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Module 2: Potentially Driver-Impairing Prescription Medications

Authors: Kathy Lococo; Renee Tyree, PharmDFaculty and Disclosures

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Medications that have known effects on the central nervous system (CNS), blood glucose levels, blood pressure, vision, or otherwise have the potential to interfere with driving skills have been termed "potentially driver-impairing" (PDI) medications.[1] PDI effects include:

  • Sedation;
  • Hypoglycemia;
  • Blurred vision;
  • Hypotension;
  • Dizziness;
  • Fainting (syncope); and
  • Loss of coordination (ataxia).

The use of PDI medications in patients who operate motor vehicles has been an issue of continual concern to law enforcement officers, physicians, attorneys, pharmacists, and traffic safety professionals in the United States and throughout the world. Often times, patients who take over-the-counter, or prescription medications are not aware of the potential impact these medications can have on their ability to drive vehicles safely.

Information for several of the medication classes came from the conclusions of an international panel of experts in the fields of psychopharmacology, behavioral psychology, drug chemistry, forensic toxicology, and medicine, plus law enforcement personnel trained in the recognition of drug effects on drivers in the field. This panel met in 2000 to review developments in the fields of drugs and human performance over the past 10 years, to identify specific effects that drugs have on driving, and to develop guidance for others when dealing with drug-impaired driving problems. The information from this panel was summarized by Couper and Logan[2] in a document called Drugs and Human Performance Fact Sheets, for a project sponsored by the National Safety Council, Committee on Alcohol and Other Drugs; the State of Washington Traffic Safety Commission; and the National Highway Traffic Safety Administration (NHTSA). Although these experts reviewed both illicit and prescription drugs, the information included in this curriculum is limited to prescription drug use.

Data describing motor vehicle crash risk associated with therapeutic classes of prescription drugs are also presented in this module. LeRoy and Morse[1] used an administrative pharmaceutical claims database in a project for NHTSA to determine how often various combinations of medications occurred among drivers who experienced a motor vehicle crash vs those who did not. Their study evaluated the medication use of 33,519 drivers who had motor vehicle crashes (5378 of whom were older than 50 years of age) and the medication use of more than 100,000 matched controls (3 for each case, matched for age and gender; 16,134 of whom were older than 50 years of age). They focused on driving impairments in drivers 50 years of age and older.

In the LeRoy and Morse[1] study, drivers were 1.2 to 7.5 times more likely to have been involved in a motor vehicle crash if they had taken medications in 35 of 90 medication classes identified as PDI. Of the 35 pharmacologic classes highlighted in their research, 27 have specific warnings about sedation, dizziness, drowsiness, and the need for caution when driving, especially until the effects of the medication on driving are known.

The list of PDI medication classes, common medications in each class, and associated odds ratios (OR) expressing the risk for a motor vehicle crash are listed in Appendix 1, as reported by LeRoy and Morse (See Resources). The OR indicates the likelihood of a motor vehicle crash of drivers taking PDI medications compared with age- and gender-matched drivers not taking PDI medications(within a 60-day window of the crash). An OR of 1 implies that a crash is equally likely in both groups. An OR greater than 1 implies that a crash is more likely among drivers taking the PDI drug. For example, an OR of 1.2 can be interpreted as a 20% increased likelihood of crashing for drivers taking specific medications compared with drivers not taking those medications. An OR of 7 would mean that the likelihood of crashing is increased 7-fold.

It deserves mention that there are limitations in the conclusions that can be drawn from the findings of case control studies. First, while such studies can determine an association between a factor and an outcome, they cannot determine that the factor caused the outcome. It is difficult and often impossible to separate the study factor of interest (eg, taking a medication) from other confounding factors that could also have been responsible for the outcome. Confounding factors include having a medical condition or multiple medical conditions, severity of medical condition(s), drug interaction conflicts, number of miles driven, use of other medications or alcohol, length of exposure to the medication of interest, etc. Second, they do not give any indication of the absolute risk for the factor being studied. Finally, there may be differences between the cases and the controls chosen, even though care is taken to match them on specific characteristics. ORs that are considered significant have a P value ≤ .05. ORs with higher P values are labeled as "NS" for not significant.

The International Council on Alcohol, Drugs, and Traffic Safety in 2007 published a categorization system[3,4] for drugs affecting driving performance that may also be useful.

Other information provided in this module was synthesized from published research on simulator and on-the-road studies of medications and driving. Information about prescription drug side effects are taken from respective drug Prescribing Information or the Physicians' Desk Reference 2009.

The combined use of certain medications and alcohol increases motor vehicle crash risk.[5,6]

The material in this module is organized according to various PDI therapeutic drug classes within the following major categories:

  • CNS depressants;
  • Cardiovascular/renal medications;
  • Hematologic agents;
  • Respiratory tract medications;
  • Hormones;
  • Gastrointestinal agents;
  • Pain relievers;
  • Neurologic medications;
  • Ophthalmics;
  • Antiparasitics; and
  • CNS stimulants.

Discussions of individual prescription drugs may be presented within therapeutic class. In all cases, the goal is to inform the reader about the full range of physiologic and psychological effects on individuals and the resulting effects on performance for the functional abilities identified in Module 1; as well as the results of crash analyses, epidemiologic analyses, and other evidence from population studies, from which a driving impairment can reasonably be inferred.

Wherever possible, summary statements or conclusions about driving impairments are applied broadly in this module, ie, to an entire therapeutic class. Exceptions to this approach, where a finding or conclusion is contraindicated for one or a small subset of specific medications, are so noted.

Central Nervous System Depressants

Throughout history, humans have sought relief from anxiety, insomnia, and muscle spasticity with substances that depress brain activity and induce a drowsy or calming effect. CNS depressants include a variety of medications such as:

  • Barbiturates such as amobarbital, phenobarbital, and secobarbital;
  • Benzodiazepines (BZDs) such as alprazolam and diazepam; and
  • Newer anxiolytic/hypnotic non-BZD type CNS depressants such as buspirone and zolpidem.

Most CNS depressants activate the neurotransmitter, gamma-aminobutyric acid (GABA), which helps to decrease brain activity and calms the CNS. Initial side effects may include drowsiness, dizziness, and decreased coordination; however, over time some level of tolerance to these symptoms typically develops.

Barbiturates

Barbiturates have been used in clinical practice since the beginning of the 20th century and have been widely used for a range of indications including the treatment of anxiety, insomnia, and seizure disorders; and as muscle relaxants and anesthetic agents. BZDs and the newer non-BZDs are preferred for insomnia and anxiety because of their wider therapeutic index and slower development of tolerance than that of the barbiturates. However, barbiturates still remain an important class of medications, and were associated with the highest risk for motor vehicle crashes among the 90 prescription drug classes studied by LeRoy and Morse.[1] With an OR of 7.5 (P < .01), the risk of crashing for drivers taking barbiturates was more than 7 times greater than the risk for drivers not taking these medications.

Barbiturates decrease anxiety, are sedating, and may cause blurred vision. Patients should be advised to make sure they know how the medicine affects them before they drive or do anything else that could be dangerous if they are dizzy or are not alert.[7] Acute doses of barbiturates have been found to impair performance on standard tests of eye-hand coordination and symbol-digit substitution tests, and serial math tests.[8] Additionally, as the cognitive tasks were made more challenging, impairments were detected at lower doses of the barbiturate. Researchers have also observed that both alcohol and barbiturates (specifically, pentobarbital) produce similar dose-related effects on all psychomotor and cognitive measures.[9]

Benzodiazepines

BZDs are used primarily to relieve anxiety, although some are used to treat other conditions such as insomnia, alcohol withdrawal symptoms, muscle spasms, panic disorders, and seizure disorders.[10] The most common side effect of BZDs is sedation. Other PDI side effects may include blurred vision, double vision, dizziness, weakness, clumsiness, and unsteadiness or ataxic gait.[2,11] BZDs that sustain their effects (and their side effects) for more than 9 hours are called long half-life BZDs.[10] Examples of long half-life BZDs include alprazolam, chlordiazepoxide, clorazepate, diazepam, lorazepam, oxazepam, and prazepam. Shorter half-life BZDs generally reach their peak within 2-3 hours. These medications include estazolam, flurazepam, quazepam, temazepam and triazolam. Patients should be cautioned against driving while they are taking some BZDs.[12] '

The duration of hypnotic effect and the profile of unwanted effects may be influenced by the distribution and elimination half-lives of the administered medication and any active metabolites formed. When half-lives are long, the medication or metabolite may accumulate during periods of nightly administration and be associated with impairments of cognitive and motor performance during waking hours. If half-lives are short, the medication and metabolites will be cleared before the next dose is ingested, and carry-over effects related to sedation or CNS depression should be minimal or absent. Jones and colleagues[10] analyzed studies that showed impairment in driving-related psychomotor and perceptual tasks as a function of time since administration of certain BZDs: clobazam (at 10 mg or 20 mg) and temazepam (15 mg) generally yielded no significant impairments; And studies with midazolam, diazepam, oxazepam, triazolam, and lormetazepam showed impairments for 5-6 hours. High-dose long-life BZDs showed significant impairments lasting up to 18-24 hours. This included nitrazepam (10 mg), flunitrazepam (2 mg), and flurazepam (30 mg).

