Published online September 1, 2006
PEDIATRICS Vol. 118 No. 3 September 2006, pp. e704-e710 (doi:10.1542/10.1542/peds.2005-2947)
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ARTICLE

Relative Benefits of Stimulant Therapy With OROS Methylphenidate Versus Mixed Amphetamine Salts Extended Release in Improving the Driving Performance of Adolescent Drivers With Attention-Deficit/Hyperactivity Disorder

Daniel J. Cox, PhD, R. Lawrence Merkel, MD, PhD, Melissa Moore, MD, Frances Thorndike, PhD, Carrie Muller, BS and Boris Kovatchev, PhD

Department of Psychiatric Medicine, University of Virginia, Charlottesville, Virginia


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. Automobile accidents are the leading cause of death among adolescents, and collisions are 2 to 4 times more likely to occur among adolescents with attention-deficit/hyperactivity disorder. Studies have demonstrated that stimulants improve driving performance. This study compared 2 long-acting stimulant medications during daytime and evening driving evaluations.

METHODS. Adolescent drivers with attention-deficit/hyperactivity disorder were compared on a driving simulator after taking 72 mg of OROS methylphenidate, 30 mg of mixed amphetamine salts extended release, or placebo in a randomized, double-blind, placebo-controlled, crossover study design. During laboratory testing, adolescents drove a driving simulator at 5:00 PM, 8:00 PM, and 11:00 PM. Driving performance was rated by adolescents and investigators.

RESULTS. The study included 35 adolescent drivers with attention-deficit/hyperactivity disorder (19 boys/16 girls). The mean age was 17.8 years. The overall Impaired Driving Score demonstrated that OROS methylphenidate led to better driving performance compared with placebo and mixed amphetamine salts extended release, whereas mixed amphetamine salts extended release demonstrated no statistical improvement over placebo. Specifically, relative to placebo, OROS methylphenidate resulted in less time driving off the road, fewer instances of speeding, less erratic speed control, more time executing left turns, and less inappropriate use of brakes. OROS methylphenidate and mixed amphetamine salts extended release worked equally well for male and female adolescents and equally as well with teenagers who have combined and inattentive subtypes of attention-deficit/hyperactivity disorder.

CONCLUSIONS. This study validates the use of stimulants to improve driving performance in adolescents with attention-deficit/hyperactivity disorder. In the study, OROS methylphenidate promoted significantly improved driving performance compared with placebo and mixed amphetamine salts extended release.

Key Words: adolescents • automobile driving • medication effects • stimulant therapy • attention-deficit/hyperactivity disorder • ADHD • OROS methylphenidate • mixed amphetamine salts extended release

Abbreviations: ADHD—attention-deficit/hyperactivity disorder • IR MPH—immediate-release methylphenidate • tid—3 times daily • OROS MPH—OROS methylphenidate • se-AMPH ER—mixed amphetamine salts extended release • IDS—Impaired Driving Score

Driving collisions are the leading cause of death among adolescents, accounting for 15 teenage deaths per day in the United States.1 Driving fatalities are significantly more likely to occur when distracting teenage passengers are in the automobile.2 Fatalities also are more likely to occur in the evenings, on the weekends, and during the summer months.3

Among children, attention-deficit/hyperactivity disorder (ADHD) is associated with an increased risk for accidents, especially bicycle and pedestrian.4–6 Anywhere from 40% to 80% of children who have a diagnosis of ADHD continue to display symptoms of the disorder into adolescence.7,8 Adolescents with ADHD also are at an increased risk for driving-related accidents; they are 2 to 4 times more likely to experience a motor vehicle accident,9–11 4 times as likely to be at fault in the accident,9 and >3 times more likely to incur associated injuries as a result of the accident.12

Stimulant treatment with immediate-release methylphenidate (IR MPH) has been demonstrated to improve driving performance in adolescents with ADHD. Simulated driving performance was assessed 1.5 to 2 hours postdose in a double-blind, crossover study that compared the effects of one 10-mg dose of IR MPH with placebo in male individuals with ADHD (aged 19–25 years) and matched control subjects without ADHD.11 When placebo was administered to both groups, participants with a diagnosis of ADHD demonstrated significantly poorer driving scores than did control subjects (P < .05); however, 1.5 hours after the administration of IR MPH, the driving performance of the group with a diagnosis of ADHD significantly improved (P < .05) and was equivalent to that of the control group.

