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Of injuries and antihistamines and dosing
Guest editorial
Of injuries and antihistamines and dosing The side effects of antihistamines are generally categorized as central, those affecting the central nervous system (CNS), or peripheral, those affecting other organ systems.1 The report by Finkle et al2 elsewhere in this issue makes the observation that the use of diphenhydramine contributes to the risk of serious injuries. The adverse events addressed are peripheral, but they originate centrally. The authors conducted a retrospective cohort study of injury in 12,106 patients whose initial antihistamine prescription was for diphenhydramine and in 24,968 patients whose initial antihistamine prescription was for loratadine. The subjects were drawn from health care claims data of a population of 1.7 million. In the 30 days after the first antihistamine prescription, the rate of all injuries was 308 per 1,000 person-years in the diphenhydramine cohort versus 137 per 1,000 person-years in the loratadine cohort. If these associations are causal, then 55% of injuries in the diphenhydramine cohort are attributable to the drug. In this review, we will consider over-the-counter (OTC) antihistamines and proprietary products containing brompheneramine, chlorpheneramine, cyproheptadine, diphenhydramine, and hydroxyzine to be first-generation antihistamines. We will consider the discontinued medications astemizole and terfenadine to be second-generation antihistamines, and we will consider azelastine, cetirizine, desloratadine, ebastine, fexofenadine, loratadine, and mizolastine to be third-generation antihistamines. First-generation antihistamines are highly lipophilic and readily cross the blood-brain barrier. They have been reported to cause drowsiness in 25% of adults.3 Second- and third-generation H1 antihistamines are lipophobic, and numerous studies have shown that they are less likely to result in sedation or impairment of psychomotor performance in adults.4 –7 The third-generation antihistamines have been associated with few adverse effects, no clinically relevant cytochrome P450-mediated drug-drug interactions, and no cardiac dysrhythmias caused by the prolongation of the QT interval.8 Reports evaluating the effects of antihistamines on the operation of motor vehicles have demonstrated that patients taking second- and third-generation antihistamines had fewer driving errors, shorter response times, smoother steering, less lane weaving, and greater speed and accuracy in covering a driving course.5–7,9,10 However, the newer agents given at doses higher than recommended may also produce a significant driving impairment.11 Because antihistamines are a top-selling class of drugs and because they are widely available over the counter, their risks demand particular attention. Most studies, in agreement with Finkle et al,2 support the premise that classic antihistamines are more likely to cause
VOLUME 89, SEPTEMBER, 2002
sedation (presumably the cause of injuries) than second- and third-generation antihistamines, which are commonly referred to as nonsedating. However, no preparation is completely free of sedating effects.11–14 A basic principle followed in comparative studies of adverse consequences of medications is that of equipotency,15 which calls for the use of clinically equivalent doses of drugs under investigation. Therefore, the lack of dosing information in the report by Finkle et al limits our understanding of the results. Sedation by antihistamines is clearly governed by doseresponse relationships. Diphenhydramine at 25 mg is much less sedating than at 50 mg.16 In fact, in adults ranging in age from 21 to 76 years, self-rating of sedation, mood, and autonomic effects, as well as performance on the digit-symbol substitution test and tests of information acquisition and recall, are all unaffected by diphenhydramine 25 mg. The 50-mg dose of diphenhydramine is marketed as a sleep aid under the name of Maximum Strength Unisom Softgels.17,18 Similarly, loratadine appears safe at 10 mg but impairs driving accuracy when administered at double that dose.11 Most studies that have investigated the effects of loratadine on driving performance and cognitive and psychomotor functioning have shown its effects at recommended doses to be comparable with placebo.19 In a meta-analysis, pooled data showed sedation in 25 of 517 patients given 10 mg of loratadine, and in 24 of 510 patients given placebo.20 The relative