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Seasonal allergic rhinitis and cognitive function
Guest editorial
Seasonal allergic rhinitis and cognitive function BACKGROUND ISSUE One of our major goals as healthcare providers is to restore normal quality of life when impaired by disease. A prerequisite for this task is to understand the nature of the disease: signs and symptoms, natural history, and pathophysiology. In the case of allergic disease, our knowledge is incomplete and constantly growing. The cardinal symptoms of rhinitis are well known: sneezing, rhinorrhea, itchy watery eyes, and nasal obstruction. The effects of the primary pathology and these symptoms on the central nervous system are real, but subtle. Many patients complain of slowed thinking, memory problems, and difficulty sustaining attention during their allergy seasons. These effects have traditionally been attributed to adverse effects of allergy pharmacotherapy, as the effects of the disease on the CNS have not been adequately studied. The literature in this field to date consists of small studies with varied results.1– 4 THIS STUDY In this edition of the Annals, Marshall and colleagues report on the effect of symptomatic allergic reactions on a wider range of cognitive abilities.5 To provide a homogeneous subject group, patients all had classic ragweed-sensitive allergic rhinitis. Groups of patients and normal controls were studied in successive ragweed seasons, and out of season. Medications that might affect the CNS were excluded. Subjects rated their symptom severity to produce a total symptom discomfort score. A minimal score was needed to enter the study. For cognitive testing, all subjects were
VOLUME 84, APRIL, 2000
given an identical battery of assessment tests at the same time of day to control for the potential effects of diurnal variables. Eight tests were administered and a detailed description of each is provided in the manuscript. They covered areas of speed of cognitive processing, ability to divide and sustain attention, working memory and recent verbal memory. The authors concluded that during ragweed seasons, allergic patients experience subtle slowed speed of cognitive processing, but not deficits in attention and recent memory. Some patients also have difficulty in working memory. Recent verbal memory and motor speed were not affected. It is interesting to note that these objective observations differ from the subjects’ own initial observation at the beginning of the study where approximately half claimed difficulty paying attention, slowed thinking, and problems remembering things. The authors caution some limitations on making general conclusions from this study. Patients in this study underwent testing after only 4 days of significant rhinitis symptoms at the beginning of the ragweed season. They were off medications for only 4 days. Cognitive defects might have only become apparent after a long symptom experience. Second, the patients in this study had to be ragweed sensitive. It was not assessed if they had sensitivity to other allergens. It is possible that allergy to multiple substances confers a greater tendency to cognitive deficits. An additional possible variable is that there could be a learning or fatigue effect as all the tests were administered in the same sequence each time.
Although this study is relatively small, it highlights the need to study subjects with active symptomatic disease when measuring performance parameters. Yet, recent papers continue to evaluate the effects of drugs using populations of healthy volunteers.6 OTHER STUDIES Despite increasing number of papers in this area, there is no universal definition of what constitutes normal performance and what degree of impairment is either tolerable or not clinically significant. A statistical difference in a laboratory test may not translate into a clinically significant observation. Further, we do not know if there is a threshold level at which clinical significance appears. We are now appreciating that there are other confounding factors that also need to be measured. Examination of these variables should reinforce the need to revisit older performance measurement data. A recent study by Craig and colleagues published in 1998 claimed that daytime fatigue often attributed to adverse effects of medications may be due to nasal congestion and associated sleep fragmentation.7 Further, sleep disturbance and sleep apnea, which occur far more commonly than realized, are important causes of motor vehicle accidents.8 –11 Yet many studies have been published claiming adverse effects of antihistamines without evaluating subjects for sleep apnea syndrome. Allowing for limitations of current data with confounding variables, how should laboratory performance studies be interpreted?