For determination of whether the difference in the pharmacokinetic profiles of IR and extended-release MPH formulations influenced driving performance throughout the day, a study was conducted to compare IR MPH dosed 3 times daily (tid) with once-daily OROS methylphenidate (OROS MPH; Concerta [McNeil Pediatrics Division of McNeil-PPC Inc, Ft Washington, PA]).13 Once-daily dosing of OROS MPH is similar to IR MPH dosed tid and minimizes the fluctuations in peak and trough plasma concentrations that are associated with MPH dosed tid.14 Therefore, in this crossover study design, OROS MPH was administered at 8:00 AM, and IR MPH was administered tid at 8:00 AM, 12:00 PM, and 4:00 PM. The driving performance of adolescents who had ADHD and were aged 16 to 19 years was assessed using a driving simulator at 2:00 PM, 5:00 PM, 8:00 PM and 11:00 PM. When participants were administered IR MPH, simulated driving performance worsened by a factor of 5 at 8:00 PM and 11:00 PM, but driving performance in participants who received OROS MPH remained stable from 2:00 PM to 11:00 PM. Not only was driving performance significantly better in participants who received OROS MPH (P < .001), but also OROS MPH demonstrated significantly less intersubject variability (P < .001), or more consistent benefits across participants.

In a subsequent study to compare driving skills in participants who did and did not receive medication, adolescents with ADHD drove their own car on a standard road course after either taking OROS MPH at 8:00 AM or receiving no medication.15 Raters who were blinded to the medication condition observed significantly fewer inattentive driving errors in adolescents who took OROS MPH (P < .01). The study demonstrated that reduction in inattentive errors was positively correlated (r = 0.60, P < .01) with mg/kg dosing of OROS MPH.

Given the evidence that stimulant therapy with MPH improves driving performance and that once-daily OROS MPH improves driving performance and is more effective at 4 hours and 7 hours after dosing compared with the IR formulation, the authors studied the effects of 2 long-acting stimulant formulations—once-daily OROS MPH and mixed amphetamine salts extended release (se-AMPH ER; Adderall XR [Shire Inc, Wayne, PA])—on simulated driving performance in adolescents with ADHD to compare how each affected adolescent driving performance.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Participants
Male and female active drivers who had ADHD and were aged 16 to 19 years were eligible to participate in the study. Participants were recruited through referrals from physicians, high school nurses, and teachers as well as advertisements in the newspaper and on the radio.

To be included in the study, adolescents had to have a diagnosis of current ADHD as determined by parent report, questionnaire, and structured clinical interviews; a positive history of stimulant responsiveness as disclosed by adolescents and parent reports; and current license to drive and reported daily driving activity. Adolescents were excluded when they had a history of tics or any adverse reactions to stimulant medication, a history of substance abuse disclosed by patient or parent, or a coexisting medical condition or medication usage that is known to interfere with the safe administration of stimulant medications.

Study Procedure
After the Internal Review Board (University of Virginia)-approved informed consent was obtained from parents (for children who were younger than 18 years) and adolescents, parents completed the ADHD Rating Scale IV16 and a research assistant administered the Diagnostic Interview Schedule for Children to confirm the diagnosis of ADHD.17 On a subsequent visit, participants met with a psychiatrist, who administered a physical examination and confirmed the ADHD diagnosis through the use of the Standardized Interview for Adult ADHD.18

Study Design
Adolescent drivers with ADHD were compared on a driving simulator after taking OROS MPH, se-AMPH ER, or placebo in a repeated-measure, randomized, double-blind, placebo-controlled, crossover study design (Fig 1). Using a random-numbers table, each participant was assigned to receive a 17-day course of OROS MPH followed by a 17-day course of se-AMPH ER or vice versa. The order of study treatment was randomized and counterbalanced so that se-AMPH ER and OROS MPH were equally likely to be tested first or second. There was no washout period between treatment sequences. Participants were switched from 1 medication to another and received OROS MPH or se-AMPH ER for at least 10 days before testing.


