stroke/vascular diseases and other toxi-cology or other issues. Of the remaining 317references, the full text was studied and epide-miological studies examining the association be-tween benzodiazepines and accidents (includingrelated outcomes like culpability, injury or acci-dent severity and impairment within a group ofdrivers) were selected. For inclusion in this review,the study design had to be comparative, includeaccident-involved or impaired road users, andprovide specific data about benzodiazepines. De-scriptive studies on the incidence and prevalenceof driving under the influence of benzodiazepinesin different countries were excluded because thefindings of those studies are in general stronglyinfluenced by legal and ethical issues, biologicalfluids collected, drug test panel and analytical cut-offs. Experimental studies were excluded becausethe focus of our review was on the associationbetween benzodiazepines and traffic accidents inreal driving situations. In addition, review articles,letters without original research data, papers pre-senting data already published and case reportswere excluded. Although the relationship betweenbenzodiazepines and accident risk, culpability,injury or accident severity was not always the pri-mary aim of the study identified, an effort wasmade to include all relevant articles. One referencewas not accessible for examination during theperiod of preparing this overview, and as a con-sequence has been excluded. The number of ref-erences included in this review was 66.

© 2010 Adis Data Information BV, All rigtits reserved. CNS Drugs 20)0.-24 (8)

642 Smink et al.

Search query: :• ' ;..'benzodiazepines' AND 'driving performance'

OR 'accident risk' OR 'traffic aocidenf

EMBASE(n = 892)

PubMed(n = 315)

1FORS»

Xn = 80)1 I

Exclusion of duplicates (n = 282)

Articles identified, titles andabstracts screened (n = 1005)

_LPrimary objective: drugs

(e.g. benzodiazepihBs)añdaccicleñtsFull text publications retrieved

(n = 317)

Studiesexamining the

associationbetween

benzodiazepinesand accident

risk, culpabilityor injury severity

(n = 52)

Cross-references(n = 14)

Included articles(n = 66)

-• • Primary objective: •other (e.g. insomnia, falls)• Excluded (n = 688),

Studies notaccessible

(n=1)

Other studies: [e.g. •experimental

studies](n = 264)

Excluded articles(n = 953)

Fig. 1. Selection process for the articles included in this review. The 14 'cross-references' are further studies identified in the referencesections of the studies found through the database search.

1.3 Data ExtractionData extracted from each study were related

to the characteristics of the study, i.e. the first au-thor, year of publication, country, study design,study population, study period, outcome of inter-est, substances of interest and method of exposuremeasurement. If the relationship between ben-zodiazepine use and accident risk, culpability, injuryor accident severity or risk of being impaired wasexpressed as a relative risk (RR), odds ratio (OR),standardized incidence ratio (SIR) or rate ratio, ad-ditional data were documented, i.e. reference group,the association studied and relative risk estimates.

2. Characteristics of the included Studies

Table I shows the characteristics of the 66included studies that reported a relationship

between benzodiazepine use and injury or accidentrisk (n = 36; 54%),[80.56,8t,2,t4,22-52] responsibilityor culpability (n=13; 2 0 [accident severity (n=16;or other outcomes (i.e. impairment or mortality,n = 8; 12%).[ 2-79] j ^ fg^ studies reported therelationship between benzodiazepine use and riskof injury in general (e.g. traffic accident-relatedinjury) but are expected to be relevant within thescope of our revieW.[29'45,46,50-52,79]

The studies presented in table I were pub-lished between 1960 and 1 June 2009. The studypopulation included the general (driving) popu-lation with or without suspicion of drug use(n = 29; 44%),P^24.25,27,32-34,37,39-47,49-52,73-80] accident-

involved persons in general with or withoutinjury (n=12 ; 18%),P5,28,30,31,38,40,48,56,57,77,81,82]

persons admitted to a hospital (n = 29;

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1,13,14,22,29,32-37,41,49,53,54,59,60,64-72,77,80,83]

and/or fatally injured, accident-involved drivers( 'n= 13 ' 2 0 % ) [23,26,27,55,58,61-64,69,70,77,80]

The study designs most frequently usedwere the case-control (n = 35;53%") ' ' 1 -14,22,23,25-27,33,34,36,37,39^1,49,53-55,57-61,63-71,80]

