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23 studies have shown diphenhydramine to decrease alertness, tamines have been demonstrated to have antagonist effects on decrease reaction time, induce somnolence, impair concentra- cognitive performance and because in using them as sleep tion, impair time estimation, impair tracking, decrease learning aids most have been demonstrated to leave a person with ability, and impair attention and memory within the first hangover inertia effects long after the sleep period has ended. 2 to 3 h post-dose (Moskowitz and Burns 1988; Gengo et al. Commercial drivers must be properly informed of the haz- 1989; Gengo and Manning 1990; Kay et al. 1997). Signifi- ards and risks of using antihistamines both for allergy relief cant adverse effects on vigilance, divided attention, working and for use as a sleep aid. Guidance information on this topic memory, and psychomotor performance have been demon- should be provided in materials prepared for overall infor- strated. Impairment has been shown even in the absence mation dissemination on chemical substances. of self-reported sleepiness or sedation. Sedative effects are dose-dependent. Interactions with alcohol can exacerbate performance decrements. SUMMARY OF OPERATIONAL CONSEQUENCES OF SLEEP-PROMOTING COMPOUNDS Diphenhydramine has repeatedly been shown to severely Table 2 summarizes the previous information regarding some impair tracking and reaction time performance in actual key points of employing various sleep-promoting compounds on-the-road driving tests. Single doses of 50 mg have been in an operational setting, whether for commercial transportation shown to cause significant impairment during a 90 km highway purposes or some other work environment. The literature test (measuring vehicle following constant speed and lateral conveying U.S. military medical research findings and oper- position). In contrast, single 25- to 100-mg doses caused no ational procedures being followed during training and military significant driving effects during a short 15-min driving test. deployment activities is presented in Appendix B to this report. Using the Iowa Driving Simulator (passenger car), Weiler et al. (2000) compared the effects demonstrated by test participants who took only a single oral dose of 50 mg diphenhydramine SECOND-GENERATION NONSEDATING with the effects corresponding to a blood alcohol concentration ANTIHISTAMINES FOR ALLERGIES of 0.1 g/100 ml. Diphenhydramine caused significantly less coherence (ability to maintain a constant distance) and impaired Second-generation antihistamines are described here to lane keeping (steering instability and crossing the centerline) ensure that descriptions of both antihistamine types remain compared with alcohol. Overall driving performance was in close proximity in this synthesis report. Acute, seasonal poorest after taking diphenhydramine, and participants were allergic reactions may inhibit a worker's operational capability, most drowsy after taking diphenhydramine (measured both which is of special concern during attention-demanding work; before and after test driving). The authors concluded that that is, commercial driving. A class of second-generation diphenhydramine clearly impairs driving performance and antihistamines (e.g., loratadine, fexofenadine, cetirizine, and may have an even greater impact than alcohol on the com- astemizole)--the so-called nonsedating antihistamines-- plex task of operating a motor vehicle (Weiler et al. 2000) are touted to offer effective symptomatic relief for treating [see also Betts et al. (1984)]. seasonal allergies. Allegedly, because they are said not to cross the bloodbrain barrier, they should not bring about No reports were located documenting involvement of worker drowsiness and, therefore, should be more suitable to first-generation antihistamines in commercial driving studies, meet some CMV drivers' needs for allergy relief. or as they might be implicated in actual crash fatalities. How- ever, examination of more than ten years of pilot fatalities in Second-generation antihistamines have improved safety U.S. general aviation crashes determined that approximately profiles compared with the older first-generation anti- 5% were involved with antihistamines (Soper et al. 2000; histamines. This is because these second-generation agents Chaturvedi et al. 2005). have increased specificity for the H-1 receptor and bulky side chains that hinder their ability to cross the bloodbrain Assessment of first-generation antihistamines. Although barrier. As a result, second-generation antihistamines are more first-generation antihistamines often provide effective treat- hydrophilic, having a higher affinity for peripheral histamine ment for allergy sufferers, such