Phenytoin and Driving Safety: A Randomized, Controlled Cross-Over Study
Condition: Cognitive Measures; Driving Simulator Performance
Study type: Interventional
Phase: Phase 4

Summary: 
      Automobile driving is a crucial aspect of everyday life, yet vehicular crashes represent a
      serious public health problem. Patients with epilepsy are at elevated risk for automobile
      crashes, causing great personal suffering and financial costs to society. Most collisions
      involving epileptic drivers are not seizure related but may instead result from cognitive
      effects upon driving performance of epilepsy and antiepileptic drugs (AEDs). Several million
      American drivers take AEDs for treatment of medical conditions besides epilepsy and may also
      be at risk for cognitive impairments that can reduce driving performance. Empirical evidence
      of the effects of AEDs on driving performance would enable development of driving guidelines
      that could lower the risk of injurious motor vehicle collisions; however, this evidence is
      currently lacking. The broad goal of our project is to determine the specific effects of the
      most commonly utilized AED, phenytoin, by assessing driving performance and cognitive
      abilities in neurologically normal volunteers taking phenytoin in a randomized, double-blind,
      placebo-controlled, crossover study. Our proposed experiments will assess: (1) cognitive
      functions using standardized neuropsychological tests (of attention, perception, memory, and
      executive functions), (2) driving performance during phenytoin and placebo administration,
      and (3) the effects of phenytoin-related cognitive performance upon driving performance. To
      measure driving performance, we will use a state-of-the-art fixed-base interactive driving
      simulator that allows us to observe driver errors in an environment that is challenging yet
      safe for the driver and tester, under conditions of optimal stimulus and response control.
      The results of this study of 30 drivers treated with phenytoin and placebo will increase the
      understanding of the role of AED-related cognitive impairment on driving safety errors. A
      better understanding of the impact of AEDs upon driving performance is necessary to
      rationally develop interventions that could help prevent crashes by drivers treated with
      AEDs.
    

Detailed description: 
      Patients with epilepsy are at elevated risk for automobile crashes, causing great personal
      suffering and financial costs to society. Most collisions involving epileptic drivers are not
      seizure related but may instead result from cognitive effects upon driving performance of
      epilepsy and antiepileptic drugs (AEDs). Several million American drivers take AEDs for
      treatment of medical conditions besides epilepsy and may also be at risk for cognitive
      impairments that can reduce driving performance. Empirical evidence of the effects of AEDs on
      driving performance would enable development of driving guidelines that could lower the risk
      of injurious motor vehicle collisions; however, this evidence is currently lacking.

      The broad goal of the current project is to determine the specific effects of AEDs on
      cognitive function and driving performance. To address this goal we will assess driving
      performance and cognitive abilities in neurologically normal volunteers taking phenytoin
      (Dilantin), the most commonly prescribed AED. Effects of phenytoin on driving performance and
      cognition will be addressed in a randomized, double-blind, placebo-controlled, crossover
      study. Driver cognition will be assessed using a battery of neuropsychological tests. Driving
      performance will be objectively assessed in all participants on standardized tasks enacted in
      a state-of-the-art driving simulator. Our 3 Specific Aims are:

      Aim 1: To assess the effects of phenytoin on cognitive abilities that are crucial to the
      driving task, including perception, attention, memory, and executive function.

      Hypothesis 1: A driver's cognitive abilities will decline during steady-state phenytoin
      administration compared to placebo. Drivers with higher blood levels of phenytoin will show
      greater decline.

      Aim 2: To assess effects of phenytoin on driving performance and safety errors in a
      state-of-the-art driving simulator.

      Hypothesis 2: Driving performance will decline and driver safety errors will increase during
      phenytoin administration compared to placebo. Drivers with higher blood levels of phenytoin
      will show greater impairments of driving.

      Aim 3: To assess the effects of phenytoin-related cognitive impairments upon driving
      performance in a state-of-the-art driving simulator.

      Hypothesis 3. Impairments of cognitive function affecting perception, attention, memory,
      executive function, and arousal will increase the likelihood of driver errors that may lead
      to a crash.

      Our hypotheses would be supported if the drivers taking phenytoin, as opposed to placebo,
      demonstrate worse cognitive performance on neuropsychological tests, and more safety errors
      and crashes in the simulator. The hypotheses would also be supported if drivers with higher
      phenytoin levels show greater impairments of cognition and driving. Once the effects of
      phenytoin on driving performance are demonstrated in this project, we will have evidence to
      support more comprehensive research addressing specific dosing and serum levels and acute
      versus chronic administration.

      There is currently no evidence concerning the effects of phenytoin on driving performance.
      Accurate driving performance data on patients receiving phenytoin would allow determination
      of fair and accurate criteria for making recommendations to drive or not to drive affecting
      millions of patients taking AEDS for epilepsy and other conditions. These data could also
      help reduce the risk of car crashes due to medication side effects.
    

Intervention name(s): Phenytoin; Placebo oral capsule
Intervention type(s): Drug; Drug
Intervention description(s): Phenytoin will be dosed to a target dose of 5 mg/kg qhs for one month; Placebo
Other intervention name(s): Dilantin
Intervention MeSH terms: Phenytoin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Other
Keywords: epilepsy; cognitive impairment; driving simulation; cross-over study