Antihistamines and Driving-Related Behavior: a Review of the Evidence for Impairment by First- Versus Second-Generation H1-Antagonists
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DOT HS 809 714 May 2004 Technical Report Documentation Page 1. Report No. 2. Government Accession No. 3. Recipient's Catalog No. DOT HS 809 714 4. Title and Subtitle 5. Report Date ANTIHISTAMINES AND DRIVING-RELATED BEHAVIOR: May 2004 A REVIEW OF THE EVIDENCE FOR IMPAIRMENT 6. Performing Organization Code 7. Author(s) 8. Performing Organization Report No. Herbert Moskowitz, Ph.D. and Candace Jeavons Wilkinson, Ph.D. 9. Performing Organization Name and Address 10. Work Unit No. (TRAIS) Herbert Moskowitz, Ph.D., Inc. 11. Contract or Grant No. 4138 Royal Crest Place, Encino, CA 91436 12. Sponsoring Agency Name and Address’ 13. Type of Report and Period Covered U.S. Department of Transportation Final Report National Highway Traffic Safety Administration Period: September 2000-February 2003 400 Seventh Street, S.W Washington, D.C. 20590 14. Sponsoring Agency Code 15. Supplementary Notes 16. Abstract A review of the scientific literature concerning the effects of antihistamines on driving-related skills was conducted. After reviewing all pertinent publications from 1998 and earlier, a total of 130 publications were found to meet criteria for inclusion in the data summaries. A data base was created with study results being indexed, and summarized, by specific drug, dose, dosing schedule (i.e., single versus repeated) and H1-antagonist generation as well as by behavioral area or subjective measure. For each H1-antagonist generation, five drugs were evaluated: chlorpheniramine, clemastine, diphenhydramine, hydroxyzine and tripolidine for the 1st-generation, and astemizole, cetirizine, fexofenadine, loratadine and terfenadine for the 2nd-generation. It was concluded that: 1. There is some slight, but ambiguous, evidence from epidemiological studies of a connection between antihistamine use and traffic collision rates. However, these studies were done primarily when use of only 1st-generation (but not 2nd- generation) antihistamines was prevalent; thus, more study is needed. 2. There is overwhelming evidence from the experimental literature that the 1st-generation antihistamines produce objective signs of skills performance impairment as well as subjective symptoms of sedation. 3. While 2nd-generation antihistamines represent a major triumph for the pharmaceutical industry in reducing potential side effects, there still remains some evidence that all antihistamines, even the 2nd- generation drugs, may cause sedation and objective skills impairment at least in some cases and for some individuals. 4. Within both the 1st- and 2nd-generation antihistamine groupings, there is considerable variation in objective evidence of impairment and in subjective effects such as sedation. Thus, there clearly are drugs that are to be preferred for use to avoid side effects such as sedation and driving-related performance impairment. 5. Methodologically, it is apparent that among the many diverse techniques for investigating driving-related impairment, some methods and behavioral domains are more sensitive to the effects of antihistamines. Future studies of antihistamines, therefore, must utilize the most methodologically-sound techniques so as to permit a better comparison between different drugs. 17. Key Word 18. Distribution Statement Antihistamines, Attention, Behavioral Impairment, Driving, This document is available to the U.S. public through the H1-Antagonists, Simulator, Driving-related Skills National Technical Information Service Performance Springfield, Virginia 22161 19. Security Classif. (of this report) 20. Security Classif. (of this page) 21. No. of Pages 22. Price Unclassified Unclassified Form DOT F 1700.7 (8-72) Reproduction of completed page authorized i TABLE OF CONTENTS 1. INTRODUCTION ...................................................................................................................1 1.1 Statement of The Problem........................................................................................1 1.2 Limitations of Epidemiological Data..........................................................................2 1.3 Clinical Pharmacology & Issue of Drug Choice.........................................................4 1.4 Prior Reviews of H1-antagonists ..............................................................................5 1.5 Focus of Current Review ..........................................................................................5 2. METHOD ...............................................................................................................................7 Reasons for Study Exclusion (Table 1) ...........................................................................7 The Ten Drugs