compounds frequently pro- receptors than for cortical sites. Their active agents enter the duce side effects such as drowsiness, sedation, fatigue, and CNS less readily, produce less sedation, and result in far less an inability to concentrate (Gengo 1996). First-generation CNS impairment than do the first-generation antihistamines. antihistamines (such as those containing diphenhydramine) Although second-generation antihistamines provide allergy were described with a particular focus on the notion that for relief, in principle they should not affect cognitive perfor- some users such antihistamines also can bring about sedation mance, making them a preferred treatment choice for many when used for sleep promotion. However, the use of first- allergy sufferers (Kay et al. 1997; Timmerman 1999; Van generation antihistamines is discouraged under task and work Cauwenberge et al. 2000). conditions that require the worker to maintain vigilance or to put forth sustained mental effort. Such cautions are issued The FMCSA has provided guidance on "Non-sedating" or because maintenance levels of all first-generation antihis- second-generation antihistamines in the Pulmonary Medical

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24 TABLE 2 OPERATIONAL CONSEQUENCES OF SLEEP-PROMOTING COMPOUNDS Average Recommended Comments/ Benzodiazepines Rx Trade Name Half-Life Use Cautions Temazepam Restoril 8.012.0 hr Daytime sleep; Need 8-hr sleep sleep period post dose maintenance Triazolam Halcion 2.04.0 hr Diazepam Valium Lorazepam Ativan Alprazolam Xanax Chlordiazeproxide Librium Clonazepam Klonopin Newer Hypnotics (Rx) (non- Sleep initiation; Benzodiazepines) napping strategy Zolpidem Ambien, Stilnox, 2.02.5 hr Sleep initiation; Promotes sleep of Myslee intermediate 47 hr length naps Zaleplon Sonata, Starnoc 1.0 hr Short naps; 20 mg w/20 mg, no for sleep hangover effects at initiation 6+ hr Eszopiclone Lunesta 5.06.0 hr Sleep initiation, & Minimal residual maintenance effects at 10 hr Indiplon & Indiplon ~ 1.5 hr Sleep initiation & Undergoing clinical modified release maintenance trials Ramelteon Rozerem Sleep initiation, Long-term but not for sleep treatment of maintenance insomnia Alternative Sleep Inducers Alterial Includes melatonin, All natural sleep Claims restful sleep L-tryptophan, inducer with no residual valerian effects Melatonin Synthetic hormone Dissipates in Effective daytime Works for some in health stores blood stream sleep inducer in people; no side in daylight darkened room effects or hangover First Generation Benadryl, Maintains in 2550 mg Maintenance level Antihistamines Unisom, body for diphenhydramine may produce Sleepgels, allergy relief induces hangover Dytuss, sleepiness sleepiness Dramamine Conference report (Turino et al. 1991), where use of these ined the effects of diphenhydramine, terfenadine (second- substances is allowed. generation: Seldane), and acrivastine on driving performance as a function of dose and time after dosing. Lateral deviations Gary Kay and his colleagues conducted laboratory exper- (lane weaving and crossings) during driving were found to iments comparing the effects of first- with second-generation vary with both the particular drug chosen and with the dose antihistamines. In a comprehensive review, Kay and colleagues administered. This prompted additional studies evaluating reported impairments to cognitive performance attributable performance of subjects driving while using either first- or to second-generation nonsedating antihistamines that ranged second-generation antihistamines (O'Hanlon and Ramaekers from none to mild (Kay et al. 1997a, b; Kay 2000; Kay and 1995; Ramaekers et al. 1995). Quig 2001). Although several comparison studies confirm the hypnotic effects of diphenhydramine, basically they showed Single doses of diphenhydramine (50 mg), clemastine no significant differences in sedation with some of the non- (2 mg), and multiple doses of triprolidine (5 and 10 mg) sedating second-generation antihistamines such as astemizole produced changes equivalent to those produced by BACs of or loratadine (Roth et al. 1987; Schweitzer et al. 1994; Gengo 0.5 to 1 mg/ml. However, terfenadine (second-generation) and Gabos 1987). was taken in single doses of up to 180 mg and multiple doses over 4 days of up to 120 mg twice per day. The single dose In a comparison of effects of three different antihistamine and multiple doses of 60 mg taken two times per day, and a drugs on driving, Ramaekers and O'Hanlon (1994) exam- 120-mg dose four times per day never produced a significant