Furthermore, BZDs or active metabolites with very long elimination half-lives can accumulate with chronic dosing and produce prolonged effects, especially in elderly or obese patients, or those with liver disease; or, with concurrent use of other medications that compete for hepatic oxidation. The 2002 Beers criteria indicate that long-acting BZDs should be avoided in older patients with certain diagnoses (chronic obstructive pulmonary disease, stress incontinence, depression, and falls).[13] Beers criteria for preferred CNS drugs in the elderly were published in 2009.[14]

Deleterious effects of BZDs on a variety of driver performance tasks have been demonstrated. Simulator and driving studies have shown that a single dose of diazepam decreases a driver's ability to maintain vehicle lane position. Drivers' eye-hand coordination, reaction times, and ability to perform multiple tasks and retrieve information were also impaired.[2] Subjects' on-road driving performance the morning after using BZDs as hypnotics showed impairment comparable to a blood alcohol concentration of 0.05%-0.10%.[15] In Leroy and Morse's research,[1] drivers taking BZDs were twice as likely to have a motor vehicle crash (OR = 2.0) than drivers not taking these medications.

Elderly drivers (67-84 years of age) exposed to a long half-life BZD for the first 7 days had an almost 50% increase in the rate of involvement in injurious motor vehicle crashes compared to age-matched controls with no exposure to BZDs in the prior year.[16] The risk remained significant (although somewhat reduced) for continuous use of longer duration up to 1 year. In contrast, no increased risk was observed after the initiation of treatment with short half-life BZDs for the first 7 days of use, or over longer durations of use. A case-control study of long-acting BZDs found a 53% increase in motor vehicle crashes in patients with 4 or less prescriptions filled in the previous year, corresponding more to transient exposures.[17]

Walsh and colleagues[18] state that based on the present knowledge, BZDs constitute a considerable risk for traffic safety, both in therapeutic doses and to a much larger degree at higher doses. When evaluating the driving risk for BZDs, it is also important to consider the high prevalence of BZD use among the elderly.[16]

Anti-Anxiety/Hypnotic -- Nonbenzodiazepine Agents

Meprobamate, the metabolite of carisoprodol, is a non-BZD anti-anxiety medication that was developed in the 1950s. Its half-life is between 6 and 17 hours, and accumulation of meprobamate during chronic therapy may occur as a result of this long half-life.[2] A single dose of meprobamate has been shown to be capable of causing significant impairment in divided attention, coordination, balance, and reaction time. It is likely that decrements in psychomotor performance would be even more pronounced with chronic dosing.

Following administration of meprobamate in the treatment of anxiety, peak plasma concentrations are typically around 10 mg/L, but can range between 3 and 26 mg/L.[2] Signs of impairment have been observed for drivers using meprobamate at blood concentrations as low as 1 mg/L.[19] In the research by Logan and colleagues,[19] the most severe driving impairment and the most overt symptoms of intoxication occurred in drivers whose combined carisoprodol and meprobamate blood concentrations were greater than 10 mg/L. Some of these drivers were involved in hit-and-run crashes, where they appeared to be unaware that they had hit another vehicle. Other observed driving behaviors included extreme lane excursions, weaving, and slow speed.

Sedative/Hypnotics -- Nonbarbiturate

In the 1990s a newer class of medications, known as "non-BZD, BZD receptor agonists" (eg, zolpidem, eszopiclone, zaleplon) were introduced for the treatment of insomnia. These agents selectively bind to the BZD1 receptor, reducing anxiety with a lower risk for abuse or dependence and fewer adverse effects than BZD. PDI side effects may include dizziness and drowsiness.[18] Use of these medications increased the crashing rate by 48% in the study by LeRoy and Morse.[1] Patient information advises that medication should be taken before bedtime, and carryover effects may last into the next day. Patients are cautioned against driving after ingesting some of these drugs, including the day after ingestion.

During a 1.5-hour driving test given 10-12 hours after the administration of zolpidem, no significant adverse effects were observed. However, impairments in coordination, cognition, and reaction time were seen within the first 4-5 hours of administration of single doses of 10-20 mg.[2]

Liddicoat and Harding[21] reported on 6 individuals arrested for driving under the influence of zolpidem, with concentrations ranging from 190 to 4400 ng/mL. Therapeutic serum levels range from 29 to 272 ng/mL; 5 of the 6 cases had serum levels above therapeutic levels. All drivers tested negative for the presence of alcohol. Three drivers had taken selective serotonin reuptake inhibitor (SSRI) antidepressants along with the zolpidem. Drivers' physical abilities were described as slow to respond, swaying with an unsteady gait, confusion, disorientation, blurred and double vision, did not recall recent events, and poor comprehension. Driving behaviors included near crashes, crashes into a parked car or other stationary object, drove over curb (all 4 wheels), erratic driving, weaving, lane crossings, incorrect stopping position at traffic signal, and failure to proceed when signal turned green. The researchers determined that because zolpidem has a very short half-life and a quick elimination period, these drivers were not taking the drug as directed (before bedtime) or were taking large doses of it. Furthermore, if taken as directed, there would be no drug left in the blood after 8 hours of sleep, or at least a very low amount of the drug.

Meskali and colleagues[22] used urban driving simulations to assess residual effects of the hypnotics zolpidem and zopiclone on older middle-age drivers (ages 55-65 years). In a double-blind, balanced, crossover study of 16 subjects, they evaluated the effects of a nighttime dose of zolpidem (10 mg), zopiclone (7.5 mg), flunitrazepam (1 mg; used as positive control), or a placebo on driving abilities the next morning. Hypnotics did not significantly increase the number of collisions, but significantly higher speeds were found with zopiclone and flunitrazepam. Zolpidem and zopiclone also induced modifications of the lateral position of the car on the road.

Another simulator study investigated the driving abilities of patients diagnosed with primary insomnia, after repeated dosing of sedative hypnotic prescription drugs.[23] Single and repeated (7-day) doses of zolpidem (10 mg), zopiclone (7.5 mg), lormetazepam (1 mg), or a placebo were administered. Treatments were administered at bedtime from day 1 to day 7, and medication effect was assessed at the beginning (day 2) and at the end (day 8) of each treatment period after a night spent in the sleep laboratory. Driving simulator tests took place 9-11 hours post-dose. Patients taking zopiclone had significantly more simulator crashes than patients taking the placebo. Zolpidem had no effect on the driving performance measures. Zopiclone and lormetazepam had significant next-day effects (9-11 hours after doses) on electroencephalographic correlates of vigilance level (BZD-like alterations in beta and alpha brain waves), a phenomenon referred to as "pharmacologic dissociation." Zolpidem did not alter next-day physiologic electroencephalograph rhythms 9-11 hours after a dose when taken as prescribed. The authors suggest that the poor driving performance associated with zopiclone and lormetazepam during the driving simulation test was related to their prolonged CNS effects. The residual effects of the hypnotics increased with increases in their half-lives. The average half-life of eszopiclone is 5 hours and that of lormetazepam 10 hours, compared with 1.9 hours for zolpidem.

There have been recent anecdotal reports of "sleep driving" after taking zolpidem.[24] Prescribing information[20,25, 26] alerts patients to this danger. Couper and Logan[2] conclude that a single 7.5-mg dose of zopiclone can cause severe residual effects on actual driving at 5 and 10 hours after a dose. Zolpidem (10-20 mg dose) causes significant impairments in coordination and cognitive skills within 4-5 hours of use. Zaleplon causes significant impairment within 3 hours of use (10 mg), but no significant impairment after 4 hours.