risk was 1.03, with a confidence interval from 0.59 to 1.77. Using 10 different methods, 20 studies did not find performance impairment in subjects taking loratadine 10 mg. However, in two performance measures, digit substitution and driving, there was a significant impairment after dosing with 20 mg and 40 mg of loratadine, respectively.20 A problem inherent in research using a retrospective pharmacy database is the potential for undetected selection bias. The occurrence of patient interactions with the healthcare system and associated costs can be established, but causation in such studies is extremely difficult to prove. In contrast, studies in which patients are randomized to treatment condition and followed prospectively allow attribution of cause and effect because the variables that introduce bias in retrospective research are equally distributed and hence controlled across treatment conditions. Drug dosage can be carefully controlled in clinical trials, and dose-response relationships can be credibly defined. Blinded, randomized clinical trials investigating the effects of antihistamines have become a cottage industry in Europe and North America, creatively using driving simulators and computer-equipped automobiles. Because these are true experimental studies, they can
221
control for effects of dose,21 dosing regimen, and dose timing;22 frequency and severity of driving errors;23 and degree of impairment relative to alcohol.10 Hence, such studies can establish causal relationships without the bias that may hamper retrospective pharmacy database studies. However, it may be difficult to conduct prospective, controlled studies to investigate the occurrence of injuries whose rates are expressed per 1,000 person-years. Finkle and colleagues rightly call for more investigation of the relation between antihistamine type and risk and for the inclusion of OTC drugs in these studies. We need to understand better who is prescribed diphenhydramine, given its OTC status. Might there be a concealed variable responsible for the observed results? Might patients receiving diphenhydramine be medically more compromised or have less capable doctors? To determine whether and how diphenhydramine use is linked to a substantial number of excess injuries, we need information about the dosing of both diphenhydramine and loratadine. If diphenhydramine is twice as effective as loratadine, then the doubling of accident rate may disappear when expressed in terms of units of antihistaminic activity. The same may apply to the CNS effects responsible for the injuries. At equipotent antihistaminic doses, the CNS effects may be similar for the two drugs. We need information about potential differences between patients who receive a prescription for diphenhydramine and those who purchase it over the counter. We need to know whether patients who require a physician’s prescription for diphenhydramine typically receive the same dose as those who obtain it over the counter. The investigators report that the diphenhydramine recipients were on average 6 years older than those who received loratadine. The older patients do not appear to be worse drivers. Are they more susceptible to the CNS effects of diphenhydramine alone, or is this also true for other first-generation and third-generation antihistamines? The authors’ control for age is adequate only if the relationship between age and medication to outcome effect is linear. There are good reasons to believe that a nonlinear relationship (or interactive effects) may be important. For example, with increasing age there are greater rates of medical comorbidity and polypharmacy that may influence the observed accident-related outcomes. The number and severity of comorbid diagnoses and the degree of polypharmacy are variables that require evaluation. Is it possible that patients who receive loratadine are sicker and more likely to stay away from hazardous situations? What if diphenhydramine, by more effectively treating the patients’ symptoms, allows them to be more active, thereby leading to increased injury rates relative to loratadine? It would be useful to know the injury rates for equally ill groups not treated with antihistamines. What is the patients’ consumption of alcohol? Are patients taking loratadine, a medicine that is only available by prescription, more likely to adhere to the dosing guidelines than those taking diphenhydramine, which can also be bought over the counter? Are patients taking other OTC medications?