Table I. Characteristics of the studies (n = 66) [see table, Supple-mental Digital Content 1 for details of the study designs, http://Iinks.adisonline.com/CNZ/A7]

Characteristics

Year of publication

<1980

1981-90

1991-2000

2001-9

Site

Europe

USA

Canada

Australia/New Zealand

Study design

Case control

Cohort

Case crossover*

Cross-sectional

Case series'"

Study population^

General (driving) population

Accident-involved persons in general

Persons admitted to a hospital

Fatally injured, accident-involved road users

Outcome of interest'

Accident or injury risk

Responsibility/culpability

Accident or injury severity

Other

Drug exposure assessment'

Toxicblogical results

Prescription data

Ouestionnaire

Not specified

n(%)

6(9)

11(17)

22 (33)

27(41)

33 (50)

16 (24)

12(18)

5(8)

35 (53)

15(23)

4(6)

7(11)

5(8)

29 (44)

12(18)

29 (44)

13(20)

36 (54)

13(20)

16 (24)

8(12)

42 (64)

22 (33)

8(12)

1(2)

One study was included in which a case-crossover design wascompared with a case-control design.

One study was included In which a case-series design and acase-crossover design were used.

Categories are not mutually exclusive.

and the cohort designs (n = 15;23%).[2'28,29,3i,42-47,50-52,79,8i] j ^ case-control stud-ies related to drugged driving, the selection of aproper control group is challenging. Only a lim-ited number of studies compared accident-involved drivers (cases) with randomly selecteddrivers (controls), representing the general drivingpopulation. Other studies differentiated between,for example, responsible and non-responsibleaccident-involved drivers, accident-involved dri-vers and other accident-involved road users, ac-cident-involved drivers with and without injury,and impaired and unimpaired drivers to be able tocompare cases with a control group. As a con-sequence, the outcomes of interest are related toaccident risk, responsibility/culpability, injury oraccident severity or impairment.

Exposure assessment was performed by usingtoxicological measurements in biofluids (n = 42;64%),[11,13,14,22-27,34,35,39,41,53-78,80,82,83] prescr ip t ion

data (e.g. pharmacy claims, statistics of benzo-diazepine sales, n = 22; 33%)[25,28.33,36-38,42-50,56,79,81]

and/or questionnaires (e.g. interviews, n = 8;12%).[34.35,39,40,5i,52,65,80] j ^ one study, the meth-od of exposure assessment was not specified.I^'Substances of interest varied from benzodiazepinesonly ( n - 1 5 ; 23%),[2'32,33,42-46,50,57,71,74,76,79,83]

benzodiazepines and ethanol (n = 8;12%)^[l 1,22,53,65,67,73,75,77] JQ vadoUS grOUpS

of medicinal and illicit drugs (n = 43;g5^\[12-14,23-31,34.41,47-49,51,52,54-56,58,6&«l,66,68-70,72,78,80-82]

Over the years, the toxico-analytical methodsused have been improved and as a consequencelimits of detection have been lowered, althoughcut-off values were not always reported.

3. Associations between BenzodiazepineUse and Acoident Risk

The associations reported between benzo-diazepine use and injury or accident risk, in-cluding related factors like culpability, injury oraccident severity or impairment, seem to be in-consistent. However, the divergent study popu-lations and comparison groups and the variety ofmethods used to express the outcome of interesthamper a comparison between results. To getmore insight into the study results, the studies

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644 Smink et al.

Table II. Studies reporting relative risk estimates for the association between benzodiazepines (BZD) and injury or accident risk,responsibility/culpability, injury or accident severity or Impairment

Study (year)

'Benzodiazepine/Driving'Collaborative Groupi ^J(1993)

IMMORTAL R4.2»"!(2005)

Barbone et al.P^'(1998)

Bramness et al.i'î(2002)

Bramness et al.i'''i(2003)

Drummer et al.'^^'(2004)

Dubois et al.P^(2008)

Dussault et a l .^^(2002)

Engeland et al.i^î(2007)

French et al.P^l(2005)

Reference group

EtOH <0.2 g/L andBZD-negativeresponsible driversand non-responsibledrivers andpedestrians injured