Antidepressants

In addition to their primary use to relieve mental depression, antidepressants are often used in the treatment of other conditions including bipolar disorder, chronic pain, and anxiety disorders. Since the introduction of the first-generation antidepressants (tricyclics and monamine oxidase inhibitors), the number of new classes of antidepressant medications has grown dramatically. Newer classes of medications include the SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), and serotonin-2 antagonist-reuptake inhibitors. Today, antidepressants are among the most commonly prescribed medications and are broadly represented on the Drug Topics top 200 drugs lists for 2008.[27]

Researchers who have reviewed controlled experimental studies with drivers have concluded that impaired performance is associated with use of the most sedative tricyclic antidepressants.[28,29] Epidemiologic studies focusing on older drivers have documented increased crash risks for users of tricyclic antidepressants, with a relative risk of 2.3.[30] New generation antidepressants do not seem to interfere with performance, however, except when used at higher doses.

Although some research has found the newer selective antidepressants (eg, moclobemide, fluoxetine, paroxetine, venlafaxine, nefazodone) to be free of detrimental effects on driving when taken at recommended therapeutic doses,[31] a more recent analysis using a pharmaceutical claims database for patients who have experienced a motor vehicle crash has found that crash likelihood is increased 19%-78% for drivers taking medications in these classes.[1] Caution is also recommended when these medications are used in combination with other sedating medications such as sedative hypnotics, narcotics, or antihistamines.[32] Prescribing information for some of these drugs advises caution about driving until patients are reasonably certain that their use of the medication does not affect their driving ability.[33]

Reviews by Spina and colleagues[34-36] note a large number of clinically significant drug interactions with antidepressants in the elderly. For example, tricyclic antidepressants and monoamine oxidase inhibitors have a high potential for pharmacodynamic drug interactions with a range of drugs prescribed in elderly patients. The newer antidepressants, such as SSRIs, SNRIs, and dual-action compounds (eg, mirtazapine) exhibit fewer drug interactions than the sedating antidepressants and long-acting BZD, but pharmacokinetic drug interactions may be seen. Some medications that may be prescribed along with antidepressants that may increase the risks for dizziness, syncope, falling, and motor vehicle crashes include antipsychotics, anxiolytics, hypnotics, opioid analgesics, diuretics, and other antihypertensive medications.[1]

Tricyclic Antidepressants and Related Nonselective Reuptake Inhibitors

Tricyclic antidepressants such as nortriptyline, imipramine, amitriptyline, and doxepin have many PDI side effects including blurred vision, fatigue, confusion, muscle weakness, and orthostatic hypotension. This class of antidepressants has been associated with a 41% increase (P < .01) in motor vehicle crash rate.[1] Drivers taking antidepressant-tranquilizer combinations (eg, amitriptyline and perphenazine combination) are more than 4 times likely to have a motor vehicle crash than drivers not taking these medications (OR = 4.5; P = .10; NS). Similarly, tricyclic antidepressant-BZD combinations increase crash likelihood by 4 times (P = .07; NS).[1]

Because tricyclic antidepressants cause sedation, prescribing information cautions against driving.[37] They may also cause blurred vision, orthostatic hypotension, tremor, tachycardia, excitement, and heart palpitations. Wang and colleagues[38] recommend that whenever possible, tricyclic antidepressants should be avoided in patients who wish to continue driving. However, if nonimpairing alternatives are not available, patients should be advised of the potential side effects, and to temporarily cease driving during the initial phase of medication initiation or following dosage adjustments. In addition, patients should also be advised that they may experience impairment even in the absence of subjective symptoms.

Experimental driving studies have shown that sedating antidepressants, such as tricyclic antidepressants, may impair critical driving skills and thereby increase the risk of being involved in a traffic accident. Ramaekers[32] found that acute doses of sedating antidepressants produced effects in lane-keeping ability that were comparable to those seen in subjects with a blood alcohol concentration of 0.8 mg/mL (0.08%). But, it was also shown that the effects on driving were not significant after subjects had been dosed for at least 1 week, or if the dose was given at nighttime and performance was measured the next day. Subjects were mostly young, healthy adults, and not taking concomitant medications.

Selective Serotonin Reuptake Inhibitors

SSRIs are used to treat depression. Examples of SSRIs include citalopram, paroxetine, fluoxetine, escitalopram, and sertraline. Medications in this class contain a warning that they may impair judgment, thinking, or motor skills, and advises patients against driving until they know how the drug affects them.[33,39] Other listed side effects that could impair driving ability may include somnolence, tremor, nervousness, and difficulty concentrating; with serotonin syndrome and hyponatremia, hallucinations.

Wang and colleagues[38] indicate that PDI side effects tend to be mild and well tolerated, while recommending that physicians counsel their patients about the medication's potential to affect driving performance. In contrast, LeRoy and Morse[1] found a 59% increased risk (P < .01) for a motor vehicle crash associated with the use of these medications.

Serotonin-2 Antagonist/Reuptake Inhibitors

Serotonin-2 antagonist-reuptake inhibitors (eg, trazodone) inhibit norepinephrine and serotonin reuptake and antagonize serotonin 5-HT2 receptors. Examples of medications in this class include trazodone and nefazodone. Trazodone prescribing information[40] warns of drowsiness and decreased concentration, and advises prescribers to inform patients of the risk for impairment before driving.

Researchers have evaluated the acute and subchronic effects of 2 doses of nefazodone (100 mg and 200 mg twice daily for 7 days) on actual driving performance, as well as on psychomotor tests and sleep latency tests in the laboratory.[41] A single administration of each dose did not impair highway driving performance and had no (or minor) effects on psychomotor performance. After repeated dosing with 200 mg twice daily (but not with the 100-mg dose), there was slight impairment in subjects' lane-keeping ability while driving on the highway. Dose-related impairments of cognitive and memory functions were found. The higher the steady-state plasma concentrations, the poorer the reaction time on a memory scanning task. Nefazodone did not appear to induce daytime sleepiness, as measured with the sleep latency tests.

LeRoy and Morse[1] found that drivers taking prescription drugs in this class experienced a 90% increase in the risk for a motor vehicle crash (OR = 1.90; P < .01) compared with drivers not taking medications in this class.

Serotonin-Norepinephrine Reuptake Inhibitors

SNRIs are used to treat depression by increasing the amounts of serotonin and norepinephrine in the brain. Examples include venlafaxine, which is also used to treat generalized anxiety disorder, social anxiety disorder, and panic disorder[42,43]; desvenlafaxine for major depressive disorder[43]; and duloxetine, which is also used to treat pain and tingling caused by diabetic neuropathy, as well as for major depressive disorder and generalized anxiety disorder.[44] This class of medications can cause sedation and dizziness and patients should be cautioned against driving until they are reasonably certain that duloxetine does not affect their ability to drive. Other PDI side effects may include weakness or tiredness, excitement or anxiety, nervousness, insomnia, and blurred vision.

While O'Hanlon and colleagues[46] found that venlafaxine (in fixed doses of 37.5 mg twice a day, and incremental doses 37.5-75.0 mg twice a day) did not generally affect driving ability, LeRoy and Morse[1] found that motor vehicle crash experience increased 78% (P < .01) for drivers taking SNRIs compared with drivers not taking these medications.

Norepinephrine and Dopamine Reuptake Inhibitors

Bupropion is used to treat depression, as well as to help people stop smoking. Patient information indicates that bupropion may impair performance of tasks requiring judgment or motor or cognitive skills, and cautions against driving until there is reasonable certainty that the drug does not impair performance.[46] Other PDI side effects may include seizure (dose-related), agitation, dizziness, tremor, and insomnia. Although LeRoy and Morse[1] found an increased crash rate associated with the use of this medication (OR = 1.19; P = .27; NS), it had the lowest OR of the antidepressant PDI medications evaluated in their case-control study.