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25 rise in lateral position tracking (SDLP). On the contrary, there in driving (Ramaekers et al. 1992; Hindmarch and Shamsi was a tendency for 60 and 120 mg to produce a slight fall 1999; Hindmarch et al. 2002). Further evidence for the lack in SDLP, suggesting a mild stimulating activity (or perhaps of cognitive decrements by fexofenadine was demonstrated a performance settling effect) of the drug. When subjects in a study in the Iowa Driving Simulator that showed that took doses of 120 mg twice per day for 4 days, impairment fexofenadine subjects had better coherence (ability to maintain was equivalent of up to that of 0.05% BAC (O'Hanlon and a constant distance from a lead car with randomly changing Ramaekers 1995). Only a few studies have reported some speed) compared with subjects with diphenhydramine. In degradation of cognitive and psychomotor performance with addition, the ability to stay in the lane, measured by steering second-generation antihistamines; see for example the study instability and crossing the centerline, was impaired in by Rice and Snyder (1993) on terfenadine: Seldane--which alcohol- and diphenhydramine-affected subjects, as com- is no longer on the market; and see also studies here reporting pared with those with only fexofenadine (Weiler et al. 2000). on the performance effects of cetirizine (Zyrtec). Of the three most popular second-generation antihistamines, fexofenadine (Allegra) appears to be the least sedating, even Several of the newer second-generation antihistamines in higher doses. are briefly described here. Loratadine and Desloratadine Cetirizine Loratadine and desloratadine (Claritin, Claritin-RediTabs, Although second-generation antihistamines are claimed by Alavert, and others) is a piperidine histamine H-1 receptor their pharmaceutical manufacturers to be nonsedating, research antagonist with anti-allergic properties and without sedative reports some second-generation antihistamines [e.g., cetirizine effects. In April 1993, the FDA approved loratadine as a (Zyrtec)] do produce some level of cognitive impairment second-generation antihistamine for use without a prescription. (Vacchiano et al. 2008). Cetirizine, which is demonstrated to Loratadine is a longer-acting antihistamine that blocks the be more sedating than the other nonsedating antihistamines, actions of histamine; it does not enter the brain through has been reported to impair cognitive performance in a the blood, and it does not cause CNS effects. Loratadine is number of studies (Ramaekers et al. 1992; Lockey et al. 1996; generally used for the relief of nasal and nonnasal symptoms Meltzer et al. 1996; Nicholson and Turner 1998; Howarth of seasonal allergic rhinitis and to treat patients with chronic et al. 1999). After investigating the effects of cetirizine on urticaria, a type of allergic skin rash. The distributor has indi- tasks such as tracking and vigilance as they relate to aviation cated that there may be occasional side effects with loratadine, personnel, Nicholson and Turner (1998) suggested that including headache, drowsiness, fatigue, and dry mouth. cetirizine should not be used by aviation personnel. Cetirizine's effects on SDLP in driving studies are a matter of contention Claritin-D is a combination of loratadine and the between different groups of investigators (O'Hanlon and decongestant pseudoephedrine (Geha and Meltzer 2001). Ramaekers 1995). One showed a single-dose of cetirizine Although potentially effective in providing relief of runny (10 mg) impaired, whereas another found no effect with that nose, sneezing, and nasal stuffiness from the common cold, dose on either the first or fourth day. Cetirizine may be slightly it is also used for relief of nasal and nonnasal symptoms of sedating even at normally recommended doses. various allergic conditions such as seasonal allergic rhinitis. Side effects of Claritin-D may include stimulation of the In 2007, the FDA approved nonprescription use of Zyrtec-D nervous system leading to nervousness, restlessness, excitabil- (combining cetirizine with a nasal decongestant) for use in ity, dizziness, and headache. Loratadine (Claritin) does obtaining relief from hay fever or other upper respiratory bring about some sedation at higher doses and is less potent allergies. than fexofenadine (Allegra) and cetirizine (Zyrtec). Pseudo- ephedrine used as a decongestant can be associated with cardiac arrhythmia, hypertension, or other adverse effects in Fexofenadine susceptible individuals. In a similar study, Nicholson et al. (2000) demonstrated that A review by Kay and Harris (1999) revealed minimal effects fexofenadine (Allegra) had no impairing effects on tracking, of loratadine on sedation, cognition, mood, and psychomotor vigilance, and other tasks related to aviation. Bower et al. performance. Satish et al. (2004) suggested seasonal allergic (2003) and Vacchiano et al. (2008) demonstrated no signifi- rhinitis (SAR) by itself diminishes task performance and cant effects of fexofenadine on a variety of cognitive perfor- decreases quality of life. These experimenters administered mance tasks, concluding that fexofenadine is comparable to desloratadine to a group of subjects who were experiencing placebo in its effect on cognitive skills involving accuracy, SAR, and gave a placebo to another group. Their performance speed, and attentiveness; each important for piloting an aircraft. was measured on simulated real-world information processing The results were comparable to those involving fexofenadine scenarios, which ranged through several levels of difficulty in assessments of the types of cognitive performance expected from easy to difficult decision-making tasks. Desloratadine

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26 either completely restored performance to the level of the In a study combining alcohol and desloratadine (7.5 mg asymptomatic placebo control or improved performance in daily), Scharf and Berkowitz (2007) demonstrated that a six of nine performance categories, which previously had been single dose of desloratadine does not potentiate alcohol- diminished by the presence of SAR. Their findings suggested mediated CNS impairment, and desloratadine alone or in com- that treatment with desloratadine has beneficial effects on bination with alcohol was safe and well-tolerated. Nicholson workplace performance when individuals suffer from SAR et al. (2003) did a study examining effects of desloratadine (Satish et al. 2004). on performance and sleepiness and concluded that 5 mg of desloratadine appears to be free of adverse effects on psycho- In the car driving experiment reported by O'Hanlon and motor performance, daytime sleep latencies, and subjective Ramaekers (1995) and briefly described earlier, loratadine in sleepiness, and could prove to be suitable for those working single doses of 10 and 20 mg produced no significant rise in skilled activity including transportation. in SDLP (lane weaving). When given in 20-mg doses four times per day for 4 days, the impairment attributable to Assessment of antihistamines. It is the intent here to cull loratadine was similar to that of terfenadine. Building on that through the results of available research studies and to report study, Vuuman et al. (2004) compared the acute effects of on those that depict the effects of various chemical com- desloratadine with diphenhydramine (active control) and pounds. It is not within the scope of this synthesis to propose placebo on performance of healthy subjects evaluated with "treatment protocols" regarding whether antihistamines could standard over-the-road driving tests, and also on a battery of or should be used by commercial drivers, nor to be specific conventional performance tests. The subjects were given either about when one should consider taking a particular anti- a single dose of 5 mg of desloratadine, 50 mg of diphen- histamine. Because so many commercial drivers experience hydramine, or placebo during each period of a randomized, seasonal discomfort attributable to allergies, rhinitis, and other double-blind, three-way crossover study. Two hours post- ailments treatable with antihistamines, more performance- dosing subjects operated a specially instrumented vehicle in oriented research should be done with second-generation, a 90-min test designed to measure their ability to (1) main- and eventually third-generation antihistamines to determine tain constant speed and lateral position while following their potential efficacy for allergy treatment (relief), without another vehicle at a constant distance, and (2) respond to producing degrading sedation effects on driving alertness, brake signals. Additional test batteries were administered. fatigue, and performance. No significant differences were noted between desloratadine and placebo on SDLP, whereas diphenhydramine significantly Based on subsequent research results, what is needed is increased SDLP. Brake reaction time was significantly faster to (1) provide summary information to commercial drivers following treatment with desloratadine than diphenhydramine. and their employers about what these new second-generation No differences were seen among treatments in deviation of antihistamines are about, (2) spell out their advantages and speed or distance to the lead car. The majority of performance disadvantages, and (3) begin to propose such guidance in an tests showed no significant differences among groups. Vuuman easy-to-relate-to format that describes their probable safe appli- et al. (2004) concluded that desloratadine at a therapeutic cation for drivers who require seasonal allergy relief several dose does not impair driving performance. times per year.