Drug-negative drivers

Subjects whileunexposed

Therapeutic' drugconcentration

Therapeutic' drugconcentration

Drug- andalcohol-free drivers

No BZD detected

Drug-free group

The person-timewhere individualswere unexposed tothe drug in question

Patients taking BZDwho did not haveconcomitant drug use

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Association

Accident risk

Accident risk

Accident risk

Injury severity

Risk of beingdetermined impairedand BZDconcentration

Risk of beingdetermined to fail animpairment test

Culpability

Unsafe driving action(a proxy measure forcrash responsibility)

Accident risk

Culpability

Accident risk

Injury risk

Exposure analysed

BZD

BZD alone

BZD

Anxiolytics

Hypnotics

By dose

By half-life

BZD

BZD

BZD alone

Long half-life BZDby age

Intermediatehalf-life BZD by age

Short haif-life BZDby age

BZD alone

BZD alone

BZD anxiolytics(diazepam,oxazepam.alprazolam)

BZD hypnotics

Concomitant useof BZD+otherdrugs

BZD dose

BZD duration

Result (95% CI)

OR 0.96 (0.8, 1.2)

Netherlands: OR 2.98 (1.31, 6.75)

Nonvay: OR 20.6 (2.1, 201.8)

OR 1.62 (1.24, 2.12)

OR 2.18 (1.52, 3.13)

OR 1.19 (0.83, 1.70)

OR for low dose 1.27 (0.80,2.01 );intermediate dose 1.68 (1.13, 2.49);high dose 2.67 (1.33, 5.39)

OR for long half-life 2.03 (1.41, 2.93);Intermediate half-life 1.19 (0.82,1.73)

OR for no injury 1.50 (1.12, 2.02); slight2.12 (1.02, 4.38); serious 1.36 (0.40,4.58); fatal 65.04 (3.11, >1000)

Adj. OR for mildly elevatedconcentration 1.60 (0.84, 3.05);moderateiy elevated 3.71 (1.34,10.27);highly elevated 3.75 (1.46, 9.63)

13 subtests and observations weresignificantly related to grouped bloodBZD concentrations. Of these, 9withstood adjustment for backgroundvariables. (ORs for being determined tofail the different tests are presented)

OR 1.27 (0.5, 3.3)

Adj. OR for age 25y 1.68 (1.34, 2.12);age 55y 1.33 (1.12, 1.57)

Adj. OR for age 25 y 1.59 (1.08, 2.33);age 55y 1.50 (1.09, 2.06)

Adj. OR for age 25 y 0.87 (0.55, 1.37);age 55 y 1.11 (0.73,1.67)

OR 2.5 (1.4, 4.3)

OR 3.6 (0.5, 28.2)

SIR 2.9 (2.5, 3.5)

SIR 3.3 (2.1, 4.7)

OR 2.31 (2.20,2.41)

OR 1.06 (1.04,1.07)

OR 1.03 (1.01, 1.05)

Continued next page

CNS Drugs 2010; 24 (8)


Table II. Contd

Study (year)

Gibson et aLl^"'(2009)

Gustavsen at al.P'i(2008)

Hebert et al.P=l(2007)

Hemmelgarn et al.P^'(1997)

Jick et al.l^si(1981)

Leveille et al.'^^(1994)

Longo et ai.l^î(2000)

Reference group

Subjects whileunexposed

The person-timewhere individualswere unexposed tothe drug in question

Subjects whiieunexposed

Unexposed group

CNS depressant-freesubjects

Non-users of BZD

Drug-free drivers

Association

Accident risk(case-seriesanalytical technique)

Accident risk

Accident risk(case-control design)

Accident risk(case-crossoverdesign)

Accident risk

Accident risk

Accident risk

Culpability

Exposure analysed

BZD

Non-BZD hypnotics

Zopiclone

Zolpidem

Nitrazepam

Flunitrazepam

Long half-life BZD

Short half-life BZD

Long half-life BZD

Short half-life BZD

Long half-life BZD

Short half-life BZD

CNS depressantdrugs, includingBZD

Current exposure

Past exposure

BZD alone

Result (95% CI)

IRR 1.94 (99% Cl 1.62, 2.32) for 4 wkperiod following the first prescription

IRR 1.37 (99% CI 0.73, 1.54) for4wkperiod following the first prescription

SIR 2.3 (2.0, 2.8)