Figure 1
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  		FIGURE 1 Study design. Participants received each treatment for 5 to 10 days, with ≥5 days between treatment phases.

 
Dosages that were determined to be approximately equivalent by the investigators and found to be optimal in terms of efficacy and tolerability during dose-titration studies in adolescents were used for comparison: OROS MPH 72 mg/day19 and se-AMPH ER 30 mg/day.20 Throughout the study, participants took 2 overlaid capsules/tablets in blister packs each day on awakening. On days 1 through 5, participants were given a half dose of study medication (36 mg/day OROS MPH or 15 mg/day se-AMPH ER), and on days 6 to 17, participants were given the full study dose of active drug (72 mg/day of OROS MPH or 30 mg/day of se-AMPH ER).

Laboratory testing occurred on days 10 and 17 in both conditions. During 1 of the 2 laboratory days, participants were randomly assigned to testing on the medication condition (either OROS MPH or se-AMPH ER). During the remaining 2 laboratory days, participants were either tested on placebo or were not required to come in for testing. Participants and research assistants were blind to medication condition. There was a minimum of 4 days and a maximum of 21 days between the 2 medication sequences, during which time participants resumed their previous medication regimen.

Driving Assessment
In the evening before laboratory days, participants were telephoned and reminded to take the medication in their blister pack the next morning at 8:00 AM. On laboratory testing days, participants came to the laboratory to complete 15-minute simulated drives at 5:00 PM, 8:00 PM, and 11:00 PM. At the end of each 15-minute simulated drive, both participant and researcher rated the driving performance on a subjective scale of 1 (poor) to 5 (good).

Driving Simulator
The Atari Research Driving Simulator (Atari Inc, Milpitas, CA) is an interactive, fixed-platform, virtual reality simulator that generates reliable, accurate, sensitive, and valid driving performance data.21–30 The simulator has three 25-inch computer screens that surround the driver, providing a 160-degree visual field, along with a programmed rearview mirror depicting rear traffic. The driving environment is realistic, incorporating a typical-sized steering wheel, gas and brake pedals, seat, and seat belt. Driving performance feedback is provided to the driver visually through the 3 screens that update at a rate of 60 times per second; audibly through quadraphonic speakers that deliver engine, tire, and road noises; and kinesthetically through forced feedback from the steering wheel and pedal pressure.

Driving Performance Variables
The simulator records data 8 times per second and generates 10 driving performance variables. Three of these variables reflect steering control (SD of steering, driving off the road, and veering across the midline), 3 reflect braking (inappropriate braking while on the open road, missed stopped signals, and collisions), and 4 reflect speed control (exceeding speed limit, SD of speed, time at stop sign deciding when to turn left, and time to complete left turns).

Impaired Driving Score
As in previous studies that discriminated high-risk individuals and predicted future driving collisions,11,15,24,26 we generated and analyzed a composite Impaired Driving Score (IDS) to compare the various aspects of driving poorly. The IDS is an accumulative effect size across the multiple driving variables: summed SDs of steering, driving off the road, veering across the midline, inappropriate braking while on the open road, missed stopped signals, collisions, exceeding speed limit, SD of speed, time at stop sign deciding when to turn left, and time to complete left turns. A higher IDS reflects poorer driving skill, with more driving across midline and off road, more speeding, higher SD of speed, less time spent at stop signs and executing left turns, and more crashes. For computation of the IDS, performance on each variable (eg, SD of speed) was converted into a z score on the basis of the participant's performances during the 3 active laboratory days and the 3 tests (5:00 PM, 8:00 PM, and 11:00 PM). The z scores then were summarized for each participant and for each test drive, generating the IDS. An IDS of 0 represents average driving, an IDS <0 represents better than average driving (eg, an IDS of –1 represents driving performance 1 SD better than average), and an IDS >0 represents worse than average driving.