Alpha-2 Receptor Antagonists

Mirtazapine is a tetracyclic antidepressant that enhances serotonin neurotransmission by blocking alpha-2 adrenergic and serotonin 5-HT2 receptors. Wang and colleagues [38] state that it is typically taken only at night due to its sedating effects, and has been shown to cause substantial impairments for many hours after dosing. Prescribing information warns about sedation and cautions against driving until the patient is reasonably certain that the drug does not adversely affect driving ability.[47] Other PDI side effects may include dizziness, anxiety, and amnesia. LeRoy and Morse[1] found that drivers taking mirtazapine had an 88% increase (P = .12; NS) in crash experience compared with drivers not taking this medication. Wang and colleagues[38] recommend that this medication be avoided whenever possible in patients who wish to continue driving.

Antipsychotics

Antipsychotics are generally used to treat schizophrenia and psychosis in dementia, which can include hallucinations, delusions, and hostility. Other uses include control of severe nausea and vomiting, severe hiccups, and moderate-to-severe pain in hospitalized patients, and to treat severe behavioral problems in children who have autistic disorders. Antipsychotic agents are divided into chemical classes. Most, if not all, antipsychotic medications have a strong potential to impair driving performance through various CNS effects. Traditional antipsychotics (eg, haloperidol and thioridazine) are heavily sedating, and produce extrapyramidal side effects.[38]

The extrapyramidal system is a neural network located in the brain that is part of the motor system involved in the coordination of movement. Extrapyramidal symptoms include dyskinesias, akathisia, and dystonia. Although the modern or "atypical" medications may have a lower tendency to cause extrapyramidal side effects, they are sedating and can cause orthostatic hypotension and dizziness.

Phenothiazines

The phenothiazines are the oldest group of antipsychotics and include chlorpromazine, mesoridazine, prochlorperazine, and thioridazine. These medications may cause some people to become drowsy or to be less alert than they are normally. Prescribing information indicates that these drugs may impair mental and/or physical abilities and that patients should be cautioned about driving.[48] Drowsiness, dizziness, blurred vision, and hypotension can occur. The side effect profile of medications in this class is extensive and includes tardive dyskinesia (involuntary irregular muscle movements), neuroleptic malignant syndrome (with severe muscle stiffness and severe confusion), muscle spasms, twitching, and uncontrollable twisting movements of the arms, legs, neck, or trunk.

Although the actions and the side -effects associated with these drugs would predict a greatly increased motor vehicle crash likelihood, the analyses of LeRoy and Morse[1] revealed that medications in this class were associated with only a modest 5% increase in motor vehicle crashes (OR = 1.05; P = .91; NS). Judd[32] noted that despite the extremely widespread use of antipsychotics, there is little evidence that this class of psychoactive medications is significantly implicated in vehicular crashes or deaths. In his review of epidemiologic evidence of crashes and medications, he concluded that "the acute administration of antipsychotics in normal individuals induces sedation and performance decrements in visual-motor coordination and specific attention behaviors, which have a deleterious effect on driving. However, antipsychotics are rarely used on an acute basis, and tolerance to sedation and decreased alertness does occur during chronic treatment." Judd[32] cautions that antipsychotic medications have the capacity to increase the effects of alcohol, sedative hypnotics, narcotics, and antihistamines; therefore, combinations of antipsychotics with these other drugs increases driving-related impairment. LeRoy and Morse[1] found that tricyclic antidepressant/phenothiazine combinations were associated with a 4.5-fold increase (P = .10; NS) in motor vehicle crash experience.

Dopamine Agonists -- Thioxanthenes

Thiothixene selectively antagonizes dopamine D2 receptors in the treatment of nervous, mental, and emotional conditions. This class carries the same cautions as the phenothiazines regarding mental and physical abilities while driving .[49] Prescription drugs in this class may also cause tardive dyskinesia and neuroleptic malignant syndrome. Other PDI side effects may include blurred vision. Thioxanthenes were associated with a 3-fold increase (P = .27; NS) in motor vehicle crashes in the research performed by LeRoy and Morse.[1]

Atypical Antipsychotics -- Dopamine and Serotonin Antagonists

During the 1990s, atypical antipsychotics such as risperidone, quetiapine, olanzapine, ziprasidone, and clozapine were introduced and have found favor due to their lowered tendency to cause extrapyramidal side effects. Side effects reported for atypical antipsychotics are medication-specific; however, general side effects include drowsiness and sedation.[50] Other PDI side effects may include dizziness, anxiety, parkinsonism, and tremor. Patients are advised to use caution when driving until they know how the medication affects them because it may impair judgment or motor skills. Clozapine carries a warning not to drive because of the risk for seizure.[51] The OR for motor vehicle crashes associated with the use of atypical antipsychotics is significant at 2.20 (P < .01).[1]

Antiemetic/Antivertigo Agents

Medications such as meclizine, promethazine, and scopolamine patch are used to prevent and treat nausea, vomiting, and dizziness caused by motion sickness.[52] Because of the risk for drowsiness, patients should be cautioned against driving. Prochlorperazine and ondansetron are used to treat nausea and vomiting caused by radiation therapy, cancer chemotherapy, and surgery. PDI side effects may include drowsiness/malaise, and blurred vision.[53] Trimethobenzamide controls nausea and vomiting for patients with the flu and other illnesses.[54] PDI side effects may include drowsiness, blurred vision, dizziness, disorientation, and convulsions. Prescribing information on some drugs in this class suggest caution against driving at least until medication effects are known. Wang and colleagues[38] report that significant impairment may be present even in the absence of subjective symptoms in patients taking antiemetics, and patients should also be warned of this possibility.[38] In a driving study by Betts and colleagues[55] subjects taking 5 mg of prochlorperazine 3 times daily showed increased carelessness and significant slowing on a maneuvering task. Also, these subjects were not aware of their driving impairments. In LeRoy and Morse's study,[1] patients taking antiemetic/antivertigo agents experienced a 63% increase (P < .01) in motor vehicle crash experience compared with patients not taking these medications.

Cardiovascular/Renal Medications

Antihypertensive Drugs

Antihypertensive drugs represent a broad class of agents that are used to lower blood pressure as well as treat a variety of other cardiovascular conditions and certain members of which demonstrate an increased OR for a motor vehicle crash.[1] The most common side effects of these medications are symptoms related to their hypotensive properties such as dizziness, fatigue, and weakness, all of which may impair driver performance. Antihypertensives that work centrally (eg, the sympatholytic agents such as clonidine or methyldopa) may also cause insomnia, confusion, and nervousness.[38]

Diuretics

Diuretics are among the oldest known medications for treating hypertension. They work in the renal tubules to remove salt and fluids from the body. Frequently, diuretics are used in low doses in combination with other antihypertensive medications. An increased risk for motor vehicle crashes has been associated with 3 classes of diuretics: loop diuretics (OR = 1.35; P < .01), potassium-sparing diuretics (OR = 1.20; P = .51; NS), and potassium-sparing diuretics in combination (OR = 1.33; P < .01). Drivers taking these medications had a 20%-35% increased incidence of crash involvement compared with drivers not taking these drugs.[1] PDI side effects associated with loop diuretics (eg, furosemide, bumetanide, ethacrynic acid, torsemide) include dizziness, weakness, orthostatic hypotension, and blurred vision.[56] PDI side effects associated with potassium-sparing diuretics (eg, spironolactone, eplerenone, triamterene) include confusion, drowsiness, and lethargy.[58] Potassium-sparing diuretics in combination with hydrochlorothiazide (another diuretic) include triamterene, spironolactone and amiloride, among others. PDI side effects include dizziness, fatigue, weakness, and postural hypotension.[58]

Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme inhibitors (eg, lisinopril, quinapril, ramipril) decrease the activity of angiotensin, dilating blood vessels and reducing blood pressure. Researchers found that drivers taking angiotensin-converting enzyme inhibitors experienced a motor vehicle crash rate that was 23% greater (OR = 1.23) than that of drivers not taking these medications (P < .01).[1] Dizziness and asthenia, are potential side effects that could impair safe driving performance.[59,60]

Calcium Channel Blockers

Calcium channel blockers (eg, amlodipine, verapamil, diltiazem) block the entry of calcium into the muscle cells of the heart and arteries, decreasing the contraction of the heart and dilating the arteries. Drivers taking these medications had a 25% greater motor vehicle crash rate than drivers not taking these medications (P < .01).[1] PDI side effects of these medications include dizziness and fatigue.[61,62]

Sympatholytic Agents

Clonidine, methyldopa, and guanabenz are examples of centrally acting antihypertensives classified as sympatholytic agents. These agents stimulate the alpha-receptors in the brain. The result of this stimulation is a decrease in sympathetic nervous system outflow and the relaxation of the peripheral arteries throughout the body. LeRoy and Morse[1] found that drivers taking sympatholytic hypotensives had a 79% increased rate of motor vehicle crash involvement (OR = 1.79; P = .01) compared with drivers not taking these drugs. PDI side effects of medications in this class may include drowsiness and dizziness.[63,64] Some of these drugs cause sedation; clonidine's prescribing information indicates that patients should be advised of the possible sedative effect, especially in combination with alcohol, barbiturates, or other sedating drugs.

