3. RESULTS

There is considerable complexity in the task of evaluating 10 drugs for evidence of subjective sedation and objective impairment of a variety of performance measures grouped into 10 specific behavioral categories. Moreover, each drug has been studied across multiple dose levels as well as for acute versus chronic dosing schedules. Therefore, the results of this review are organized into the following major sections below: Overall impairment, Impairment by individual drugs, and Impairment by behavioral categories and subjective sedation.

3.1. Overall Impairment

3.1.1. Impairment Findings by Study for each Drug (Figure 1 and Appendix D)

Of the 135 studies which examined acute or repeated dosing (or both) of any of the 10 key drugs, 120 tested 1st generation drugs and 87 tested 2nd generation drugs. (Since many studies evaluated several drugs, often from both generations, the numbers overlap. Also, the three studies which only evaluated residual effects are excluded from the data summaries.) As can be seen in Figure 1, the most frequently studied drugs for the 1st and 2nd generations, respectively, were diphenhydramine (49 of 120 studies, or 41%) and terfenadine (37 of 87 studies, or 43%). As noted earlier, only a single study of fexofenadine had been published as of the 12/98 cutoff date (i.e. for the published articles of the studies) for this review. Thus, those findings must be viewed cautiously until additional studies are reported to determine if those findings generalize or not to other samples of subjects and measures.

First, we considered the category of studies , (as distinguished from the number of behavioral task measures of which typically there are several per study), which tested either acute or chronic doses and found any evidence of statistically significant impairment (relative to a placebo control treatment) of either objective or subjective measures . We found that 88% (106 of 120) of the studies of the 1st generation drugs found impairment as compared to 22% (19 of 87) of the studies of the 2nd generation drugs. And as expected, for each of the five drugs within each generation, more studies found impairment than not for the 1st generation drugs, whereas the majority of the studies of the 2nd generation drugs found no significant impairment. Nonetheless, there is considerable variability for the findings of significant impairment within each drug generation. Specifically, the significant findings range from 69% (11 of 16 studies of clemastine) to 95% (18 of 19 studies of chlorpheniramine) for the 1st generation drugs, and from 9% (1 of 11studies of astemizole) to 35% (7 of 20 studies of cetirizine) for the 2nd generation drugs. This excludes, of course, the single study of fexofenadine which did find some evidence of impairment. Given this wide variability, a more focused analysis is needed.

3.1.2. Impairment Findings as a function of Objective/Subjective Measures,Drug Generation, and Dosing Schedule (Acute versus Repeated) (Figure 2)

Since the overall impairment findings by study obviously reflect considerable variation in terms of objective versus subjective measures as well as acute versus repeated dosing, the next step was to summarize the findings as a function of these key factors. Moreover, instead of evaluating impairment at the study level, all subsequent analyses focused on the findings for the individual and specific “behavioral task measures ” which, as described earlier, present a finer level of analysis for this comparative review of 1st versus 2nd generation antihistamines. That is, for a given study, the individual test findings reflect the outcome of the statistical significance test for impairment for a given drug, at a given dose and dosing schedule, and for a specific measure within one of the 10 behavioral categories or for subjective sedation.

Considering first the acute dose findings (Figure 2), the 1st generation drugs as a group were found more often than not to be impairing in both objective and subjective measures. The 2nd generation drugs, in contrast, showed substantially fewer findings of impairment for either objective or subjective measures.

Relative to the acute effects, the repeated dose findings for both drug generations generally show less impairment, at least for the objective measures, as might be expected given that tolerance may develop with chronic dosing. For the subjective measures, however, the 1st generation drugs still have more findings of significant sedation than not even after repeated dosing. In contrast, none of the findings for the 2nd generation drugs indicate any significant sedation after repeated doses. Again, there is wide variability in these studies and so no firm conclusions can be drawn from this review. For example, the repeated dose studies range from investigations of two doses in a single day to multiple doses over several weeks. An additional limitation, as noted earlier, is the fact that far fewer studies (and test findings) are available in this review for the effects of repeated dosing. Therefore, no figure is included here for the limited number of repeated dose findings and the remainder of the results section will focus only on the acute dose findings.

3.2. Impairment by Individual Drugs as a function of Acute Dose Level

As noted earlier, details of the impairment findings as a function of drug generation, individual drugs, as well as specific dose can be found in Appendix B (e.g., number of NO versus YES impairment findings as well as %YES; presented for each category as well as for summaries).