Statistical Analysis
IDS and individual driving parameters were compared using repeated measures analyses of variance of 3 medications (OROS MPH, se-AMPH ER, and placebo) at 3 time points (5:00 PM, 8:00 PM, and 11:00 PM), with 3 ADHD subtypes (combined, inattentive, and hyperactive), and with both genders (male and female). Planned contrasts compared IDS under different medication conditions at 5:00 PM, 8:00 PM, and 11:00 PM.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Participants
Nineteen male and 16 female ADHD drivers participated in the study. Participant demographics are listed in Table 1. Before entering the study, 2 adolescents were taking no medication, 21 adolescents were taking MPH formulations, and 12 adolescents were taking amphetamine formulations. Comorbid psychiatric diagnoses were determined by clinical interview for 6 participants (1 adolescent satisfied the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria31 for agoraphobia, 1 for conduct disorder with marijuana abuse, 1 with obsessive compulsive disorder, 1 with obsessive compulsive disorder and hypomania, and 2 with nicotine dependence). With an average of 21 ± 15 months of driving experience, participants reported an average of 1.1 crashes and 1.0 moving vehicle violations. Throughout the study, 2 participants had their laboratory testing rescheduled because they failed to take their medication on time. Adolescent self-reports of symptom improvement at baseline, half study dose (day 5), and full study dose (day 17) of OROS MPH and se-AMPH ER indicated that both medications improved ADHD symptoms compared with baseline, with a trend for OROS MPH to have a better response than se-AMPH ER (P = .55).


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  		TABLE 1 Participant Demographics

 
Objective Driving Simulator Data
Overall driving performance was better with active treatment. As seen in Fig 2, there was a significant medication effect (F = 7.16, P < .001). There was neither a gender x medication interaction effect (F = 0.93, P = .40) nor an ADHD subtype x medication interaction effect (F = 0.17, P = .85).


Figure 2
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  		FIGURE 2 IDS (error bars indicate SEM). Lower IDS denotes better driving performance. {square}, placebo; {square}, se-AMPH ER; {blacksquare}, OROS MPH. Medication versus placebo: P = 0.01; OROS MPH versus placebo: P = 0.001; se-AMPH ER versus placebo: P = 0.24; OROS MPH versus se-AMPH ER: P = 0.03.

 
Separate contrasts demonstrated that OROS MPH was associated with better driving performance than placebo (t = 3.31, P < .001) and se-AMPH ER (t = 2.15, P = .03), whereas se-AMPH ER was not associated with better driving than placebo (t = 1.17, P = .24; Fig 2). Under placebo and se-AMPH ER conditions, the worst driving performance was seen at 8:00 PM, and the best driving performance for both OROS MPH and se-AMPH ER was seen at 11:00 PM, 15 hours after taking the study medication (Fig 2). Throughout the study, 19 participants responded an average of >1 SD better than placebo across all 3 times on OROS MPH, 8 participants responded an average of >1 SD on se-AMPH ER than placebo, and 8 participants responded no better than an average of >1 SD on either medication (ie, nonresponders) than placebo. In terms of specific driving performance variables, OROS MPH led to fewer inattentive driving errors (penetration of the oncoming traffic lane and fewer excursions off the road), less hyperactive driving (less speeding), and fewer impulsive driving errors (less erratic speed control, less impulsive braking, more time deciding when to turn, and more deliberate turns) compared with se-AMPH ER and placebo (Table 2).


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  		TABLE 2 Specific Driving Performance Variables: OROS MPH Versus Placebo, OROS MPH Versus se-AMPH ER, and se-AMPH ER Versus Placebo

 
Subjective Driving Performance Ratings
Subjective ratings of the adolescents and the investigators were compared with repeated-measures analyses of variance of 3 medication conditions at 3 simulator trial time points (5:00 PM, 8:00 PM, and 11:00 PM) and 2 ratings (participant and researcher; Fig 3). Participants' ratings were not different from researchers' ratings on the 3 medications (F = 0.38, P = .538). Participants were aware of improved driving on OROS MPH compared with placebo (F = 7.56, P = .008) but were not aware of either improved driving while taking se-AMPH ER compared with placebo (F = 3.70, P = .059) or improved driving while taking OROS MPH compared with se-AMPH ER (F = 0.81, P = .373).