222
In the United States, diphenhydramine is the most used OTC medication for the treatment of allergic rhinitis.10 An estimated 47% of persons with allergies take OTC products, most containing a first-generation antihistamine.10 Despite some gaps, the findings reported by Finkle et al, based on review of more than 37,000 prescriptions, are too concerning to ignore. It is clear that emergency departments need to collect information regarding the use of antihistamines when they treat patients for trauma. If first-generation antihistamines add significantly to the incidence of personal injury, then their distribution, especially over the counter, must be reevaluated and the reimbursement for third-generation agents by health programs must be considered in a new light. “O that men should put an enemy in their mouths to steal away their brains.” —Othelo HENRY MILGROM, MD*†‡ BRUCE BENDER, PhD‡§ FREDERICK WAMBOLDT, MD†§ Departments of *Pediatrics and †Medicine, National Jewish Medical and Research Center, Denver, CO ‡ Department of Pediatrics, University of Colorado Health Sciences Center, Denver, CO § Department of Psychiatry, University of Colorado Health Sciences Center, Denver, CO REFERENCES 1. Milgrom H, Bender B. Adverse effects of medications for rhinitis. Ann Allergy Asthma Immunol 1997;78:439 – 446. 2. Finkle W, Adams J, Greenland S, Melmon K. Increased risk of serious injury following an initial prescription for diphenhydramine. Ann Allergy Asthma Immunol 2002;89:242–248. 3. Simons FER, Simons KJ. H1-receptor antagonist treatment of chronic rhinitis. J Allergy Clin Immunol 1988;81:975–980. 4. Clarke CH, Nicholson AN. Performance studies with antihistamines. Br J Clin Pharmacol 1978;6:31–35. 5. Moskowitz H, Burns M. Effects of terfenadine, diphenhydramine, and placebo on skills performance. Cutis 1988;42:14 –18. 6. Aso T, Sakai Y. Effects of terfenadine, a novel antihistamine, on actual driving performance. Ann Allergy 1989;62:250. 7. Betts T, Markman D, Debenham S, et al. Effects of two antihistamine drugs on actual driving performance. BMJ 1984;288: 281–282. 8. Ten Eick AP, Blumer JL, Reed MD. Safety of antihistamines in children. Drug Saf 2001;24:119 –147. 9. Reidel W, Schoenmakers E, O’Hanlon J. The effects of loratadine alone and in combination with alcohol on actual driving performance: Maastricht, The Netherlands, 1987. 10. Weiler JM, Bloomfield JR, Woodworth GG, et al. Effects of fexofenadine, diphenhydramine, and alcohol on driving performance: a randomized, placebo-controlled trial in the Iowa driving simulator. Ann Intern Med 2000;132:354 –363. 11. O’Hanlon JF, Ramaekers JG. Antihistamine effects on actual driving performance in a standard test: a summary of Dutch experience, 1989 –1994. Allergy 1995;50:234 –242. 12. Hindmarch I, Shamsi Z. Antihistamines: models to assess sed-
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
13. 14.
15. 16.
17.
ative properties, assessment of sedation, safety and other sideeffects. Clin Exp Allergy 1999;29(Suppl):133–142. Mann RD, Pearce GL, Dunn N, Shakir S. Sedation with “nonsedating” antihistamines: four prescription-event monitoring studies in general practice. BMJ 2000;320:1184 –1186. Simons FE, Fraser TG, Reggin JD, Simons KJ. Individual differences in central nervous system response to antihistamines (H1-receptor antagonists). Ann Allergy Asthma Immunol 1995; 75:507–514. Lee TH, Dudley J, Demonaco HJ. Drug effects on driving performance. Ann Intern Med 2000;133:656 – 657. Witek TJ Jr, Canestrari DA, Miller RD, et al. Characterization of daytime sleepiness and psychomotor performance following H1 receptor antagonists. Ann Allergy Asthma Immunol 1995; 74:419 – 426. Scavone JM, Greenblatt DJ, Harmatz JS, et al. Pharmacokinetics and pharmacodynamics of diphenhydramine 25 mg in young and elderly volunteers. J Clin Pharmacol 1998;38: 603– 609.
VOLUME 89, SEPTEMBER, 2002
18. Physicians’ Desk Reference. Montvale, NJ: Medical Economics Thomson Healthcare, 2002:2762. 19. Ramaekers JG, Uiterwijk MM, O’Hanlon JF. Effects of loratadine and cetirizine on actual driving and psychometric test performance, and EEG during driving. Eur J Clin Pharmacol 1992;42:363–369. 20. Hansen GR. Loratadine in the high performance aerospace environment. Aviat Space Environ Med 1999;70:919 –924. 21. Vuurman EF, Uiterwijk MM, Rosenzweig P, O’Hanlon JF. Effects of mizolastine and clemastine on actual driving and psychomotor performance in healthy volunteers. Eur J Clin Pharmacol 1994;47:253–259. 22. Ramaekers JG, O’Hanlon JF. Acrivastine, terfenadine and diphenhydramine effects on driving performance as a function of dose and time after dosing. Eur J Clin Pharmacol 1994;47: 261–266. 23. Gengo FM, Gabos C. Antihistamines, drowsiness, and psychomotor impairment: central nervous system effect of cetirizine. Ann Allergy 1987;59:53–57.