3.2.1 Dose Response Curves for Objective Measures (Figure 3A)

Looking at the overall findings for all objective measures grouped together, the acute dose findings for each drug separately show the clearest dose response effects for all of the 1st generation drugs except perhaps chlorpheniramine. And, while the 2nd generation drugs typically show few findings of any significant impairment, a dose-response still is apparent.
That is, when impairment was reported, usually a higher dose was being tested.

3.2.2 Objective Measures by Individual Drugs and by Generation (Figure 3B)

For the 2nd -generation drugs, all 45 findings for astemizole, with doses ranging from 10 to 40 mg, showed no significant impairment. In contrast, cetirizine was reported to cause significant impairment of objective measures in 18% of the cases (14 of 80 findings), whereas the other 2nd generation drugs had fewer reports of impairment
(4 of 53 findings or 8% for loratadine, and 5 of 126 findings or 4% for terfenadine). As expected, the 1st generation drugs more often showed significant impairment: 61% (70 of 114 findings) for tripolidine and 53% (112 of 211 findings) for diphenhydramine, the two drugs used most frequently as positive control treatments in many of the studies.

3.2.3 Dose Response Curves for Subjective Measures (Figure 4A, Table 4 in Appendix A)

The subjective measures reveal even stronger dose response curves, particularly for the typically sedating 1st generation drugs. For example, significant sedation was reported increasingly more often when higher doses of diphenhydramine were tested: 57% for 25 mg, 71% for 50 mg, 85% for 75 or 100 mg, and 100% for >100mg. In contrast, the 2nd generation drugs were strikingly devoid of any significant findings of subjective sedation, that is, with the exception of cetirizine. Specifically, at all doses tested, cetirizine was reported to show some evidence of significant sedation: 33% (1 of 3 findings) for 5 mg, 14% (2 of14 findings) for the indicated dose of 10 mg, and 17% (1 of 6 findings) for the highest dose tested, 20 mg.

3.2.4 Subjective Measures of Sedation by Individual Drugs and by Generation (Figure 4B)

Looking at the subjective measures of sedation by drug generation, the older H₁ -antagonists had significant findings for 67% of the cases (62 of 92 findings) in contrast to only 5% (4 of 79 findings) for the newer drugs. As noted, cetirizine was the only 2nd -generation drug showing significant sedation (17%, 4 of 23 of the findings), whereas each of the five 1st -generation drugs produced significant sedation in over 50% of the times tested. Specifically, significant impairment was reported in 55% (6 of 11) of the test findings for clemastine, 64% (18 of 28 findings) for tripolidine, 67% (8 of 12 findings) for chlorpheniramine, 72% (26 of 36 findings) for diphenhydramine, and 80% (4 of 5 findings) for hydroxyzine.

3.3. Acute Dose Impairment by Behavioral Categories

This next section presents the impairment results of the reviewed studies as a function of the 10 behavioral categories of driving-related performance measures. As noted earlier, only the acute dose findings are presented since there were relatively few repeated dose studies.

3.3. 1. DRIVING AND PILOTING (Figure 5, Table 5 in Appendix A)

There were 55 testing findings produced by the 17 studies which examined the effects of at least one of the key drugs on driving behaviors. Note that this category includes measures of actual driving on the road, or in a closed course, as well as a variety of measures from many different types of driving simulators and some piloting tasks. With such a wide range of different tasks and measures, it is not surprising that some of the tasks are not sensitive and so, for the 1st generation drugs as a class, only 48% (11 of 23) of the findings showed significant impairment. This compares to significant impairment reported in 13% (4 of 32) of the findings for the 2nd generation drugs.

Notably, when considering only the specific subset of on-road driving measures, the number of significant findings of impairment by the 1st generation drugs is much more pronounced, with 89% (8 of 9 findings) showing significant on-road driving impairment, versus only 10% (2 of 20 findings) for the 2nd generation drugs. Also, looking at the findings for the individual drugs, it is clear that all of the 1st generation drugs studied consistently show the on-road driving impairment. In contrast, the only 2nd generation drugs showing significant impairment of on-road driving skills were cetirizine (1 of 2 findings) and terfenadine (1 of 11 findings). The findings for these two drugs mirror those for the complete group of driving measures. That is, significant impairment of any type of driving-related behavior was found in 29% (2 of 7 tests) of the findings for cetirizine and in 13% (2 of 16 test findings) for terfenadine. The other two 2nd generation drugs studied showed no impairment; (astemizole was not studied).

