, Volume 169, Issue 1, pp 84–90 | Cite as

Driving ability after acute and sub-chronic administration of levocetirizine and diphenhydramine: a randomized, double-blind, placebo-controlled trial

  • Joris C. VersterEmail author
  • A. Marit de Weert
  • Saskia I. R. Bijtjes
  • Mounir Aarab
  • Armand W. A. A. van Oosterwijck
  • Erik J. E. Eijken
  • Marinus N. Verbaten
  • Edmund R. Volkerts
Original Investigation



Sedation following antihistamine use poses a danger to ambulant patients involved in daily activities such as driving.


To investigate effects of levocetirizine (5 mg), diphenhydramine (50 mg), and placebo on driving ability during normal traffic.


Forty-eight healthy volunteers participated in a double-blind, placebo-controlled, randomized clinical trial. Treatments were administrated on days 1, 2, 3 and 4, exactly 1.5 h before the start of the standardized driving test (performed on day 1 and day 4). In the standardized driving test, subjects were instructed to drive with a steady lateral position, while maintaining a constant speed (95 km/h). Primary parameter was the standard deviation of lateral position (SDLP; cm). Statistical analyses were performed separately for day 1 and day 4, using analysis of variance and an equivalence test. Equivalence to placebo was evidenced if the 95% confidence interval lay between −2.6 cm and +2.6 cm.


SDLP after levocetirizine was equivalent to placebo on both day 1 (−0.66 cm; +1.12 cm) and day 4 (−0.37 cm; +1.28 cm). In contrast, SDLP after diphenhydramine differed significantly from placebo on both day 1 (P<0.0001) and day 4 (P<0.0003). On day 1, the 95% confidence interval of diphenhydramine (+1.85 cm; +3.63 cm) was partially above the upper equivalence limit (+2.6 cm), indicating clinically relevant driving impairment. On day 4, however, the 95% confidence interval of diphenhydramine (+0.74 cm; +2.38 cm) was contained within the acceptance range.


In contrast to diphenhydramine, driving performance was not significantly affected while using 5 mg levocetirizine once daily.


Levocetirizine Diphenhydramine Antihistamine Driving 



This study was financially supported by UCB Pharma.