223
Of injuries and antihistamines and dosing The side effects of antihistamines are generally categorized as central, those affecting the central nervous system (CNS), or peripheral, those affecting other organ systems.1 The report by Finkle et al2 elsewhere in this issue makes the observation that the use of diphenhydramine contributes to the risk of serious injuries. The adverse events addressed are peripheral, but they originate centrally. The authors conducted a retrospective cohort study of injury in 12,106 patients whose initial antihistamine prescription was for diphenhydramine and in 24,968 patients whose initial antihistamine prescription was for loratadine. The subjects were drawn from health care claims data of a population of 1.7 million. In the 30 days after the first antihistamine prescription, the rate of all injuries was 308 per 1,000 person-years in the diphenhydramine cohort versus 137 per 1,000 person-years in the loratadine cohort. If these associations are causal, then 55% of injuries in the diphenhydramine cohort are attributable to the drug. In this review, we will consider over-the-counter (OTC) antihistamines and proprietary products containing brompheneramine, chlorpheneramine, cyproheptadine, diphenhydramine, and hydroxyzine to be first-generation antihistamines. We will consider the discontinued medications astemizole and terfenadine to be second-generation antihistamines, and we will consider azelastine, cetirizine, desloratadine, ebastine, fexofenadine, loratadine, and mizolastine to be third-generation antihistamines. First-generation antihistamines are highly lipophilic and readily cross the blood-brain barrier. They have been reported to cause drowsiness in 25% of adults.3 Second- and third-generation H1 antihistamines are lipophobic, and numerous studies have shown that they are less likely to result in sedation or impairment of psychomotor performance in adults.4 –7 The third-generation antihistamines have been associated with few adverse effects, no clinically relevant cytochrome P450-mediated drug-drug interactions, and no cardiac dysrhythmias caused by the prolongation of the QT interval.8 Reports evaluating the effects of antihistamines on the operation of motor vehicles have demonstrated that patients taking second- and third-generation antihistamines had fewer driving errors, shorter response times, smoother steering, less lane weaving, and greater speed and accuracy in covering a driving course.5–7,9,10 However, the newer agents given at doses higher than recommended may also produce a significant driving impairment.11 Because antihistamines are a top-selling class of drugs and because they are widely available over the counter, their risks demand particular attention. Most studies, in agreement with Finkle et al,2 support the premise that classic antihistamines are more likely to cause
VOLUME 89, SEPTEMBER, 2002
sedation (presumably the cause of injuries) than second- and third-generation antihistamines, which are commonly referred to as nonsedating. However, no preparation is completely free of sedating effects.11–14 A basic principle followed in comparative studies of adverse consequences of medications is that of equipotency,15 which calls for the use of clinically equivalent doses of drugs under investigation. Therefore, the lack of dosing information in the report by Finkle et al limits our understanding of the results. Sedation by antihistamines is clearly governed by doseresponse relationships. Diphenhydramine at 25 mg is much less sedating than at 50 mg.16 In fact, in adults ranging in age from 21 to 76 years, self-rating of sedation, mood, and autonomic effects, as well as performance on the digit-symbol substitution test and tests of information acquisition and recall, are all unaffected by diphenhydramine 25 mg. The 50-mg dose of diphenhydramine is marketed as a sleep aid under the name of Maximum Strength Unisom Softgels.17,18 Similarly, loratadine appears safe at 10 mg but impairs driving accuracy when administered at double that dose.11 Most studies that have investigated the effects of loratadine on driving performance and cognitive and psychomotor functioning have shown its effects at recommended doses to be comparable with placebo.19 In a meta-analysis, pooled data showed sedation in 25 of 517 patients given 10 mg of loratadine, and in 24 of 510 patients given placebo.20 The relative risk was 1.03, with a confidence interval from 0.59 