First-generation histamine receptor antagonists such as diphenhydramine are known to cause central nervous system depressant effects. Decrements in cognitive and psychomotor performance after administration of antihistamines are generally attributed to increased sedative effects. Second-generation histamine-receptor antagonists such as loratadine are considered less sedating. Kay and associates conducted a study to assess drug effects on sedation, mood, cognition and psychomotor functioning.

Ninety-eight healthy patients were randomly assigned to receive loratadine (in a single dose of 10 mg), diphenhydramine (in a single dose of 50 mg, followed by two doses of 25 mg and one placebo tablet on day one, and then four daily doses of 25 mg), or one placebo tablet four times daily. Patients were tested before treatment, on day one after administration of medication or placebo, and on days three and five of the study. After the initial dose of diphenhydramine, patients demonstrated poorer cognitive performance than those taking loratadine or placebo on measures of divided attention, working memory and vigilance. Patients taking diphenhydramine reported more sleepiness and fatigue than patients taking loratadine. Following administration of diphenhydramine, patients also demonstrated lower levels of motivation and rated the quality of test performance as lower than did those receiving loratadine. On days three and five of the study, patients who received diphenhydramine did not perform as well on a test of tracking errors (reflecting lapses of attention) as those who received placebo. Adverse events were minor in all study groups and did not preclude completion of the study. Results of this study demonstrated differences in psychomotor performance, mood and sedation between groups taking diphenhydramine and groups taking loratadine. Drug effects were principally limited to initial dosing; however, on day three, after the dosage of diphenhydramine had been lowered, patients continued to report central nervous system depressant effects on mood and sedation. These patients also continued to make significantly more tracking errors. Results for loratadine were comparable with results for placebo. Loratadine had no more effect on mood or sedation than placebo. Cognitive and psychomotor test findings demonstrated no differences when loratadine or placebo was administered.

The authors conclude that decrements in performance associated with diphenhydramine therapy extend beyond the well-established hazards associated with driving and operating heavy machinery. The tasks selected for this study were chosen specifically to mimic the demands of the modern work-place. The findings demonstrate that sedating antihistamines may increase the risk of error, particularly when psychomotor tasks are performed under divided attention. Furthermore, the decrease in motivation and quality of performance may translate into decreased productivity for workers and students.