Joris C. Verster
Utrecht Institute for Pharmaceutical Sciences, Utrecht University Section Psychopharmacology, Utrecht, The Netherlands
Driving and flying under the influence of drugs are common, since most people who use psychoactive medication are outpatients who participate fully in society. Psychoac-tive medication may produce adverse effects that impair driving and flying such as reduced alertness, psychomotor impairment, and impaired vision. Most commonly prescribed psychoactive drugs include hypnotics, antidepres-sants, antihistamines, analgesics, and stimulant drugs. Within these categories of medicines, significant differences concerning their impact on driving and flying ability are evident. For example, benzodiazepines and tricyclic anti-depressants (TCAs) significantly impair driving and flying, whereas selective serotonin reuptake inhibitors (SSRIs) do not. These differences should be taken into account when prescribing psychoactive medication to patients who are willing to drive a car or fly a plane.
Current Concepts and State of Knowledge Introduction
In modern society, driving and flying are common modes of transportation. The majority of adults in Western society drive a car on a daily basis and worldwide over 50,000 commercial flights are performed daily. Unfortunately, driving and flying are not without risk: accidents can happen that may result in injury or even death. The World Health organization is concerned about the worldwide increase in traffic accidents and launched various campaigns to enhance traffic safety (Peden et al. 2004). Traffic accidents are often caused by human error, distraction, and reduced alertness.
Psychoactive medication may cause sedation and reduce alertness. Therefore, these drugs can impair performance and increase the risk of traffic accidents. It is estimated that alcohol and psychoactive drugs are involved in 5-35% of road accidents (Verster et al. 2009). These percentages seem high, but one should consider that most people who use psychoactive medication are outpatients who are therefore likely to participate in traffic.
Experimental studies have shown that ► alcohol impairs driving performance in a dose-dependent manner. Since alcohol is the most frequently used psychoactive substance, this is of great concern. About 50 years ago, Borkenstein and colleagues performed a landmark study that showed the relationship between ► blood alcohol concentration (BAC) and the risk of becoming involved in traffic accidents. After the results of this study became public, many countries enforced laws to limit driving after alcohol consumption. Most commonly applied legal limits to drive a car are 0.05% (e.g., the Netherlands), 0.08% (UK and USA). During the last decade, many countries are lowering their legal limit to further reduce traffic accidents.
For example, for novice drivers in The Netherlands, the legal limit is lowered to BAC 0.02%. The main reason for this is the fact that young novice drivers are inexperienced drivers and often overestimate their driving skills. Despite returning public campaigns and intensified police controls, a minority of people still drive a car while intoxicated, putting themselves and others at risk. Currently, alcohol is still the number one cause of traffic accident death among young drivers.
Insomnia and sleep apnea are examples of common sleep disturbances. People who suffer from these sleep complaints do not wake up refreshed and this is reflected by daytime sleepiness. The reduced alertness and distraction produced by sleepiness is the cause of many traffic accidents. This is one of the reasons that throughout the European Union, current traffic safety campaigns specifically warn against sleepy driving. The use of sleep medication is meant to help patients fall asleep or maintain sleep during the night. Unfortunately, many hypnotic drugs produce residual effects after the patient has woken up. That is, patients feel sedated and drowsy after waking up. Particularly, the traditional hypnotic drugs, i.e., the ► benzodiazepines, have shown this unfavorable adverse effect profile. A number of these hypnotics, including ► flurazepam, ► oxazepam, and ► temazepam, were studied applying the on-the-road driving test in real traffic (Verster et al. 2004). In this test, subjects drive a car over a 100-km public highway. They are instructed to maintain a constant speed (95 km/h) and steady lateral position within the right slower traffic lane. Primary parameter of the test is the Standard Deviation of Lateral Position (SDLP), i.e., the weaving of the car. A camera mounted on the roof of the car records the SDLP (see Fig. 1).
Benzodiazepine hypnotics were administered at bedtime and driving performance was tested the following morning (10-11 h after intake) and afternoon (16-17 h after intake). In the morning test, benzodiazepine hypnotics significantly impaired driving performance in a dose-dependent manner. Using twice the recommended dose (which is common in practice), driving was also significantly impaired in the afternoon. Epidemiological evidence confirmed these findings by revealing increased traffic accident risks for those using benzodiazepine hypnotics. ► Tolerance to the impairing effects develops slowly: increased traffic accident risks have been reported in chronic users (>1 year) as well. ► Zopiclone, a nonben-zodiazepine hypnotic, showed no improvement relative to the benzodiazepines. Significant increased weaving in the driving tests showed that driving was impaired and epi-demiological evidence revealed a fourfold increased traffic accident risk for drivers who use zopiclone. ► Zolpidem and ► zaleplon, two other nonbenzodiazepines, did not impair driving performance when used as recommended. Future research should develop new hypnotics, preferably with a different mechanism of action, that do not produce residual effects on driving ability.
Benzodiazepines are also used for the treatment of anxiety. It is not surprising that these anxiolytics impair driving performance similar to benzodiazepines that are used as hypnotics (Verster et al. 2005). In fact, driving impairment is often much more profound because the time between drug intake and driving is much shorter when compared with hypnotics. On-the-road studies have shown significant impairment with benzodiazepine anxiolytics such as ► alprazolam, ► diazepam, and ► lor-azepam. Epidemiological evidence shows that tolerance develops slowly when using these drugs. Driving studies confirmed that after 1 week of treatment, benzodiazepine anxiolytics also significantly impair driving performance and even after 4 weeks of treatment SDLP was significantly increased in patients treated with diazepam. TCAs such as ► imipramine and ► amitriptyline also significantly impair driving performance. Although tolerance develops more quickly when compared with benzodiaze-pines, in terms of traffic safety TCAs were no improvement. In contrast, a newer class of antidepressants, the SSRIs such as ► paroxetine and ► fluoxetine, and related compounds such as venlafaxine showed no impairing effects on driving performance. Also, ritanserin and ondansetron (both 5-HTantagonists), and ► buspirone do not affect driving ability. Thus, in terms of traffic safety, SSRIs and related compounds seem first-choice treatments.