Vasodilators

Nitroglycerin relaxes smooth muscles and widens blood vessels to relieve chest pain, decrease blood pressure, and increase heart rate. In LeRoy and Morse's study,[1] drivers taking vasodilators had a 31% increased rate (P = .02) of motor vehicle collisions compared with drivers not taking medications in this class. Prescribing information indicates that nitroglycerin tablets may cause severe headache, symptoms of postural hypotension, and blurring of vision.[65]

Antiarrhythmics

Antiarrhythmics are used to treat irregular heartbeats. Examples include quinidine, mexiletine, procainamide, disopyramide, and amiodarone. PDI side effects may include malaise, fatigue, tremor, blurred vision, dizziness, fatigue/weakness, and visual halos.[66,67] LeRoy and Morse[1] found that drivers taking antiarrhythmics had a motor vehicle crash rate that was 46% (P = 0.19; NS) higher that that for drivers not taking medications in this class.

Digitalis Glycosides

Digoxin is an approved treatment for congestive heart failure and certain cardiac arrhythmias. PDI side effects may include dizziness, apathy, confusion and blurred or yellow vision.[68] In the study by LeRoy and Morse,[1] drivers taking prescription drugs in this class had a 29% (P = .09; NS) increased rate of motor vehicle crashes compared with drivers not taking these drugs.

Digoxin has a low safety profile because the therapeutic and toxic serum levels are known to be close. Digoxin toxicity is a result of both dosing and cumulative effects. Patients with toxic levels of digoxin can demonstrate visual symptoms. Digoxin's visual side effects overlap with those of amiodarone, and include blurred or yellow vision.

A number of medications can also significantly increase serum levels of digoxin, potentially inducing toxic levels. These include quinidine, verapamil, amiodarone, propafenone, indomethacin, itraconazole, alprazolam, and spironolactone.[68]

Cardiac polypharmacy has been associated with color vision and acuity changes in older persons.[69] The addition of amiodarone therapy in patients using digoxin has been associated with visual "shining," glare, color vision anomalies, and decreased visual acuity.

Hematologic Agents

Hematologic agents encompass several categories of medications including:

  • Oral anticoagulants (coumarin derivatives or vitamin K antagonists);
  • Heparin and related preparations (eg, enoxaparin, fondaparinux, tinzaparin);
  • Platelet aggregation inhibitors (eg, clopidogrel, aspirin + extended-release dipyridamole); and
  • Platelet-reducing agents (eg, anagrelide).

Medications in each of these classes have not been studied specifically for their impact on driver performance measures; however, some of these agents were associated with an increased likelihood of a motor vehicle crash in the epidemiologic research of LeRoy and Morse.[1] Drivers taking platelet-reducing agents had a motor vehicle crash rate that was 3 times higher (P = .44; NS) than the rate for drivers not taking these drugs. PDI side effects associated with platelet-reducing agents may include dizziness and asthenia.[70] Drivers taking heparin and related products were twice as likely (P = .45; NS) to be crash-involved than drivers not taking heparin.[1] PDI side effects associated with heparin and related preparations include dizziness, hypotension, and confusion.[71,72]

The OR of crashing for the coumarin type oral anticoagulants is 1.31 (P = .04) and 1.69 for the platelet aggregation inhibitors (P = .01).[1] Patients taking oral anticoagulants such as warfarin/coumarin do not typically experience side effects that would impair driver performance; however, the conditions that this class of medications are used to treat can themselves be driver-impairing. PDI effects associated with platelet aggregation inhibitors may include dizziness, fatigue, arthralgia, and back pain.[73]

Respiratory Tract Medications

Antihistamines

There are more than 60 antihistamines available for oral administration. These medications are being used by an estimated 40 million people in the United States daily. Many are available without a prescription. Not only are antihistamines used to treat allergic conditions such as rhinitis and the respiratory symptoms associated with colds and the flu, they are also used to treat motion sickness, vertigo, vascular headaches, nausea, itching, anxiety, and insomnia.[74] Such widespread use highlights the increased potential safety risk to drivers.

Antihistamines are generally categorized as first-generation vs second-generation (and later), which indicates whether they have ingredients that cause greater or lesser sedation. First-generation antihistamines contain compounds called anticholinergics, which tend to produce the side effects of dry mouth, nose, and throat that differentiate this group from second-generation antihistamines. The newer, second-generation antihistamines do not contain anticholinergic effects. In addition, second-generation antihistamines cross the blood-brain barrier poorly, and do not usually cause sedation at recommended doses.

First-generation antihistamines, such as diphenhydramine, chlorpheniramine, clemastine, hydroxyzine, and triprolidine freely pass the blood-brain barrier and have an attraction to central H1 receptors. This lack of specificity directly correlates to increased sedation and anticholinergic effects. Many of the first-generation antihistamines have half-lives as long as 24 hours and unwanted side effects may be experienced into the next day, as an "antihistamine hangover." In addition, because older antihistamines are sedating, they also disrupt the normal sleep architecture. Altered nighttime sleep patterns lead to daytime fatigue and sleepiness.[75] As mentioned in earlier modules of this curriculum, driving while fatigued can result in performance impairments similar to those observed while under the influence of alcohol.

Second- and third-generation antihistamines developed over the past 10 years, such as cetirizine, loratadine, and fexofenadine, are far more selective for peripheral H1 receptors and, correspondingly, this class has a far-improved side-effect profile. Second- and third-generation antihistamines do not tend to distribute into the CNS at standard doses, and are therefore relatively nonsedating.[74] However, taking a second-generation antihistamine at higher-than-recommended doses can produce a detectable level of sedation.[38] Being relatively devoid of sedation and CNS impairment, second- and third-generation antihistamines are less likely to impair driving than first-generation antihistamines.

Studies have demonstrated that first-generation antihistamines at a single therapeutic dose can significantly impair cognitive and psychomotor performance. Weiler and colleagues[76] used the Iowa Driving Simulator in a randomized, double-blind study to measure "coherence," a subject's ability to continuously match variations in the speed of a car he/she is following, among individuals dosed with one of the following:

  • Diphenhydramine (50 mg), a first-generation antihistamine available over the counter;
  • Alcohol (0.1% blood alcohol concentration);
  • Fexofenadine (60 mg), a second-generation antihistamine available by prescription; or
  • Placebo.

Secondary measures obtained in the simulator included lane-keeping (steering instability and crossing the centerline) and the time that it took to respond to a vehicle that unexpectedly blocked the lane ahead. Subjects also reported drowsiness.

The principle conclusions in the report were that subjects were better able to match the speed of the car ahead, drove farther behind that car, and had better steering control after taking alcohol or fexofenadine than after taking diphenhydramine.[76] Alcohol impaired the secondary tasks, especially response time to the blocking vehicle, but overall driving performance was poorest among the study participants who took diphenhydramine. Self-reports of drowsiness were not a good predictor of impairment on the primary or secondary tasks in this study, suggesting that "drivers cannot use drowsiness to indicate when they should not drive." Based on these results, the report authors issue a special caution regarding the use of "first-generation" (sedating) antihistamines, suggesting that they "... may have an even greater impact than does alcohol on the complex task of operating an automobile." However, as cautioned by Moskowitz and Wilkinson,[74] while second-generation antihistamines represent a major triumph for the pharmaceutical industry in reducing potential side effects, there remains some evidence that all antihistamines may cause sedation and objective skills impairment, at least in some cases and for some individuals.

Moskowitz and Wilkinson[74] evaluated the results of 130 experimental studies measuring the effects of first- and second-generation H1 antagonists on behavioral and cognitive performance skills important for driving, and subjective measures of sedation.