  1. Blanc PD, Trupin L, Eisner M et al. (2001) The work impact of asthma and rhinitis: findings from a population-based survey. J Clin Epidemiol 54:610–618CrossRefPubMedGoogle Scholar
  2. Boonyaratevej N, Suriyawongpaisal P, Takkinsatien A, Wanvarie S, Rajatanavin R, Apiyasawat P, the Thai Osteoporosis Study Group (2001) Physical activity and risk factors for hip fractures in Thai women. Osteoporos Int 12:244–248CrossRefPubMedGoogle Scholar
  3. Borkenstein RF, Crowther RP, Shumate RP, Ziel HB, Zylman R (1964) The role of the drinking driver in traffic accidents. Dept. of Police Administration, Indiana University, Bloomington, IndianaGoogle Scholar
  4. Cauci M, King MG, Saxarra H, Tulloch BJ, Husband AJ (1993) A Minnesota Multiphasic Personality Inventory profile of women with allergic rhinitis. Psychosom Med 55:533–540PubMedGoogle Scholar
  5. Clough GF, Boutsiouki P, Church MK (2001) Comparison of the effects of levocetirizine and loratadine on histamine-induced wheal, flare, and itch in human skin. Allergy 56:985–988CrossRefPubMedGoogle Scholar
  6. Devalia JL, De Vos C, Hanotte F, Baltes E (2001) A randomized, double-blind, crossover comparison among cetirizine, levocetirizine and UCB 28557 on histamine-induced cutaneous responses in healthy adult volunteers. Allergy 56:50–57CrossRefPubMedGoogle Scholar
  7. Didier A, Doussau-Thuron S, Murris-Espin M (2000) Comparative analysis of sedative effects of mequitazine and other antihistamine drugs: review of the literature. Curr Ther Res Clin Exp 61:770–780CrossRefGoogle Scholar
  8. Fireman P (1997) Treatment of allergic rhinitis: effect on occupation productivity and work force costs. Allergy Asthma Proc 18:63–67PubMedGoogle Scholar
  9. Gandon JM, Allain H (2002) Lack of effect of single and repeated doses of levocetirizine, a new antihistamine drug, on cognitive and psychomotor functions in healthy volunteers. Br J Clin Pharmacol 54:51–58CrossRefPubMedGoogle Scholar
  10. Gengo FM, Gabos C (1987) Antihistamines, drowsiness, and psychomotor impairment: central nervous system effect of cetirizine. Ann Allergy 59:53–57PubMedGoogle Scholar
  11. Gengo FM, Gabos C, Miller JK (1989) The pharmacodynamics of diphenhydramine-induced drowsiness and changes in mental performance. Clin Pharmacol Ther 45:15–21PubMedGoogle Scholar
  12. Gengo FM, Gabos C, Mechtler L (1990) Quantitative effects of cetirizine and diphenhydramine on mental performance measured using an automobile driving simulator. Ann Allergy 64:520–526PubMedGoogle Scholar
  13. Gillard M, Van der Perren C, Moguilevsky N, Massingham R, Chatelain P (2002) Binding characteristics of cetirizine and levocetirizine to human H1 histamine receptors: contribution of Lys191 and Thr194. Mol Pharmacol 61:391–399CrossRefPubMedGoogle Scholar
  14. Gilmore TM, Alexander BH, Mueller BA, Rivara FP (1996) Occupational injuries and medication use. Am J Ind Med 30:234–239CrossRefPubMedGoogle Scholar
  15. Hindmarch I, Johnson S, Meadows R, Kirkpatrick T, Shamsi Z (2001) The acute and sub-chronic effects of levocetirizine, cetirizine, loratadine, promethazine and placebo on cognitive function, psychomotor performance, and weal and flare. Curr Med Res Opin 17:241–255CrossRefPubMedGoogle Scholar
  16. Jones B, Jarvis P, Lewis JA, Ebbutt AF (1996) Trials to assess equivalence: the importance of rigorous methods. BMJ 313:36–39PubMedGoogle Scholar
  17. Kay GG (2000) The effects of antihistamines on cognition and performance. J Allergy Clin Immunol 105:S622–S627PubMedGoogle Scholar
  18. Kay GG, Quig ME (2001) Impact of sedating antihistamines on safety and productivity. Allergy Asthma Proc 22:281–283PubMedGoogle Scholar
  19. Kay GG, Berman B, Mockoviak SH, Morris CE, Reeves D, Starbuck V et al (1997) Initial and steady-state effects of diphenhydramine and loratadine on sedation, cognition, mood and psychomotor performance. Arch Intern Med 157:2350–2356CrossRefPubMedGoogle Scholar
  20. Leynadier F, Mees K, Arendt C, Pinelli M-E (2001) Efficacy and safety of levocetirizine in seasonal allergic rhinitis. Acta Otorhinolaryngol Belg 55:305–312PubMedGoogle Scholar
  21. Louwerens JW, Gloerich ABM, De Vries G, Brookhuis KA, O'Hanlon JF (1987) The relationship between drivers' blood alcohol concentration (BAC) and actual driving performance during high speed travel. In: Noordzij PC, Roszbach R (eds) Alcohol, drugs and traffic safety. Proceedings of the 10th International Conference on Alcohol, Drugs and Traffic Safety, Amsterdam, Excerpta Medica, pp 183–192Google Scholar
  22. Marshall PS, Colon EA (1993) Effects of allergy season on mood and cognitive function. Ann Allergy 71:251–258PubMedGoogle Scholar
  23. Mattila MJ, Mattila M, Konno K (1986) Acute and subacute actions on human performance and interactions with diazepam of temelastine (SK&F93944) and diphenhydramine. Eur J Clin Pharmacol 31:291–298PubMedGoogle Scholar