About 15% ofthe population suffers from ► depression at least once during their life and the disease is 2-3 times more common among females. Research has shown that both treated and untreated depression may impair driving performance (Ramaekers 2003). Traditionally, depression was treated with TCAs, ► mianserin, and ► mirtazapine. The first week after treatment initiation, these drugs significantly impair driving performance. Thereafter tolerance develops. Nocturnal treatment increases the time between drug use and driving and may be a solution for patients who want to drive a car. Research showed no driving impairment the morning following bedtime
Larie Furthest Lane Furthest Position of center left center right the car within the lane
Driving and Flying Under Influence of Drugs. Fig. 1. SDLP and the instrumented vehicle. (a) The Standard Deviation of Lateral Position (SDLP). SDLP represents the weaving of the car and is a measure of overall vehicle control. With increased SDLP, driving becomes unsafe. (b) The instrumented test vehicle. A camera, mounted on the roof of the car, continuously records the position of the car within the right traffic lane, by tracking the relative distance of the car from delineated stripe in the middle of the road.
administration of these antidepressants. SSRIs (e.g.,
► escitalopram) and ► moclobemide are also used to treat depression and do not affect driving performance. The World Health Organization expects depression to be the second highest cause of mental disability by 2030. By that time, many outpatients will be treated with antide-pressants. Therefore, it is of great importance that pharmaceutical companies continue the search for new antidepressants without negative effects on driving ability.
The first-generation antihistamines such as diphenhydra-mine and triprolidine are effective against hay fever but had the disadvantage to produce significant sedation. Patients using these antihistamines often report sleepiness and reduced alertness. Driving studies showed significant impairment, both after acute and subchronic use (Verster and Volkerts 2004). Second-generation antihistamines such as cetirizine and loratadine produce much less sedation and driving tests have not consistently shown impairment. The magnitude of impairment, if any, differed between individuals and depended on the administered dose, time between drug intake and driving, gender, and age. Tolerance usually develops after 4-5 days of treatment, but a subgroup of patients shows increased vulnerability to the potential sedative effects of antihistamines and continues to experience adverse effects that may impair driving.
The third-generation antihistamines (fexofenadine, desloratadine, and levocetirizine) were developed to establish treatment options devoid of sedative effects. Driving studies showed that these antihistamines are a considerable improvement: with similar or improved clinical efficacy, these compounds do not affect driving ability.
Pain significantly impairs driving performance (Veldhuijzen et al. 2006a). Common pharmacological treatment of pain includes ► non steroid anti-inflammatory drugs (NSAIDs) and opioids. Laboratory tests of cognitive functioning and psychomotor skills generally do not show significant performance impairment in patients using NSAIDs or acetaminophen. Laboratory studies failed to find consistent results when testing ► opioids such as
► morphine and ► oxycodone (Zacny 1996). Up to now, one driving study examined the effects of bromfenac (an NSAID no longer marketed) and oxycodone. Neither analgesic affected driving performance. Chronic pain patients are often treated with antidepressants such as amitriptyline instead of opioids and NSAIDs. A driving study showed that 13 h after treatment administration, amitriptyline (25 mg) significantly impaired performance in neuropathic pain patients (Veldhuijzen et al. 2006b). After 2 weeks of daily use, tolerance developed to the impairing effects of amitriptyline. More driving research is needed to examine the effects of analgesics on driving ability.
Stimulant drugs are used to improve attention and daytime alertness in the treatment of ADHD and narcolepsy. The effects of 3,4-methylenedioxymethamphetamine (► MDMA) and ► methylphenidate on driving performance have been studied in recreational MDMA users. Methylphenidate has been studied in patients with ADHD as well. Driving performance after using methylphenidate and MDMA was significantly improved when compared with placebo.
Table 1 gives an overview of most commonly used psy-choactive drugs and their effects on driving ability. Classification is conducted according to the categorization of the International Council on Alcohol, Drugs and Traffic Safety (ICADTS). Drugs are allocated to one of the following categories:
1. Presumed to be safe or unlikely to produce an effect
2. Likely to produce minor or moderate adverse effects
3. Likely to produce severe effects or presumed to be potentially dangerous
To make the categories understandable, a comparison with BAC is made. Driving impairment for the categories I, II, and III are equivalent to BAC<0.5 g/l (<0.05%), BAC 0.5-0.8 g/l (0.05-0.08%), and BAC>0.8 g/l (>0.08%).
It is evident from Table 1 that for many diseases, a number of treatment options are available. These treatments differ greatly on how and if they affect driving ability. Physicians should take this into account when prescribing psychoactive medication for patients who want to drive a car.
Flying is an example of complex behavior. Alcohol and psychoactive medication may affect skills and abilities to fly a plane, especially during take-off and landing maneuvers. In addition, radio communication and following instructions during the flight require efficient use of working memory and decision-making processes.
Aircraft personnel have specific guidelines for alcohol use. The US Federation Aviation Administration (FAA)
Driving and Flying Under Influence of Drugs. Table 1. International Council on Alcohol, Drugs and Traffic Safety (ICADTS) categorization of commonly used psychoactive medication. For a complete listing, see Verster et al. (2009).
Category 1 (Presumed to be safe or unlikely to produce an effect)
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