Selected for Review (Table 2).................................................................9 Number of Studies and Test Findings for each Skill Category and Subjective Sedation: Acute and Repeated Dosing (Table 3) .........................................10 3. RESULTS ............................................................................................................................12 3.1. Overall Impairment ................................................................................................12 3.2. Impairment by Individual Drugs as a Function of Acute Dose Level.......................13 3.3. Acute Dose Impairment by Behavioral Categories.................................................14 3.3.1. DRIVING AND PILOTING.......................................................................14 3.3.2. PSYCHOMOTOR SKILLS......................................................................15 3.3.3. PERCEPTION.........................................................................................15 3.3.4. VISUAL FUNCTIONS & CRITICAL FLICKER FUSION .........................16 3.3.5. COGNITIVE TASKS ...............................................................................16 3.3.6. DIVIDED ATTENTION ............................................................................17 3.3.7. VIGILANCE TASKS ............................................................................17 3.3.8. TRACKING.............................................................................................18 3.3.9. REACTION TIME....................................................................................18 3.3.10. PHYSIOLOGICAL MEASURES OF SEDATION ..................................19 4. SUMMARY AND DISCUSSION ...........................................................................................20 5. CONCLUSIONS...................................................................................................................24 REFERENCE LIST A Articles Referenced in Report........................................................................................25 REFERENCE LIST B Articles Included in the Review......................................................................................27 FIGURES..................................................................................................................................36 APPENDICES...........................................................................................................................57 Appendix A - Tables of Impairment Findings by Behavioral Category (Tables 4-15) Appendix B - Example of an Impairment Summary Sheet (YES/NO) by Behavioral Category Appendix C - Example of a Study Summary Sheet (n=138 studies from 130 references) Appendix D - Summary Table of Impairment Findings by Study (includes all 10 Drugs) LIST OF TABLES 1. Reasons for Study Exclusion .................................................................................................7 2. The Ten Drugs Selected for Review...................................................................................... 9 3. Number of Studies and Test Findings for each Skill Category and Subjective Sedation...... 10 4-14. Summary of Test Results by Behavioral Category (Appendix A)................................... 57 Table 4. SUBJECTIVE MEASURES OF SEDATION Table 5. DRIVING AND PILOTING Table 6. PSYCHOMOTOR SKILLS Table 7. PERCEPTION Table 8. VISUAL FUNCTIONS & CRITICAL FLICKER FUSION Table 9. COGNITIVE TASKS Table 10. DIVIDED ATTENTION Table 11. VIGILANCE TASKS Table 12. TRACKING Table 13. REACTION TIME Table 14. PHYSIOLOGICAL MEASURES OF SEDATION LIST OF FIGURES (Appearing as a complete set at end of report, from pages 36 through 56.) Page: 1. Impairment Findings by Study for each Drug ....................................................... 37 2. Impairment Findings as a Function of Objective/Subjective Measures and Drug Generation (Acute Doses Only) ........................................................... 38 3A. Dose Response Curves for Objective Measures ................................................. 39 3B. Objective Measures: Impairment Findings by Drug and Generation ................... 40 4A. Dose Response Curves for Subjective Measures ............................................... 41 4B. Subjective Measures: Impairment Findings by Drug and Generation .................. 42 5. Summary of Impairment Results for DRIVING/PILOTING ................................... 43 6. Summary of Impairment Results for PSYCHOMOTOR SKILLS .......................... 44 7. Summary of Impairment Results for PERCEPTION ............................................ 45 8A. Summary of Impairment Results for VISUAL FUNCTIONS ................................. 46 8B. Summary of Impairment Results for CRITICAL FLICKER FUSION ..................... 47 9. Summary of Impairment Results