3.3. 2. PSYCHOMOTOR SKILLS (Figure 6, Table 6 in Appendix A)

A total of 35 studies evaluated the impairing effects of antihistamines on psychomotor skills and yielded 70 test findings. For the 1st generation drugs, 44% (22 of 50) of the findings showed significant impairment whereas none of the 20 findings for the 2nd generation drugs demonstrated significant impairment. (However, only astemizole, cetirizine and terfenadine were studied). Again, there is considerable variability in the type of psychomotor skills and specific task demands evaluated in these studies. Thus, this behavioral category does not appear particularly sensitive to detecting impairment. Of note, analysis of the specific subcategories revealed that tasks measuring balance (e.g., body sway, hand steadiness) seemed most sensitive to impairment by the 1st generation drugs (10 of 15 findings, or 67% versus none of the 4 tests for the 2nd generation drugs). In contrast, tasks requiring dexterity (e.g., picking up beads and other fine-motor tasks) were notably insensitive: none of the findings (4 each) for either the 1st generation or the 2nd generation drugs showed significant performance deficits. In addition, finger tapping tests were found to show significant impairment for 50% (8 of 16) of the findings for 1st generation drugs versus none of the 3 tests for the 2nd generation drugs.

3.3. 3. PERCEPTION (Figure 7, Table 7 in Appendix A)

This category reflects varied tasks of perception (e.g., visual discrimination, time estimation) including singular visual search tasks (i.e., those not performed in the context of divided attention). No clear conclusions can be made for this category, however, since the available data from this review are quite limited: 14 studies produced a total of 26 test findings. For the 1st generation drugs, 35% (6 of 17) of the findings for the 1st generation drugs evidenced significant impairment of perceptual tasks whereas no impairment was reported in any of the 9 tests for the 2nd generation drugs (which only included astemizole, cetirizine and terfenadine). Looking at the figures for the individual 1st generation drugs, however, it appears that diphenhydramine was more often impairing than not (56% or 5 of 9 test findings) for perceptual tasks.

3.3. 4. VISUAL FUNCTIONS & CRITICAL FLICKER FUSION (Figures 8A & 8B, Table 8)

Measures of visual functions included saccadic eye movements, smooth pursuit, dynamic visual acuity, visual field, pupillary diameter and extraocular muscle control. Such measures were examined in 16 studies, producing 31 test findings regarding impairment. Significant impairment was found in 10 of the 15 tests (67%) for the 1st generation drugs versus only 1 of the 16 tests (6%) for the 2nd generation drugs. It should be pointed out, however, that the single finding of significant impairment for the 2nd generation drugs involved dynamic visual acuity and loratadine 40 mg, a dose which is much higher than the recommended 10 mg dose. It also should be noted that the most often studied 1st generation drug for this visual function category was tripolidine 10 mg which was found to cause significant impairment in 89% (8 of 9) of the tests. Since all of these test findings came from the same group of investigators, however, one cannot tease apart the effect of tripolidine versus the inherent greater sensitivity (i.e., via decreased variability) afforded by using a single, standardized measure, namely dynamic visual acuity, and by the same group of investigators.

Some investigators have classified critical flicker fusion (CFF) as a measure of information processing while others consider it to reflect a more basic visual perception task. In this review, the CFF task simply was analyzed separately as a subset of the visual functions category. A total of 29 studies examined CFF, producing 52 test findings. Significantly impaired CFF was found in 52% (15 of 29) of the test finding for the 1st generation drugs. In contrast, the 2nd generation drugs were only found to impair CFF in one of the 23 times tested (4%); this single finding involved terfenadine 60 mg. As was the case with visual functions, the significant impairment by 1st generation drugs was most apparent in the studies of tripolidine (100% of the 10 tests). Again, the consistency of these findings may be due partly to the fact that they largely came from the same investigators who were using a more homogenous set of standardized CFF measures and methods.