SIR 2.2 (1.4, 3.4)

SIR 2.7 (1.8, 3.9)

SIR 4.0 (2.4, 6.4)

Crude OR 1.57 (1.18, 1.96)

Crude OR 1.11 (0.94,1.30)

Crude OR 0.99 (0.81, 1.21)

Crude OR 1.04 (0.92,1.17)

Adj. rate ratio 1.45 (1.04, 2.03)after initiation; 1.26 (1.09,1.45)up to 1 y

Adj. rate ratio 1.04 (0.81,1.34) afterinitiation; 0.91 (0.82, 1.01) up to 1 y

Adj. RR comparing at-fault drivers withpassengers 1.1 (0.6, 2.2)

Adj. OR 0.9 (0.4, 2.0)

Adj. OR 1.2 (0.5, 2.7)

OR at therapeutic concentrations 3.3;above therapeutic concentrations 3.6.The difference in proportions ofculpable drivers across BZD groups(including the drug-free group) wassignificant for BZD in combination withother drugs (p<0.01), but not for BZDalone (p> 0.05)

Longo et al.i^l(2001)

MacPherson et al.l^^'(1984)

McGwin et al.l'«"(2000)

Drug-free drivers

Drug-negativedrivers, BAC0.005-0.075 g/dL(also presented:higher BAC)

Drivers not reportingBZD use

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Culpability

Accident risk

Accident risk

Culpability

BZD alone

CNS depressantdrugs, includingBZD

BZD

BZD

RR 1.8 at concentrations <0.26 of Cma»;RR 2 at concentrations 0.26-1.0 ofCmoxi RR 4 a' concentrations >Cmox

OR for diazepam 1.59 (p < 0.01 ); foroxazepam 14.13 (p<0.00077); forchlordiazepoxide 1.23; for other CNSdepressants 1.64; (or all CNSdepressants 1.94 (p< 0.00083)

Adj. OR 5.2 (0.9, 30.0)

Adj. OR 1.0 (0.2, 4.6)

Continued next page

CNS Drugs 2010, 24 (8)

646 Smink et al.

Table II. Contd

Study (year) Reference group Association Exposure analysed Result (95% CI)

Meulemans et al.''(1998)

BZD-negativesubjects (all others)

Injury severity BZD RR of being severely injured [ISS >16j;1.66 (1.18, 2.81); RR of low probabilityof survival [ASCOT <50%]: 1.48 (0.51,4.07); RR of death: 2.01 (1.04, 4.09);RR of severe cranial or spinal trauma:1.97 (1.34,3.48); RR of severe thoracictrauma: 1.46(0.91,2.54)

Movig et al.^^l(2004)

Mura et al. l" l(2003)

Neutel et aM''^'(1995)

Randomly recruiteddrivers

Drug-free patients

Unexposed subjects

Accident risk

Accident risk

Risk of traffic accidentinjury

BZD alone

BZD alone

Hypnotics

Adj. OR 5.1 (1.8,14.0)

OR 1.7 (1.2, 2.4)

OR within 4wk of index prescription 3.9(1.9, 8.3); within 2wk of indexprescription 6.5 (1.9, 22.4)

Anxiolytics

Neutell'"!(1998)

Oster et al.'"«!(1990)

Unexposed subjects

Non-users of BZD,users of drugs otherthan BZD

Risk of traffic accidentinjury

Risk of accident-related medicalencounters (any type)

New users

Repeat users

Short-acting BZD

Long-acting BZD

BZD

OR within 4 wk of index prescription 2.5(1.2, 5.2); within 2wk of indexprescription 5.6 (1.7, 18.4)

OR 3.4 (1.7, 6.8)

OR 1.4 (0.4, 5.4)

OR for triazolam 3.2 (1.4, 7.3);lorazepam 2.4 (1.0,6.3); oxazepam 1.0(0.3, 3.7)

OR for flurazepam 5.1 (2.3,11.6);diazepam 3.1 (1.4, 6.5)

Adj. RR 1.15 (1.05, 1.26) users vsnonusers

Adj. RR 1.28 (1.04, 1.56) for recentlyfilled prescription vs other months

Adj. RR 1.30 (1.09, 1.55) for three ormore prescriptions vs one prescription

Rapoport et ai.l'^l(2008)

Ray et al.l"^(1992)

Skegg et aLi-isi(1979)

Smink et al.'°=i(2005)

Subjects whiieunexposed

Non-users of any ofthe study drugs

Non-users

No drug use and BAC<0.5g/L

© 2010 Adis Data information BV. Ali rights reserved.