Impairment of actual, on-road driving was found in 89% of the studies evaluating first-generation antihistamines, and 10% of the studies evaluating second-generation antihistamines. All of the first-generation antihistamines studied (chlorpheniramine, clemastine, diphenhydramine, hydroxyzine, and tripolidine) showed on-road driving impairment. In contrast, the only 2 second-generation antihistamines that showed on-road driving impairments were cetirizine and terfenadine. In 1 of the studies, the effects of cetirizine on driving performance after a single 10-mg dose resembled those of alcohol. Subjects taking cetirizine drove with significantly greater variability in speed and lateral position (weaving) when compared with placebo.[77] Vermeeran and O'Hanlon[78] concluded that fexofenadine had no effect on driving performance after being taken in the recommended dosage of 60 mg twice daily.

Divided attention tasks consisting of tracking and visual search are also impaired by first-generation antihistamines.[74] First-generation drugs impaired divided attention tasks in 69% of the studies evaluated, whereas second-generation drugs impaired divided attention tasks in only 13% of the studies.

First-generation antihistamines also impaired sustained attention (vigilance) in 86% of the studies. None of the second-generation antihistamines showed evidence of impaired vigilance.

In terms of tracking performance, all 5 of the first-generation antihistamines demonstrated significant impairment; in 69% of the tests evaluated, first-generation antihistamines impaired tracking ability. Only 2 of the second-generation antihistamines tested (cetirizine and fexofenadine) impaired tracking performance; tracking was impaired in 19% of the tests evaluating second-generation antihistamines.

Reaction time was significantly slowed in 48% of the studies evaluating first-generation antihistamines; this compares to 11% of the studies evaluating second-generation antihistamines. Cetirizine was the only second-generation antihistamine that showed significant impairment in reaction time. Tashiro and colleagues[79] analyzed brake reaction time for subjects performing a divided attention test and found that subjects taking a second-generation antihistamine (fexofenadine HCl 120 mg) showed no difference compared with placebo, while subjects taking a first-generation antihistamine (hydroxyzine HC1 30 mg) had significantly slowed brake reaction times.

In terms of objective sedation measures, such as the multiple sleep latency test, which uses electroencephalograph frequencies to detect the onset of sleep, 100% of the test findings evaluating first-generation drugs showed significant sedation compared with only 9% of the test findings evaluating second-generation antihistamines. The only second-generation antihistamine that showed significant objective sedation was cetirizine. In terms of subjective sedation, Moskowitz and Wilkinson[74] found that the older antihistamines were associated with subjective sedation in 67% of the findings evaluated, and the newer antihistamines were associated with subjective sedation in 5% of the findings. Each of the 5 first-generation antihistamines produced significant feelings of sleepiness, whereas cetirizine was the only second-generation antihistamine associated with subjects' feelings of sleepiness. Tashiro and colleagues[79] found that in tests of subjective sleepiness, subjects given hydroxyzine were significantly less alert/more sedated than those who were administered fexofenadine or the placebo. There were no significant differences in subjective alertness/sleepiness between fexofenadine and the placebo groups. Significantly, Wang and colleagues[38] report that subjects may experience impairment in the absence of any reported subjective symptoms of impairment.

From their review, Moskowitz and Wilkinson[74] concluded that the proper selection of a second-generation antihistamine will produce little impairment in the performance of skills necessary for safe driving, and only a small effect on traffic crashes. Of particular note, the US Federal Aviation Administration has authorized the use of fexofenadine and loratadine by pilots when needed. In the United States, 32 driver licensing agencies have special laws that include medication use in defining impaired driving. Patients would be considered impaired under these laws if they drove vehicles while taking any of the first-generation antihistamines or cetirizine.[75]

In the case-control study by LeRoy and Morse,[1] patients taking antihistamines (prescription) evidenced a 55% higher rate (P < .01) of motor vehicle crashes (OR = 1.55) compared with drivers who were not taking antihistamines. First- vs second-generation antihistamines were not distinguished in their research.

Bronchodilators

Bronchodilators are either short- or long-acting and are intended to improve airflow. They are adrenoreceptor agonists that work primarily by relaxing airway smooth muscles and inhibiting the release of bronchoconstricting substances from mast cells. Beta-adrenergic selective agents have been widely used in the treatment of asthma and include albuterol, pirbuterol, salmeterol, formoterol, and levalbuterol. This class of medication is known to produce short-term and long-term side effects such as increased heart rate, dizziness, arrhythmias, nervousness, musculoskeletal pain, and fatigue.[80,81] These systemic side effects, as well as the disease state that they are used to treat, may play a role in this class of medication's elevated rate of motor vehicle crashes.[1] Compared to drivers not taking these medications, drivers taking beta-adrenergic agents were 35% more likely to be involved in a crash (OR = 1.35; P < .01), and drivers taking combined beta-adrenergic and glucocorticoid products were at more than twice the risk for crash involvement (OR = 2.4; P = .06; NS).

Non-Narcotic Antitussives

Prescription non-narcotic antitussives, such as benzonatate, relieve symptomatic coughs due to the common cold, flu, pneumonia, and bronchitis. Common side effects that may affect driving performance include dizziness, sedation, and burning sensation in the eyes.[82] Uncommon side effects include confusion and hallucinations. In research conducted by LeRoy and Morse,[1] drivers using non-narcotic antitussives were 2.23 times more likely (P < .01) to be involved in a motor vehicle crash than drivers not using this medication.

Hormones/Hormonal Mechanism of Action

Hypoglycemics

In addition to insulin, there are 5 classes of oral diabetes mellitus medications, which help in lowering blood glucose levels by different mechanisms. Blood glucose control can be achieved with the use of a single agent, or a combination, with or without insulin. The 5 classes are listed below.

  • Sulfonylureas stimulate the pancreas to make more insulin (glipizide, glyburide, glimepiride);
  • Biguanides (nonsulfonylureas) turn off the liver's production of excess glucose (metformin hydrochloride);
  • Thiazolidinediones increase the body's sensitivity to insulin (rosiglitazone maleate, pioglitazone); and
  • Meglitinides stimulate the body's sensitivity to insulin (repaglinide).
  • Alpha-glucosidase inhibitors decreases the intestine's absorption of carbohydrate (acarbose, miglitol).

Of the hypoglycemics, insulin was associated with the highest OR (1.80) (P < .01) for a motor vehicle crash in the study by LeRoy and Morse.[1] The other hypoglycemic agents studied had ORs ranging from 1.35 to 1.50. None of the common side effects of the hypoglycemics would predict a direct relationship with impaired driving. Uncommon side effects may include dyspnea, dizziness, and drowsiness, which would fall into the PDI category.

Within this class of medication, compliance may have more to do with PDI effects than metabolic effects of the drug. Taking too much insulin or delaying or missing a scheduled meal or snack can cause low blood glucose (hypoglycemia), and can result in shakiness, lightheadedness or dizziness, confusion, difficulty concentrating, drowsiness, weakness, and seizures. These symptoms are driver-impairing. Low blood glucose, left untreated, can lead to unconsciousness. Hyperglycemia results from too little insulin, and also has symptoms that may impair driving, such as weakness, blurred vision, and decreased consciousness. High blood glucose symptoms may result from skipping an insulin dose or from overeating.

A study has identified a direct relationship between the medications used in the treatment of diabetes mellitus and an increased risk for impairment resulting in falls.[83] This study is relevant to the topic of driving, because vehicle crash involvement in the elderly has been significantly associated with a recent history of falls.[84] Because falling and crashing are 2 adverse mobility outcomes, they may share the same underlying causes. Among the medications studied by Lee and colleagues,[83] only anti-diabetic agents showed a moderate association with recurrent falls (OR = 2.9; P = .01). Because the study cohort contained a large proportion of patients with diabetes mellitus not on drug treatment (25.7%), direct comparisons could be made between individuals with antidiabetic medication and those without this medication.

The study indicated that antidiabetic medications were related to recurrent falls but the medical condition itself, ie, being diabetic, was not. Thus, hypoglycemic side effects of drugs could be the cause of falls among older diabetics.

Gastrointestinal Agents

Gastric Acid Secretion Reducers

Gastrointestinal agents such as esomeprazole, lansoprazole, pantoprazole, and ranitidine block gastric acid secretion. The medications in this class vary in level of potency and some of them may cause drowsiness or dizziness.[85-87] Empirical studies documenting the effects of gastric acid secretion reducers on driving are not available; however LeRoy and Morse[1] found a 55% higher likelihood (P < .01) of a motor vehicle crash for drivers using these medications compared with drivers not using them.