3.3. 5. COGNITIVE TASKS (Figure 9, Table 9 in Appendix A)

The category of cognitive tasks includes tasks of complex psychomotor skills (e.g., card sorting), memory (auditory and visual), trail-making tests and a variety of tasks requiring problem solving (arithmetic, numerical and logical reasoning) and cognitive flexibility (Stroop color/word task). As such, this category of cognitive tasks, like psychomotor skills, reflects a wide range of tasks and measures with the result of increased variability and concomitant decreased sensitivity to detecting impairment. Of the 63 studies which examined cognitive tasks, a total of 201 test findings evaluated impairment. For the 1st generation drugs, only 37% (46 of 126) of the test findings showed statistically significant impairment as compared to only 3% (2 of 75 tests) for the 2nd generation drugs. Moreover, the two cases of impairment for the 2nd generation drugs involved higher than recommended doses, cetirizine 20 mg and loratadine 40 mg, and both tested digit symbol substitution skills.

Given the large number of test findings and the wide variety of tasks represented, specific subsets of cognitive tasks also were analyzed. Results showed that digit symbol substitution tests were found to be impaired by 1st generation drugs in 38% (17 of 45) of the test findings versus only 7% (2 of 28 findings) for the 2nd generation drugs. Memory tasks were impaired in 39% (13 of 33) of the tests of 1st generation drugs whereas no significant memory impairment was found in any of the 13 tests for the 2nd generation drugs. Trail-making tasks appeared to provide the most sensitive measures in this category, albeit with rather limited data available in this review, with 50% (5 of 10) of the findings for the 1st generation drugs showing significant impairment versus none of the 5 tests for the 2nd generation drugs.

3.3. 6. DIVIDED ATTENTION (Figure 10, Table 10 in Appendix A)

Divided attention tasks were examined in 28 studies, producing 52 test findings concerning impairment. Typically, the divided-attention task consisted of the concurrent performance of a tracking and visual search task. In other cases, some investigators employed other types of dual tasks such as simultaneous tracking and continuous memory tasks. As expected, given the complex demands of most divided-attention tasks, this behavioral category was found to be relatively sensitive for detecting significant impairment. The 1st generation drugs were found to impair divided-attention skills in 69% (20 of 29) of the findings versus 13% (3 of 23 test findings) for the 2nd generation drugs. The most frequently studied 1st generation drug, diphenhydramine, was found to impair divided-attention tasks in 77% (13 of 17) of test findings. For the 2nd generation drugs, one finding of significant impairment was found for each of the following drugs: cetirizine (from a total of 6 tests), loratadine (of 8 tests) and terfenadine (of 8 tests); all of these significant findings occurred at the recommended doses. Interestingly, two cases of an apparent performance- enhancing effect (i.e., performance was significantly better after the active drug relative to placebo) also were reported for loratadine 10 mg (Kay et al., 1997) and terfenadine 60 mg (Moskowitz & Burns, 1988). This suggests there may be a possible arousing or stimulating effect of these specific 2nd -generation drugs.

3.3. 7. VIGILANCE TASKS (Figure 11, Table 11 in Appendix A)

Vigilance was evaluated in 25 studies, producing a total of 46 test findings. As clearly shown in the figures, both for each drug as well as for the overall findings by drug generation, nearly all of the 1st generation drugs consistently were found to cause significant impairment of the measures of sustained attention. In marked contrast, not one of the 2nd generation drugs showed any evidence of impairment. By generation, the older drugs were found to impair vigilance 86% of the times tested (25 of 29 findings) whereas all 17 tests for the new drugs found no evidence of any significant impairment. Such findings attest to the sensitivity of vigilance tasks to detect CNS sedation.

Moreover, an interesting finding concerning vigilance comes from an earlier study in our laboratory (Moskowitz & Burns, 1988). In brief, that study found an apparent alerting or stimulating effect evidenced in the terfenadine 60 mg treatment condition which showed better vigilance performance (i.e., faster response times) relative to the placebo control. As noted earlier, fexofenadine has a chemical structure nearly identical to that of terfenadine's active metabolite. The single study of fexofenadine (Vermeeren & O'Hanlon, 1998; Ref#122) also examined vigilance but found neither impairment nor improved performance. The authors of that study suggested that such findings indicate that fexofenadine does not act pharmacologically like classic stimulants since typically the “latter enhance signal detection performance in vigilance tests.” Of note, as discussed for some of the other behavioralcategories, there are a number of findings in this review of other apparently alerting or stimulating effects reported for terfenadine. Since the safety implications of this issue need to be evaluated in more depth, additional studies of the 2nd -generation drugs are eagerly awaited. This is particularly important for fexofenadine, since it is only beginning to be studied and terfenadine is no longer on the market.