Accident risk

Injurious crashinvolvement

Accident risk

Accident severity

BZD

Current users ofBZD

By dose

Sedatives,anxiolytics andantipsychotics

Sedatives andanxiolytics

Antipsychotics

BZD

OR 1.12 (1.01, 1.34)

RR 1.5 (1.1, 2.0)

RR increased with dose and wassubstantial for high doses [2.4 (1.3,4.4)for >20 mg diazepam]

RR (point estimate) 5.2 (p<0.05)

RR 4.9 (p< 0.01)

RR6.3

Adj. OR 0.4 (0.2, 0.7)

Continued next page

CNS Drugs 2010; 24 (8)


Table II. Contd

Study (year)

Tamblyn et al.poi(2005)

Reference group

Never users

Association

Risk of injury

Exposure analysed

BZD

Result (95% CI)

Risk of injury with increasing dosagevaried by drug from a hazard ratio of0.92 (0.60,1.42) for alprazolam to 2.20(1.39, 3.47) for flurazeparn per 1standardized adult dose increase. Therisk of injury varied by BZD,independent of half-life, as did the riskassociated with increasing dosage forindividual products

Vinkers et al.™(2003)

Wadsworth et al.P^'(2003)

Wadsworth et al.l==l(2005)

Adj.=adjusted; ASCOT

Non-users

Non-users

Non-users

Mortality risk (allcause)

Accidents outsidework

Accident risk (any)

Risk of any injury

Risk of non-workinjury

Road traffic accidentrisk

Any BZD

Long half-life BZD

Sleeping tablets

BZD

BZD

BZD

BZD

RR 0.77 (0.51, 1.17)

RR 1.38 (0.73, 2.63)

Unadj. OR 2.33 (1.31, 4.15); adj. OR1.76 (0.95, 3.24). Sleeping tablet usewas associated with accidents, minorinjuries and cognitive failures both atwork and outside work

OR 2.01 (0.71,5.67)

OR 2.17 (0.89, 5.32)

OR 4.43 (1.89, 10.38)

OR 0.01 (0.00,1.21)

= a severity characterization of trauma; BAC = blood alcohol concentration; C„o, = maximum (peak) plasma drugconcentration; EtOH = ethanol; IRR = incidence rate ratio; ISS = lnjury Severity Score; OR = odds ratio; RR = relative risk; SIR = standardizedincidence ratio; UnadJ. = unadjusted.

presenting relative risk estimates have been se-lected and are presented in table II (n = 34; 52%).

Table II shows the relationship betweenbenzodiazepine use and injury or accident risk,responsibility/culpability, injury or accident se-verity or risk of being determined impaired ex-pressed as RR, OR, SIR or rate ratio (95% CI).Presented are the first authors and the yearof publication, the reference group used and theratio (95% CI) relevant to the association be-tween benzodiazepine use and the outcome ofinterest.

Several studies did not show a significant as-sociation between benzodiazepine use and injuryor accident risk, responsibility/culpability, injuryor accident severity or mortality.I ' ' ' ' - ' ^Drummer et al.' ' studied the association be-tween alcohol and drug use and the culpabilityof 3398 fatally injured, crash-involved drivers.Benzodiazepines only were present in 1.0%(34/3398) of the drivers and showed positivebut non-significant associations with culpability

(OR 1.27; 95% CI 0.5, 3.3). The 'Benzodiazepine/Driving' Collaborative Group' ^^ studied therelationship between the presence of alcohol(quantitative) and/or benzodiazepines (qualita-tive by using immunoassay) in the plasma of 2852injured drivers and responsibility, estimated bythe investigators in conjunction with the police.No significant difference was found with respectto the degree of responsibility of drivers with ablood alcohol concentration <0.2g/L, with orwithout benzodiazepine use (OR 0.96; 95% CI0.8, 1.2 and OR 1, respectively). Other studiesprovide data that do indicate an association be-tween benzodiazepine use and injury or accidentrisk, responsibility/culpability or injury or acci-dent severity [13'14,27-33,39,41,42,44,46-51,56,57,59,80,83]