Figure 3
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  		FIGURE 3 Subjective ratings (1–5) of driving performance (error bars indicate SEM). {square}, placebo; {square}, se-AMPH ER; {blacksquare}, OROS MPH.

 
Posthoc Validation
Because all participants reported a history of being stimulant responders, an MPH Improvement Score was computed (OROS MPH minus placebo). The MPH Improvement Score correlated with history of collisions (r = –0.35, P < .05), indicating that the more responsive driving performance was to MPH in the laboratory, the fewer lifetime collisions were reported.

Adverse Events
Throughout the study, there was only 1 adverse event reported, urinary difficulty. The adverse event occurred during treatment with OROS MPH 36 mg and resolved after 2 days without discontinuation of the medicine.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
In this study to compare driving skill in adolescents as a result of treatment with 2 long-acting stimulant formulations, OROS MPH led to better steering (less driving across midline and off road), better speed control (less speeding and less erratic speeds), and less impulsive driving (less inappropriate breaking and taking more time to decide when to proceed at intersections and execute left turns). All participants in the study were given 72 mg of OROS MPH and 30 mg of se-AMPH ER. These well-tolerated and effective doses of OROS MPH19 and se-AMPH ER20 in adolescents resulted in improvement in driving skills at different time points, with OROS MPH demonstrating significantly improved driving performance among both male and female adolescent drivers and among drivers with ADHD combined and inattentive subtypes. (Conclusions regarding ADHD hyperactive subtype cannot be drawn because of the n of 2.)

Performance on OROS MPH relative to placebo was considered to be clinically significant. When comparing the overall IDS while taking placebo, this was equivalent to the relative driving performance of 75- to 80-year-old drivers, whereas performance while taking OROS MPH was equivalent to that of drivers between the ages of 55 and 59 years.28 In addition, improvement in driving performance with OROS MPH treatment relative to placebo significantly correlated with lifetime reported history of collisions. This can be understood in light of the fact that participants were stimulant responsive and all but 2 of the participants had been taking stimulant medication since they began driving. The 2 participants who were not currently taking stimulant medications had taken stimulant medications at some time during their driving career. This suggests that adolescents who have ADHD, have a history of taking stimulant medications, and benefit from stimulant medications have fewer collisions.

Although this study was powered sufficiently to demonstrate that 72 mg of OROS MPH was superior to both placebo (P < .001) and 30 mg of se-AMPH ER (P = .03), it probably was underpowered to find a significant benefit of se-AMPH ER relative to placebo. Using the current research design, power analysis suggests an 80% chance of finding a .05 or less difference between 30 mg of se-AMPH ER, and placebo would require a sample size of 73 subjects.

Another possible reason as to why this study did not find significant effects for se-AMPH ER on driving skills is because the response to OROS MPH was more consistent across participants and time points. Although both medications demonstrated similar treatment results at 5:00 PM, differences in treatment were found later in the evening (Figs 2 and 3). This resulted in smaller SDs relative to se-AMPH ER, which allowed for greater power.

Although it has been demonstrated that OROS MPH has at least 12 hours of therapeutic benefits for children,32 there have been no reported investigations beyond 12 hours. Also, there have been no similar time course investigations of the therapeutic benefits of OROS MPH among adolescents. Therefore, this and our previous study15 are the first studies to demonstrate that OROS MPH has therapeutic benefits among adolescents for up to 15 hours. In fact, Fig 2 indicates that driving performance on OROS MPH was steadily improving until 11:00 PM (15 hours postdose), indicating no rebound effect, let alone waning, of its therapeutic benefits. Furthermore, Fig 3 indicates that the adolescents were aware of these persistent benefits at the time of testing. If adolescents could appreciate such benefits of stimulant therapy, then this could be critical to support medication adherence.