3.3. 8. TRACKING (Figures 12A & 12B, Table 12 in Appendix A)

A total of 80 test findings was produced by the 39 studies which evaluated tracking performance. This behavioral category included measures of different types of tracking tasks, including pursuit, compensatory, critical and adaptive tracking. Significant impairment was reported for 69% (33 of 48 tests) versus 19% (6 of 32 tests), respectively, of the findings for the 1st and 2nd generation drugs. As seen in Figure 12A, for the individual drugs, all five of the 1st generation drugs demonstrated significant impairment for nearly all test findings reviewed. In contrast, for the five 2nd -generation drugs tested, only cetirizine and fexofenadine were found to impair tracking. Specifically, two of the three findings for cetirizine, and both of the two findings for fexofenadine, showed significantly impaired tracking performance.

Focusing next on the subset of 26 studies which evaluated either critical or adaptive tracking (Figure 12B), the 52 test findings for this specific subcategory revealed significant impairment for over 90% (28 of 31) of the findings for the 1st generation drugs, in contrast to 19% (4 of 21 findings) for the 2nd generation drugs. Moreover, two of the three findings of no impairment for the older drugs actually showed trends (p <0.08). Therefore, if a less stringent criterion for statistical significance is allowed, the findings of impairment by the 1st generation drugs increase to 97% (30 of 31 findings). Clearly, consistent with what prior investigators and reviewers have reported, the current review's findings confirm that critical and adaptive tracking tasks appear to provide sensitive measures of driving-related performance.

3.3. 9. REACTION TIME (Figure 13, Table 13 in Appendix A)

This category included simple and complex reaction time tasks, as well as some that were not easily classified into either category since the published task descriptions often were quite limited if not lacking. Overall, there were 50 studies which included reaction time tasks, producing 98 test findings for this behavioral category. For the 1st generation drugs, 48% (29 of 61) of the test findings were found to show significant slowing of reaction time; this compares to 11% (4 of 37 findings) for the 2nd generation drugs. As seen in Figure 13 for the individual drugs, diphenhydramine and tripolidine, respectively, had the most notable impairing effects (54% or 13 of 24 findings, and 50% or 6 of 12 findings), whereas cetirizine was the only 2nd generation drug showing significant impairment (40%, 4 of 10 findings).

Looking at the subcategories, the simple reaction time tasks appeared to be somewhat more sensitive to detecting impairment than were the complex (or choice) reaction time tasks, at least for the 1st generation drugs. Specifically, 42% (11 of 26) of the findings showed significant slowing of choice reaction time versus 60% (15 of 25 test findings) for simple reaction time. Perhaps the relative insensitivity of complex (or choice) reaction time tasks is due to the greater variation in the specific measures employed across studies. In contrast, there may be less variability in the measures of simple reaction time. However, for the 2nd generation drugs, no distinction was seen for the findings of significant slowing of simple reaction time (11% or 1 of 9 findings) versus complex reaction time (12% or 3 of 26 findings).

3.3. 10. PHYSIOLOGICAL MEASURES OF SEDATION (Figures 14A & 14B, Table 14)

Physiological measures of sedation included spectral analysis of electroencephalograph (EEG) waves, evoked response potentials (ERP's such as P300, etc.), as well as the highly standardized Multiple Sleep Latency Test (MSLT) which utilizes EEG frequencies to detect the onset of sleep. A total of 23 studies evaluated one or more of these various objective measures of sedation, producing 56 test findings. Significant objective sedation was reported for 79% (22 of 28) of the findings for the 1st generation drugs versus 14% (4 of 28 findings) for the 2nd generation drugs. As clearly evident in Figure 14A, all five of the older drugs showed significant sedation in most cases and three of the four new drugs also showed some sedation (there were no data for this category from the single fexofenadine study).

If we next focus only on the subset of the MSLT measures, as shown in Figure 14B, the results are quite striking. Now 100% of the 9 test findings for the 1st generation drugs shows significant sedation as compared to only 9% (1 of 11) of the findings for the 2nd generation. While admittedly small numbers of test findings are available, it is interesting that the single finding of significant objective sedation found for the new drugs is due to cetirizine which, consistent with the findings from many of the other behavioral categories in this review, seems to stand out in the group of otherwise relatively “non-sedating” new drugs.