Mura et al.t'^' studied the prevalence of alcoholand other psychoactive substances in bloodsamples of 900 non-fatally injured drivers (cases)and 900 patients visiting the same emergencydepartments for a non-traumatic reason (controls).The percentage of drivers and controls positive

© 2010 Adis Data Information BV. All rights reserved. CNS Drugs 2010; 24 (8)

648 Smink et al.

for benzodiazepines only was 9.4% and 5.5%,respectively. The results suggest an increasedrisk in traffic accidents with the use of benzo-diazepines (OR 1.7; 95% CI 1.2, 2.4). Moviget al.''"' described a study among 110 injuredmotorists (cases) and 816 randomly selected dri-vers (controls). Benzodiazepines were detected in10% (11/110) of the cases and 1.5% (12/816) of thecontrols. For benzodiazepines, the OR for injuryin road accidents was 5.1 (95% CI 1.8, 14.0).Neutel'''^' studied the relationship between thefirst prescription for benzodiazepines and hospi-talization after a traffic accident in injured pas-sengers and drivers. They showed that the highestrisk for accidents occurred within the first weeksafter the index prescription fill date. Barboneet al.' ' presented a case-crossover study explor-ing the association between road traffic accidentsand the use of psychoactive drugs (e.g. benzo-diazepines) as indicated by prescription data. Therisk associated with benzodiazepines seemedto be higher with anxiolytics compared withhypnotics, and a long half-life (OR 2.03; 95% CI1.41, 2.93) compared with an intermediate half-life (OR 1.19; 95% CI 0.82,1.73). Evidence for adose-effect relationship between benzodiazepineuse and accident risk was also given.' ' In addi-tion. Longo et al.'* ' showed a linear relationshipbetween the blood concentration of benzo-diazepines and culpability for accident-involveddrivers who tested positive for benzodiazepinesalone. Bramness et al.' ' '*' illustrated the risks ofbenzodiazepine use in drivers by indicating a re-lationship between the blood benzodiazepineconcentration and impairment.

4. Discussion

Sixty-six studies, published between 1960 andJune 2009 have been included in this review, re-porting the relationship between benzodiazepineuse and injury or accident risk (n = 36; 54%), re-sponsibility or culpability (n= 13; 20%), injury oraccident severity (n = 16; 24%) or other outcomes(i.e. impairment or mortality, n = 8; 12%). A fewstudies reported the relationship between benzo-diazepine use and risk of injury in general (e.g.traffic accident-related injury). The literature

indicated that the highest risk for accidentsoccurred within the first weeks after the indexprescription fill date. The risk associated withbenzodiazepines seemed to be higher with anxio-lytics compared with hypnotics, and with agentswith a long half-life compared with an inter-mediate half-life. Evidence for a dose-effectrelationship between benzodiazepine use andaccident risk was also given. The divergent studydesigns, study populations and comparisongroups and the variety of methods used to expressthe outcome of interest hamper a comparisonbetween results. This prevents us from making anaccurate estimate of the strength of the associa-tion between benzodiazepine use and trafficaccidents or related outcomes. Some of the epi-demiological studies included in this review seemto present conflicting results. The key question iswhether or not discrepancies can be explained bydifferences in methodological factors like studypopulation, exposure measure, outcome or studydesign.

In general, the study population has to be largeenough to enable the detection of a difference (ifany) between the groups compared. For example,in one study benzodiazepines only were presentin 1.0% of the drivers and showed positive butnon-significant associations with culpability.'^^'Potential confounders, which may be both a riskfactor for accidents and associated with benzo-diazepine use (e.g. health status, the indicationfor benzodiazepine use, sex, age and driving fre-quency), should be taken into account but datamight be difficult to collect. Confounding by indi-cation is a reason for concern in epidemiologicalstudies related to benzodiazepines and driving.