to 1.77. Using 10 different methods, 20 studies did not find performance impairment in subjects taking loratadine 10 mg. However, in two performance measures, digit substitution and driving, there was a significant impairment after dosing with 20 mg and 40 mg of loratadine, respectively.20 A problem inherent in research using a retrospective pharmacy database is the potential for undetected selection bias. The occurrence of patient interactions with the healthcare system and associated costs can be established, but causation in such studies is extremely difficult to prove. In contrast, studies in which patients are randomized to treatment condition and followed prospectively allow attribution of cause and effect because the variables that introduce bias in retrospective research are equally distributed and hence controlled across treatment conditions. Drug dosage can be carefully controlled in clinical trials, and dose-response relationships can be credibly defined. Blinded, randomized clinical trials investigating the effects of antihistamines have become a cottage industry in Europe and North America, creatively using driving simulators and computer-equipped automobiles. Because these are true experimental studies, they can
221
control for effects of dose,21 dosing regimen, and dose timing;22 frequency and severity of driving errors;23 and degree of impairment relative to alcohol.10 Hence, such studies can establish causal relationships without the bias that may hamper retrospective pharmacy database studies. However, it may be difficult to conduct prospective, controlled studies to investigate the occurrence of injuries whose rates are expressed per 1,000 person-years. Finkle and colleagues rightly call for more investigation of the relation between antihistamine type and risk and for the inclusion of OTC drugs in these studies. We need to understand better who is prescribed diphenhydramine, given its OTC status. Might there be a concealed variable responsible for the observed results? Might patients receiving diphenhydramine be medically more compromised or have less capable doctors? To determine whether and how diphenhydramine use is linked to a substantial number of excess injuries, we need information about the dosing of both diphenhydramine and loratadine. If diphenhydramine is twice as effective as loratadine, then the doubling of accident rate may disappear when expressed in terms of units of antihistaminic activity. The same may apply to the CNS effects responsible for the injuries. At equipotent antihistaminic doses, the CNS effects may be similar for the two drugs. We need information about potential differences between patients who receive a prescription for diphenhydramine and those who purchase it over the counter. We need to know whether patients who require a physician’s prescription for diphenhydramine typically receive the same dose as those who obtain it over the counter. The investigators report that the diphenhydramine recipients were on average 6 years older than those who received loratadine. The older patients do not appear to be worse drivers. Are they more susceptible to the CNS effects of diphenhydramine alone, or is this also true for other first-generation and third-generation antihistamines? The authors’ control for age is adequate only if the relationship between age and medication to outcome effect is linear. There are good reasons to believe that a nonlinear relationship (or interactive effects) may be important. For example, with increasing age there are greater rates of medical comorbidity and polypharmacy that may influence the observed accident-related outcomes. The number and severity of comorbid diagnoses and the degree of polypharmacy are variables that require evaluation. Is it possible that patients who receive loratadine are sicker and more likely to stay away from hazardous situations? What if diphenhydramine, by more effectively treating the patients’ symptoms, allows them to be more active, thereby leading to increased injury rates relative to loratadine? It would be useful to know the injury rates for equally ill groups not treated with antihistamines. What is the patients’ consumption of alcohol? Are patients taking loratadine, a medicine that is only available by prescription, more likely to adhere to the dosing guidelines than those taking diphenhydramine, which can also be bought over the counter? Are patients taking other OTC medications?