  24. Moskowitz H, Burns M (1988) Effects of terfenadine, diphenhydramine, and placebo on skills performance. Cutis 42:14–18PubMedGoogle Scholar
  25. Nolen TM (1997) Sedative effects of antihistamines: safety, performance, learning and quality of life. Clin Ther 19:39–55CrossRefGoogle Scholar
  26. O' Hanlon JF (1984) Driving performance under the influence of drugs: rationale for, and application of, a new test. Br J Clin Pharmacol 18:121S–129SPubMedGoogle Scholar
  27. O'Hanlon JF, Ramaekers JG (1995) Antihistamine effects on actual driving performance in a standard test: a summary of Dutch experience. Allergy 50:234–242PubMedGoogle Scholar
  28. O'Hanlon JF, Haak TW, Blaauw GJ, Riemersma JBJ (1982) Diazepam impairs lateral position control in highway driving. Science 217:79–81PubMedGoogle Scholar
  29. Ramaekers JG, O'Hanlon JF (1994) Acrivastine, terfenadine and diphenhydramine effects on driving performance as a function of dose and time after dosing. J Clin Pharmacol 47:261–266Google Scholar
  30. Rice VJ, Snyder HL (1993) The effects of Benadryl and Histamal on psychomotor performance and perceived performance. Aviat Space Environ Med 64:726–734PubMedGoogle Scholar
  31. Roehrs T, Zwyghuizen-Doorenbos, Roth T (1993a) Sedative effects and plasma concentrations following single doses of triazolam, diphenhydramine, ethanol and placebo. Sleep 16:301–305PubMedGoogle Scholar
  32. Roehrs T, Claiborue D, Knox M, Roth T (1993b) Effects of ethanol, diphenhydramine, and triazolam after a nap. Neuropsychopharmacology 9:239–245Google Scholar
  33. Röhmel J (1998) Therapeutic equivalence investigations. Statistical considerations. Stat Med 17:1703–1714CrossRefPubMedGoogle Scholar
  34. Roth T, Roehrs T, Koshorek G, Sicklesteel J, Zorick F (1987) Sedative effects of antihistamines. J Allergy Clin Immunol 80:94–98PubMedGoogle Scholar
  35. Schweitzer PK, Meuhibach MJ, Walsh JK (1994) Sleepiness and performance during three-day administration of cetirizine or diphenhydramine. J Allergy Clin Immunol 94:716–724PubMedGoogle Scholar
  36. Simons FER (1999) H1-receptor antagonists: safety issues. Ann Allergy Asthma Immunol 83:481–488PubMedGoogle Scholar
  37. Snyder SH, Snowman AM (1987) Receptor effects of cetirizine. Ann Allergy 59:4–8PubMedGoogle Scholar
  38. Spaeth J, Klimek I, Mösges R (1996) Sedation in allergic rhinitis is caused by the condition and not by the antihistamine treatment. Allergy 51:893–906PubMedGoogle Scholar
  39. Verster JC, Volkerts ER, van Oosterwijck AWWA, Aarab M, Bijtjes SIR, de Weert AM, Eijken EJE, Verbaten MN (2003) Acute and subchronic effects of levocetirizine and diphenhydramine on memory functioning, psychomotor performance, and mood. J Allergy Clin Immunol 111:623–627CrossRefPubMedGoogle Scholar
  40. Volkerts ER, Van Laar MW (1995) Specific review of psychometric effects of cetirizine. Allergy 50:55–60Google Scholar
  41. Volkerts ER, van Willigenburg PP, van Laar MW, Maes RAA (1992) Does cetirizine belong to the new generation of antihistamines? An investigation into its acute and subchronic effects on highway driving, psychometric test performance, and EEG during driving. Hum Psychopharmacol 7:227–238Google Scholar
  42. Vuurman EPFM, Van Veggel LMA, Uiterwijk MMC, Leutner D, O'Hanlon JF (1993) Seasonal allergic rhinitis and antihistamine effects on children's learning. Ann Allergy 71:121–126PubMedGoogle Scholar
  43. Vuurman EFPM, Van Veggel LMA, Sanders RL, Muntjewerff ND, O'Hanlon JF (1996) Effects of semprex-D and diphenhydramine on learning in young adults with seasonal allergic rhinitis. Ann Allergy Asthma Immunol 76:247–252PubMedGoogle Scholar
  44. Wang DY, Hanotte F, De Vos C, Clement P (2001) Effect of cetirizine, levocetirizine, and dextrocetirizine on histamine-induced nasal response in healthy adult volunteers. Allergy 56:339–343CrossRefPubMedGoogle Scholar
  45. Weiler JM, Bloomfield JR, Woodworth GG, Grant AR, Layton TA, Brown TL et al (2000) Effects of fexofenadine, diphenhydramine, and alcohol on driving performance. Ann Intern Med 132:354–362PubMedGoogle Scholar
  46. Wilken JA, Berkowitz R, Kane R (2002) Decrements in vigilance and cognitive functioning associated with ragweed-induced allergic rhinitis. Ann Allergy Asthma Immunol 89:372–380PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Joris C. Verster
    • 1
    Email author
  • A. Marit de Weert
    • 1
  • Saskia I. R. Bijtjes
    • 1
  • Mounir Aarab
    • 1
  • Armand W. A. A. van Oosterwijck
    • 1
  • Erik J. E. Eijken
    • 1
  • Marinus N. Verbaten
    • 1
  • Edmund R. Volkerts
    • 1
  1. 1.Utrecht Institute for Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands

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