Exposure data might be questioned whencollected retrospectively. By using interviewsor questionnaires as exposure measures,''*"' '-^ 'recall bias can influence the results. In studiesusing prescription data,'25.28-33'36-38,42-50,56,79,81]

outcome data might be biased by the use ofbenzodiazepines without prescription, the prescrip-tions for benzodiazepines not filled, prescribedbenzodiazepines not taken or the use of non-prescription medication, alcohol or (other) drugsof abuse (e.g. smoking). Benzodiazepine-likesubstances (e.g. zolpidem and zopiclone) are not

© 2010 Adis Data informafion BV. Aii rights reserved. CNS Drugs 2010; 24 (8)


included in this review, although the literatureindicates that these drugs may impair drivingperformanceJ ' "' '' "' ' The validity of toxico-logieal results as an exposure measure is de-pendent on the drug test panel and the cut-offvalues applied, the sensitivity and specificity ofthe analytical methods used, the matrix analysedand the time period between accident and samp-ling. The use of an immunoenzymatic techniquealone ^ ' '*' '* ' ' is not specific and sensitiveenough to detect all benzodiazepines in ther-apeutic concentrations and benzodiazepine-likesubstances (e.g. zolpidem and zopiclone). It isknown that the window of detection of drugsvaries between urine, serum and oral fluid. Byusing different biological matrices for either casesor controls or both, exposure data might bebiased and this may influence the associationfound.t ' l The concomitant use of alcohol orother psychoactive substances is common prac-tice in real traffic situations, which makes riskassessment for benzodiazepine use alone difficult.

In studies related to driving under the influ-ence of alcohol or drugs, the selection of a propercontrol group is challenging. Using the generaldriving population as a control group might beproblematic due to non-participation, which maylead to selection bias. The problem of selectionof a proper control group can be solved by usinga case-crossover design in which cases are self-matched for periods not related to traffic acci-dents. ^ ^ Misclassification of cases and controlsmay influence results, which underlines the im-portance of a proper exposure assessment as wellas outcome definition. For example, the methodused to assess responsibility or culpability variedbetween the different studies. In one study,the investigators assessed responsibility in con-junction with the police, without knowledge ofthe blood alcohol concentration. In this study,subjects were considered responsible if they werethe only person involved or if they had committedan evident driving error.t l In other studies,the culpability assessment method described byRobertson and Drummer' ^l was used. Eightfactors possibly mitigating drivers' responsibilityin each accident were scored (i.e. condition ofroad, condition of vehicle, driving conditions.

accident type, witness observations, road lawobedience, difficulty of task and level of fati-gue).f ' 'l Drivers were divided into three groups:culpable, contributory or non-culpable. Theculpability ratio was defined as the proportion ofdrivers who were culpable to those not culpableand was calculated for various drug groups. ^ ' '

The influence of differences in methodologicalfactors on outcome remains unclear. However,the number of studies providing evidence thatthe use of benzodiazepines is associated with anincreased accident risk is growing, despite thenegative findings, which can be partly explainedby methodological factors.

Several studies indicate that the use of benzo-diazepines with a long half-life, increasing dosageand the first weeks of use of benzodiazepinesare associated with the greatest accidentrisk [32,33,42,44,56,59] Unfortunately, the classifica-tion of benzodiazepines by using the half-life(i.e. short, intermediate and long) is not harmo-nized.[^ '"' °' ' In addition, the number of stud-ies comparing anxiolytics with hypnotics is

P84256]

A complicating factor in studying the re-lationship between benzodiazepines and trafficaccidents is the variety of pharmacokineticproperties and pharmacodynamic effects of theindividual substances, which dictate not only thetherapeutic use but also the potentially unwantedeffects like over-sedation, cognitive impairment,tolerance, withdrawal symptoms and potentialfor abuse. The degree and duration of action of asubstance is determined by, for example, dose,the rate and extent of drug distribution, lipophil-icity, receptor affinity and tolerance. It is im-portant to realize that the duration of action isnot equivalent to the elimination half-life.t 'Tolerance seems to develop selectively to differentdrug effects. Withdrawal symptoms are related tothe duration of the treatment, the dose and thehalf-life of the benzodiazepine.I^ ' The potentialfor abuse depends on factors such as the half-life,speed of onset and speed of offset. In general,benzodiazepines with a short half-life are asso-ciated with an increased abuse potential due to arapid offset. However, diazepam may be abuseddue to its rapid onset although withdrawal is

© 2010 Adis Data Infarmatian BV. Aii rights reserved. CNS Drugs 2010; 24 (8)

650 Smink et al.

delayed due to its active metabolites, which havea long half-life.[ ' '1 The differences between theindividual substances might explain some of thevariability in epidemiological studies.