222
In the United States, diphenhydramine is the most used OTC medication for the treatment of allergic rhinitis.10 An estimated 47% of persons with allergies take OTC products, most containing a first-generation antihistamine.10 Despite some gaps, the findings reported by Finkle et al, based on review of more than 37,000 prescriptions, are too concerning to ignore. It is clear that emergency departments need to collect information regarding the use of antihistamines when they treat patients for trauma. If first-generation antihistamines add significantly to the incidence of personal injury, then their distribution, especially over the counter, must be reevaluated and the reimbursement for third-generation agents by health programs must be considered in a new light. “O that men should put an enemy in their mouths to steal away their brains.” —Othelo HENRY MILGROM, MD*†‡ BRUCE BENDER, PhD‡§ FREDERICK WAMBOLDT, MD†§ Departments of *Pediatrics and †Medicine, National Jewish Medical and Research Center, Denver, CO ‡ Department of Pediatrics, University of Colorado Health Sciences Center, Denver, CO § Department of Psychiatry, University of Colorado Health Sciences Center, Denver, CO REFERENCES 1. Milgrom H, Bender B. Adverse effects of medications for rhinitis. Ann Allergy Asthma Immunol 1997;78:439 – 446. 2. Finkle W, Adams J, Greenland S, Melmon K. Increased risk of serious injury following an initial prescription for diphenhydramine. Ann Allergy Asthma Immunol 2002;89:242–248. 3. Simons FER, Simons KJ. H1-receptor antagonist treatment of chronic rhinitis. J Allergy Clin Immunol 1988;81:975–980. 4. Clarke CH, Nicholson AN. Performance studies with antihistamines. Br J Clin Pharmacol 1978;6:31–35. 5. Moskowitz H, Burns M. Effects of terfenadine, diphenhydramine, and placebo on skills performance. Cutis 1988;42:14 –18. 6. Aso T, Sakai Y. Effects of terfenadine, a novel antihistamine, on actual driving performance. Ann Allergy 1989;62:250. 7. Betts T, Markman D, Debenham S, et al. Effects of two antihistamine drugs on actual driving performance. BMJ 1984;288: 281–282. 8. Ten Eick AP, Blumer JL, Reed MD. Safety of antihistamines in children. Drug Saf 2001;24:119 –147. 9. Reidel W, Schoenmakers E, O’Hanlon J. The effects of loratadine alone and in combination with alcohol on actual driving performance: Maastricht, The Netherlands, 1987. 10. Weiler JM, Bloomfield JR, Woodworth GG, et al. Effects of fexofenadine, diphenhydramine, and alcohol on driving performance: a randomized, placebo-controlled trial in the Iowa driving simulator. Ann Intern Med 2000;132:354 –363. 11. O’Hanlon JF, Ramaekers JG. Antihistamine effects on actual driving performance in a standard test: a summary of Dutch experience, 1989 –1994. Allergy 1995;50:234 –242. 12. Hindmarch I, Shamsi Z. Antihistamines: models to assess sed-
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
13. 14.
15. 16.
17.
ative properties, assessment of sedation, safety and other sideeffects. Clin Exp Allergy 1999;29(Suppl):133–142. Mann RD, Pearce GL, Dunn N, Shakir S. Sedation with “nonsedating” antihistamines: four prescription-event monitoring studies in general practice. BMJ 2000;320:1184 –1186. Simons FE, Fraser TG, Reggin JD, Simons KJ. Individual differences in central nervous system response to antihistamines (H1-receptor antagonists). Ann Allergy Asthma Immunol 1995; 75:507–514. Lee TH, Dudley J, Demonaco HJ. Drug effects on driving performance. Ann Intern Med 2000;133:656 – 657. Witek TJ Jr, Canestrari DA, Miller RD, et al. Characterization of daytime sleepiness and psychomotor performance following H1 receptor antagonists. Ann Allergy Asthma Immunol 1995; 74:419 – 426. Scavone JM, Greenblatt DJ, Harmatz JS, et al. Pharmacokinetics and pharmacodynamics of diphenhydramine 25 mg in young and elderly volunteers. J Clin Pharmacol 1998;38: 603– 609.
VOLUME 89, SEPTEMBER, 2002
18. Physicians’ Desk Reference. Montvale, NJ: Medical Economics Thomson Healthcare, 2002:2762. 19. Ramaekers JG, Uiterwijk MM, O’Hanlon JF. Effects of loratadine and cetirizine on actual driving and psychometric test performance, and EEG during driving. Eur J Clin Pharmacol 1992;42:363–369. 20. Hansen GR. Loratadine in the high performance aerospace environment. Aviat Space Environ Med 1999;70:919 –924. 21. Vuurman EF, Uiterwijk MM, Rosenzweig P, O’Hanlon JF. Effects of mizolastine and clemastine on actual driving and psychomotor performance in healthy volunteers. Eur J Clin Pharmacol 1994;47:253–259. 22. Ramaekers JG, O’Hanlon JF. Acrivastine, terfenadine and diphenhydramine effects on driving performance as a function of dose and time after dosing. Eur J Clin Pharmacol 1994;47: 261–266. 23. Gengo FM, Gabos C. Antihistamines, drowsiness, and psychomotor impairment: central nervous system effect of cetirizine. Ann Allergy 1987;59:53–57.
223