Anticholinergics/Antispasmodics

The anticholinergic/antispasmodics are a group of medications that include the natural belladonna alkaloids (atropine, belladonna, hyoscyamine, and scopolamine) and related products. They are used to relieve cramps or spasms of the stomach, intestines, and bladder. Some are used together with antacids or other medicines to treat peptic ulcer, and others are used to prevent nausea, vomiting, and motion sickness. LeRoy and Morse[1] found an 85% higher motor vehicle crash experience associated with the belladonna alkaloids (P = .03). PDI side effects of belladonna alkaloids may include confusion, blurred vision, dizziness, and drowsiness. Prescribing information indicates that patients should be cautioned not to drive in the event of these side effects.[89,90]

Other anticholinergics/antispasmodics such as dicyclomine may cause confusion, dizziness, drowsiness, tingling, weakness, blurred vision, and double vision. Prescribing information indicates that patients should be cautioned against driving while taking this drug.[90] LeRoy and Morse[1] found that drivers taking anticholinergics/antispasmodics had a 20% increased likelihood of crashing (OR = 1.2; P = .59; NS) compared with drivers not taking these medications.

Pain Relievers

Narcotic Analgesics

Every year, millions of prescriptions for narcotic analgesics are written for patients as a means to manage chronic and acute pain.[91] Narcotic analgesics are opioid derivatives that selectively bind to the opioid receptors of the CNS and carry the general warning to avoid driving due to the CNS depressant effects. Side effects may include dizziness, lightheadedness, feeling faint, drowsiness, and weakness.[92-94] Visual changes may occur. Wang and colleagues[38] report that patients using narcotic analgesics may be impaired even in the absence of subjective symptoms of impairment.

There are 4 broad classes of opioids: (1) endogenous opioid peptides produced in the body (eg, endorphins), (2) opium alkaloids (eg, morphine, codeine), (3) semisynthetic opioids (eg, oxycodone, hydrocodone, hydromorphone), and (4) fully synthetic opioids (eg, meperidine, methadone, fentanyl, propoxyphene, butorphanol, tramadol).

With over 2.2 times the likelihood (P < .01) of crash involvement for drivers using narcotic analgesics compared with drivers not using these medications,[1] studies have demonstrated the impairing psychomotor effects of narcotic analgesics in acute, "narcotic-naive" patients. It is commonly accepted that opioid-naïve patients should be instructed not to drive. However, there is controversy surrounding what recommendations should be made to patients taking stable opioid doses.[95] Patients with chronic pain on a stable opioid analgesic regimen may be capable of operating a motor vehicle safely during daytime, good-weather conditions.[91]

Acute Dosing

Laboratory studies have shown that nontolerant individuals receiving single doses of methadone have experienced dose-dependent impairments in reaction time, visual acuity, information processing, and sedation.[2]

In research conducted by Verster and colleagues[96] subjects were given either oxycodone/paracetamol 5/325 mg; oxycodone/paracetamol 10/650 mg; or placebo, and were road-tested 1 hour after dosing. Each subject participated in each medicine or control treatment, separated by a 7-day washout period. Oxycodone is an opioid agonist that is often prescribed in combination with paracetamol to reduce the opioid dosage while retaining the analgesic efficacy, to reduce opioid-related adverse effects. Drive test results showed no significant differences between the opioid treatments and the placebo; however, there was a significant difference in the drivers' ability to keep the vehicle centered within the lane between the high dose and the low dose of the opioid medication. The difference between the high dose and the placebo was not significant, and is less than that observed with blood alcohol concentrations of .05%. There were also no significant differences between the opioid treatments and the placebo on any of the laboratory tests (memory scanning test, a tracking task, and a divided attention task), although performance was worse under both opioid treatment conditions than the placebo condition.

Compared with the placebo, subjective mental effort during driving was significantly elevated after the high dose of the opioid, but not after the low dose of the drug. Also, a significant dose-response relationship on mental effort was found for the opioid drug. Verster and colleagues[96] suggest that the lack of impairment they observed on the drive test may have been related to the participants reporting increased effort during driving while under the influence of this medication. Finally, compared to the placebo, subjective alertness was significantly decreased for both doses of the opioid, and there was also a significant dose-response relationship. Furthermore, after the drive test, self-reported level of sedation was significantly increased in the high-dose opioid condition, as was dysphoria. There was a significant dose-response relationship for the opioid medications on the dysphoria scores.

Stable Dosing

Fishbain and colleagues[95] conducted a structured, evidence-based review of the literature between 1966 and 2001 to determine whether opioids affect the driving ability of patients who are on stable doses of this medication or who would be presumed to have developed some tolerance to the sedative effects of opioids. This review suggested that driving-related skills are not impaired in patients stabilized on long-term opioid therapy when used alone, and noted that the following advice should being given to patients[95]:

  • Do not drive after initiating narcotic therapy or after a dose increase, for 4-5 days;
  • Do not drive if feeling sedated;
  • Report cognitive decline, sedation or unsteadiness to your prescriber, so that a reduction in dosage can be initiated;
  • Do not use alcohol;
  • Avoid taking over-the-counter antihistamines; and
  • Do not change your medication regimen without consulting your prescriber.

Another review concluded that opioids do represent a risk to traffic safety based on present knowledge; however, the degree of impairment is dependent on the particular opioid, dose, and history of use.[18]

Nonsteroidal Anti-Inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medications to relieve pain and inflammation from many conditions such as arthritis (rheumatism). The common NSAIDs, such as ibuprofen and naproxen, block the action of both cyclooxygenase (COX)-1 and COX-2 enzymes. The more selective COX-2 inhibitors (celecoxib, meloxicam) have a decreased side effect profile.

In general this class of medications is rarely associated with impaired driver performance; however, there have been isolated reports of confusion after taking phenylbutazone and indomethacin.[38] Adverse events may occur more often in elderly patients.

When PDI side effects occur, they consist of drowsiness, dizziness, lightheadedness, lowered alertness, and blurred vision. Because of potential side effects, patients are cautioned about operating a motor vehicle while taking some of these medications. LeRoy and Morse[1] found a 58% increase (P < .01) in crash risk for drivers taking NSAIDs compared to drivers not taking these medications.

Skeletal Muscle Relaxants

Skeletal muscle relaxants by convention have been classified into 1 group; however, they are actually a heterogeneous group of medications commonly used to treat 2 different types of underlying conditions -- spasticity from upper motor neuron syndromes, and muscular pain or spasms from peripheral musculoskeletal conditions. Medications classified as skeletal muscle relaxants are baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, dantrolene, metaxalone, methocarbamol, orphenadrine, and tizanidine.

The manufacturers of these drugs suggest that patients be warned that their mental and/or physical abilities required for driving an automobile may be impaired, and that they should be cautious about driving. As a class, skeletal muscle relaxants have CNS-related side effects: drowsiness, dizziness, decreased alertness, blurred vision, and ataxia.[97] Their use has been associated with a 2-fold increase in the risk for motor vehicle crashes (OR = 2.09; P < .01).[1] Muscle relaxants are included on the Beers List of potentially inappropriate medications in older adults.[13] Most muscle relaxants are poorly tolerated by elderly patients, because they cause anticholinergic adverse effects, sedation, and weakness. Also, their effectiveness at doses tolerated by elderly patients is questionable.[13]

Carisoprodol has a short half-life, approximately 100 minutes. A single 700-mg dose does not significantly affect psychomotor and cognitive test performance within 3 hours of dosing. However, with chronic dosing, it is likely that decrements in psychomotor performance would be more pronounced. Similarly, in individuals with impaired kidney or liver function, the altered metabolism of carisoprodol would result in a half-life 2-3 times that of normal individuals.[2] In a study of cases of driving while intoxicated, carisoprodol was detected in concentrations at or above the recommended therapeutic dose; all subjects were involved in crashes or were observed to exhibit severe weaving on the road. In some cases, subjects had been involved in hit-and-run crashes, where they struck other vehicles or fixed objects without appearing to be aware they had hit anything.[17]

It is the consensus of experts that a single therapeutic dose of carisoprodol is unlikely to cause significant performance impairment in healthy individuals. However, chronic doses of this medication may produce moderate-to-severe impairment of psychomotor skills associated with safe driving.[2]