Some studies indicate a blood concentration-effect relationship.t^ ' ''' ' ' More informationabout the relationship between dose, blood con-centration and effect is needed to establish limitsindicating impairment that are incompatiblewith safe driving behaviour. Inter- and intra-individual variation should be taken into accountand the maximally permitted impairment (e.g.comparable to the effects of a blood alcoholconcentration of 0.5 g/L) should be defined. Thevalidity of limits at sub-therapeutic concentra-tions may be questioned. Depending on the half-life of the benzodiazepine, it may take severaldays after the last intake before a patient isallowed to drive again. A suggestion may be to setlimits related to (above) therapeutic concentra-tions, for example, by using generally approvedliterature references reporting the therapeuticrange, or to individualize the limits on the basisof the individual prescription data. It is importantto realize that the indication for the prescrip-tion may also be associated with an increasedaccident risk. To date, information about the re-lationship between the blood concentration ofbenzodiazepines and driving impairment providedby epidemiological studies seems to be insuffi-cient to define threshold values for the individualsubstances.

Clear evidence of increased culpability asso-ciated with benzodiazepine use is scarce.t 'l Moreresearch has to be done to clarify the relationshipbetween benzodiazepine use and culpability, givenan accident.

The relationship between benzodiazepine useand injury severity is not entirely clear either.Results of studies exploring the relationshipbetween the use of benzodiazepines and injuryseverity are difficult to compare, due to the dif-ferences in study population as well as outcomeassessment. In some studies including all accident-involved drivers, the seriousness of the accidentwas assessed on the basis of hospital admis-sion.t ' i In studies including injured accident-involved patients admitted to hospital, injury

severity has been expressed by using differentscoring systems, e.g. injury severity score (ISS),abbreviated injury scale (AIS) or a severity char-acterization of trauma (ASCOT).!' ' ' ^-'''l Inother studies, a comparison between groupshas been made, e.g. single, multiple and poly-

Harmonization of epidemiological research ondriving under the influence of drugs (e.g. benzo-diazepines) would enable better comparison be-tween results. Rapoport et al.'^''' succeeded inincluding 11 epidemiological and 16 experimentalstudies in a meta-analysis. They concluded thatbenzodiazepine use was linked to driving im-pairment and that benzodiazepine users had asignificantly increased risk of an accident com-pared with nonusers. To study the associationbetween benzodiazepine use and accidents, thecase-control study design may be preferred,comparing responsible accident-involved driverswith the general driving population. Analysis ofblood samples by using a sensitive and selectiveanalytical method (e.g. liquid chromatographytandem mass spectrometry) may be preferred toassess exposure to benzodiazepines of cases andcontrols. If blood sampling is not allowed or isexpected to lead to non-response, the use of oralfluids (of cases as well as controls) as a matrix toscreen for benzodiazepines may be considered.In addition, prescription data may be helpful togain more insight into the dose/concentration/accident relationship.

5. Conclusions

Evidence is growing that exposure to benzo-diazepines is related to increased accident risk.The literature indicates that the greatest accidentrisk is associated with the use of long half-lifebenzodiazepines, increasing dosage and the firstweeks of use of benzodiazepines. Clear evidenceof increased culpability associated with benzo-diazepine use is scarce. More research has to bedone to elucidate the relationship between benzo-diazepine use and injury severity. Harmonizationof epidemiological research on driving under theinfluence of drugs such as benzodiazepines wouldenable better comparisons between results.

© 2010 Adis Data Information BV, All rights reserved. CNS Drugs 2010: 24 (8)


Acicnowledgements

No sources of funding were used to assist in the prepara-tion of this review. The authors have no conflicts of interestthat are directly relevant to the content of this review.

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Correspondence: Dr Beitske E. Smink, Department of Tox-icology, Netherlands Forensic Institute, P.O. Box 24044,2490AA The Hague, the Netherlands.E-n\ail; [email protected]

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