A limitation of the study is the dosing of OROS MPH as it compares with the dosing of se-AMPH ER. There is an approximate 2:1 difference in potency between D,L-amphetamine and methylphenidate.33 Therefore, assuming that 2 mg of MPH is therapeutically equivalent to 1 mg of amphetamine and assuming a 12% loss of MPH in the OROS MPH preparation, we calculated that 30 mg of se-AMPH ER would be approximately equivalent to 72 mg of OROS MPH. However, because potency does not equate with efficacy, we also assessed doses that were found to be optimal during dose-titration studies of the 2 long-acting stimulant formulations in adolescents with ADHD.19,20 Wilens et al19 conducted a short-term, multisite study in adolescents with ADHD, during which 177 adolescents were assigned an individualized dose of OROS MPH that was titrated to optimal efficacy and tolerability. In the study, OROS MPH was associated with clinically and statistically significant improvements in ADHD compared with placebo, and the optimal dose of OROS MPH for most adolescents in the study was 72 mg/day (36.7%), followed by 54 mg/day (28.2%), 36 mg/day (27.7%), and 18 mg/day (7.4%).19 Grcevich et al20 conducted a long-term, open-label extension study of a short-term, randomized, placebo-controlled, forced-dose-escalation study to assess the efficacy and the tolerability of se-AMPH ER, in which adolescents with ADHD received se-AMPH ER 10 mg/day during the first week, which was decreased or increased for dose optimization to a maximum of 60 mg/day. At the study end point, mean ADHD Rating Scale scores improved significantly, and most adolescents in the study responded optimally to 30 mg/day (32%) of se-AMPH ER, followed by 20 mg/day (31%), 40 mg/day (19%), 50 mg/day (7%), 10 mg/day (6%), and 60 mg/day (5%). By general guidelines, medications were of equivalent doses, although a different outcome may have been achieved with higher/individualized doses. Although potency and optimal dosing of OROS MPH and se-AMPH ER were taken into consideration while deciding on the dosing of each drug for the current study, the approximate equivalency that was decided on may not be correct, and higher doses of se-AMPH ER may have demonstrated more robust effects. In addition, the medication dosages of se-AMPH ER and OROS MPH were not optimized for each patient during this study, and although that led to no differential bias, additional studies should be conducted using a dose optimization study design.

An additional limitation of this study is that it had few participants with hyperactive subtype, limiting our extrapolation of these results to this subgroup. Similarly, because this study had only 3 participants with comorbid disorders, the relative impact of such additional diagnoses cannot be addressed in the current study.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
This study adds to the literature demonstrating that stimulant therapy improves driving performance in adolescents with ADHD, and the results suggest that OROS MPH should be the initial treatment of choice for adolescent drivers. However, adolescents who have ADHD and have had a robust response with se-AMPH ER should not necessarily be changed to OROS MPH, especially if they had not previously responded as well to MPH therapy. Given the elevated risk for driving mishaps among adolescents with ADHD and given that fatal collisions are more likely to occur in the evenings, on weekends, and during the summer months, the current findings suggest that the use of stimulant medication to manage the symptoms of ADHD should not be limited to school hours/days.


   ACKNOWLEDGMENTS
 
This study was supported by funding from McNeil Pediatrics Division of McNeil-PPC Inc.

Special thanks are extended to psychiatry residents Drs Liza Schaffner and Mudhasir Bashir for many contributions to this study, including diagnostic interviews, physical examinations, and medication management. Data analytical support was provided by Likun Hou.


   FOOTNOTES
 
Accepted Mar 20, 2006.

Address correspondence to Daniel Cox, PhD, Box 800-223, University of Virginia Health System, Charlottesville, VA 22908. E-mail: djc4f{at}virginia.edu

Financial Disclosure: This study was supported by funding from McNeil Pediatrics Division of McNeil-PPC Inc.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. National Highway Traffic Safety Administration. Young Drivers Traffic Safety Facts 2003. Washington, DC: US Department of Transportation; 2003
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  3. National Center for Statistics and Analysis, National Highway Traffic Safety Administration. Fatality Analysis Reporting System (FARS) Web-based Encyclopedia. Available at: www-fars.nhtsa.dot.gov/. Accessed May 16, 2005
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