Neurologic Agents

Anti-Parkinson's Drugs

Many medications and classes of medications are used in the treatment of Parkinson's disease (PD) symptoms, including tremors, stiffness, and slowness of movement. PD symptoms are caused primarily by a dopamine deficiency and medications that compensate for the dopamine deficiency such as carbidopa/levodopa, pramipexole, ropinirole, entacapune are routinely used alone or in combination. Amantadine, an antiviral medication, is also used to treat stiffness and shaking associated with P'D, although the mechanism of action is unknown. Common known side effects of these medications that may impact driving ability are excessive daytime sleepiness, dizziness, blurred vision, involuntary movements, hallucinations, and confusion.[98] These medications carry a warning about the side effect of drowsiness, which may cause patients to fall asleep during activities of daily living. Medications used to treat P'D has been associated with a 62% increase (P = .05) in the likelihood of motor vehicle crash involvement.[1]

Homann and colleagues[99] reviewed research published between July 1999 and May 2001 on the prevalence of sleep attacks in patients taking dopamine agonists for 'PD. They found that up to 30% of patients taking these medications had sleep attacks, with men comprising two-thirds of the cases. Sleep attacks are defined as events of overwhelming sleepiness that occur without warning or with a prodrome that is too short or overpowering to act on. Patients with sleep attacks ranged in age from 34 to 87 years. Duration of the disease ranged from 1 to 20 years; in 2 patients, sleep events happened upon first exposure to the medications, in others they occurred with drug exposures ranging from 2 weeks to 20 years. Sleep events occurred in 124 patients: 96 included sleep attacks, 4 had sleep episodes where onset was not sudden but it was irresistible, and 23 had events that were not defined in the publication. These sleep events were associated with the following PD medications: levodopa alone in 8 patients, ergot agonists (apomorphine in 2 patients, bromocriptine in 13 patients, cabergoline in 1 patient, lisuride or piribedil in 23 patients, pergolide in 5 patients), and non-ergot agonists (pramipexole in 32 patients and ropinirole in 38 patients). Sleep events happened at both high and low doses of the drugs. In 17 of the 124 cases, the sleep event happened during driving, leading to motor vehicle crashes in 10 cases.

It is not known whether the cause of the sleep attacks is drug-related or disease related, because patients with PD experience alterations in their sleep patterns that result in daytime sleepiness.[100] Dopaminergic agents also induce sleepiness. Patients are advised to avoid driving until they know how the medication affects them, particularly during the first 3-5 days of therapy and any time the dose is increased. Moreover, patients should be made aware of the following[98,100]

  • Patients being treated with dopaminergic agents have reported suddenly falling asleep while engaged in activities of daily living. This includes driving a car, and it has sometimes resulted in crashes;
  • Although some patients reported feeling sleepy, others had no warning signs such as excessive drowsiness, and believed they were alert immediately before the event;
  • Sudden sleep attacks are not limited to the initiation of drug therapy; and
  • Patients considered to be at risk of falling asleep behind the wheel should be cautioned strongly to avoid driving.

Anticonvulsants

Anticonvulsants belong to a diverse class of medications developed to prevent epileptic seizures. Barbiturates and BZD, already discussed, are commonly used to prevent and treat seizure disorders, as are anticonvulsants clonazepam, gabapentin, topiramate, valproic acid, oxcarbazepine, phenytoin, carbamazepine, and lamotrigine. Anticonvulsants suppress abnormal neurologic activity in the brain and are also prescribed for the treatment of bipolar disorder, anxiety, and aggression. PDI side effects of these drugs include drowsiness, fatigue, dizziness, blurred vision, double vision, abnormal eye movements, confusion, tremor, ataxia, memory problems, and decreased alertness.[101] Patients should be cautioned against driving at least until they know how the drug affects their mental or motor ability. Anticonvulsants have been associated with nearly twice the likelihood (OR = 1.97; P < .01) of a motor vehicle crash.[1] Wang and colleagues[38] note that individually, anticonvulsants may be mildly impairing; however, these medications are typically used in combination with antidepressants, antipsychotics, and/or anxiolytics, which increases psychomotor performance impairments.

Topiramate received US Food and Drug Administration approval for prevention of migraine headaches in August 2004, and is being prescribed for off-label uses such as psychiatric and eating disorders, neuropathic pain, and alcohol and drug dependency.[102] In forensic toxicology investigations of topiramate-positive drivers, psychomotor impairment was evident with blood concentrations within normal therapeutic range. As an example, a 31-year-old woman was prescribed topiramate for an eating disorder. She drove off the highway and crashed into the median. Responding officers noted thick slurred speech, heavy eyelids, and dilated pupils. She had a lack of coordination and could not stand unassisted and was arrested for driving while under the influence of alcohol. The only drug identified in her blood was topiramate at therapeutic levels (8.1 mg/L). Gordon and Logan[102] note that as anti-epileptic medications are increasingly used to treat psychiatric disorders, their prevalence in impaired driving cases has increased. For psychiatric patients, there must be specific instructions about the dangers of driving while taking these medications.

Ophthalmics

Eye Antihistamines

Eye antihistamines are used to relieve itching of the eye due to allergic conjunctivitis. Medications in this class include levocabastine, ketotifen, epinastine, azelastine, and olopatadine. Side effects may include blurred vision, eye burning or stinging, and tiredness.[103] Although there are no warnings indicated on the package inserts regarding side effects and driving safety, LeRoy and Morse[1] found a 67% increase in crash likelihood (P = 0.11; NS) associated with the use of these medications.

Eye Sulfonamides

Sulfonamide ophthalmic preparations are used to treat infections of the eye. Medications in this class include sulfacetamide and sulfisoxazole. Common side effects include local irritation, stinging, and burning.[104] LeRoy and Morse[1] found a 76% increase in crash likelihood (P = .15; NS) associated with the use of these medications.

Antiparasitic Agents

Antiparasitic agents as a general class are not PDI medications, with the exception of the antimalarial drugs.[1] Antimalarial drugs include hydroxychloroquine, mefloquine, atovaquone and proguanil, chloroquine phosphate oral, and quinine. Hydroxychloroquine is also used to treat lupus and rheumatoid arthritis. Side effects of drugs in this class include dizziness, fatigue, myopathy and weakness, decreased visual accommodation, disturbance in color perception, and visual field defects.[105-108] Some of the medications in this class contain a warning related to fine motor coordination and decreased alertness and the ability to operate a motor vehicle safely.[109] LeRoy and Morse[1] found a 34% increase in crash likelihood (P = .15; NS) associated with the use of these medications.

Central Nervous System Stimulants

Antinarcolepsy and antihyperkinesis medications are classified as CNS stimulants and fall into 1 of 4 classes: (1) mixed amphetamine salts, (2) dextroamphetamine, (3) methylphenidate, and (4) pemoline.

CNS stimulants increase activity in certain areas of the brain and are associated with side effects that may impair driving performance, such as overconfidence, nervousness, anxiety, insomnia, and rebound effects as the stimulant's effect wears off.[38] In epidemiologic studies, it has been reported that persons taking amphetamine and methamphetamine-type CNS stimulants are involved in run-off-the-road type crashes; engage in high-speed, inattentive driving; exhibit diminished divided attention; fail to stop; and high-risk driving.[2] Observed behaviors include driving over the lane lines, erratic driving, and crashes.

Overall, CNS stimulants are most commonly associated with physiologic reactions, with observable behavioral impairments being less frequent.[10] At lower doses, amphetamines have few effects on cognitive functioning and may result in enhancement of some psychomotor tasks. However, study subjects were willing to make more high-risk choices. Performance effects following higher doses may include agitation, inability to focus attention on divided attention tasks, inattention, restlessness, motor excitation, increased reaction time, time distortion, depressed reflexes, poor balance and coordination, and inability to follow directions.[2]

Drug Combinations

Many of the drugs discussed in this unit have significant impairment on their own that may be mitigated as tolerance develops. However, patients often are prescribed more than 1 medication, which can alter the previously acquired tolerance. For example, patients with chronic pain may take narcotic analgesics, antihistamines to potentiate the effects of the narcotic analgesic, an anxiolytic, and an antidepressant. In concert, there may be a significant impairing effect.

This activity is supported by a cooperative agreement with the National Highway Traffic Safety Administration.

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