371
LABORATORY PERFORMANCE STUDIES Surrogate endpoints always invite controversy, as translation into real life situations is difficult at best. As one author in the field concluded: no psychometric test or battery of tests has ever been shown to predict the affect of drugs on actual performance or behavior in real life.12 Laboratory studies showing an effect on performance based on objective measures also typically show a subjective response (ie, the subject reports feeling sleepy). Although the subjective report of sleepiness is often viewed as a negative, in real-world situations this subjective awareness can motivate subjects to heighten vigilance and take corrective action. For example, a study designed to compare the effects on flying performance of a second-generation antihistamine, (terfenadine), two first-generation antihistamines (chlorpheniramine and diphenhydramine), and placebo showed no significant differences in flight performance among 12 pilots evaluated. Although some pilots reported adverse effects, all compensated and flew well.13 Most studies showing performance effects after taking antihistamines have evaluated healthy volunteers rather than persons taking the drug for its intended use.14,15,18 –27 The value of data from studies that looked at healthy volunteers taking higher than usual doses of classical antihistamines at unlikely schedules is questionable. Psychometric studies of healthy volunteers might not be as predictive as clinical studies of patients with allergic rhinitis. Few comparisons of first-generation and second-generation antihistamines looked at sedative effects in persons with allergic rhinitis.1–3,25–26 Those that did often failed to control the patient groups carefully for severity of disease and concomitant treatment.14 –26 Accordingly, the possibility exists that different results would be obtained when the performance impairment caused by the symptoms is factored in. Most laboratory studies that showed effects were designed to maximize the
372
probability of detecting an effect by taking measurements at a time when maximal blood concentrations are expected to occur, typically 1 to 3 hours after drug administration. This could represent an unfair comparison, as sedation or performance impairment would be at peak for one drug under study and might not be for the comparator. The best method of determining performance impairment with antihistamines would involve dosing schedules designed to achieve steady state. Dosing strategies also make it difficult to interpret the results of many of these studies. For example, in virtually all studies in adults, diphenhydramine has been used as a positive control, and has been frequently administered in doses that are typically used in sleep aids (ⱖ50 mg). Diphenhydramine as an oral antihistamine is supplied in 25-mg doses. Yet, no studies in adults have been published that evaluated the sedative effects at this dose. In fact, some studies show no difference for diphenhydramine from placebo for performance variables when measured at times other than when peak blood concentration occurs after a first dose.21,25 IMPLICATIONS Patients who suffer from allergies can be in a double jeopardy situation when it comes to taking medication throughout the season. Although there may be relief of symptoms, the price in terms of convenience, expense and adverse effects may be a less attractive proposition than suffering from the untreated disease. With appropriate education, allergy sufferers should be allowed to choose from a variety of therapeutic options that suit their lifestyle. Any therapeutic intervention requires a benefit risk analysis, which may vary depending on the individual, the severity of symptoms, and overall lifestyle. The intervention should be evaluated for efficacy as well for potential adverse effects. Balance is needed to complete the equation. Further studies performed on wellcontrolled and balanced groups of al-
lergic individuals will help us understand better the real-world place for specific allergy therapies. HOWARD M DRUCE, MD Clinical Associate Professor of Medicine Division of Allergy and Immunology UMDNJ-New Jersey Medical School Newark, New Jersey REFERENCES 1. Burns M, Shanaman JE, Shellenberger CH. A laboratory study of patients with chronic allergic rhinitis: antihistamine effects on skilled performance. J Allergy Clin Immunol 1994;93: 716 –724. 2. Vuurman EFPM, van Veggel, Uiterwijk MMC, et al. Seasonal allergic rhinitis and antihistamine effects on children’s learning. Ann Allergy 1993;71: 121–126. 3. Vuurman EFPM, van Veggel LMA, Sanders RL, et al. Effects of Semprex-D and diphenhydramine on learning in young adults with seasonal allergic rhinitis. Ann Allergy Asthma Immunol 1996;76:247–252. 4. Marshall PS, Colon EA. Effects of allergy season on mood and cognitive function. Ann Allergy 1993;71: 251–258. 5. Marshall PS, O’Hara C, Steinberg P. Effects of seasonal allergic rhinitis on selected cognitive abilities. Ann Allergy Asthma Immunol 2000;84: 403– 410. 6. Hindmarch I, Shamsi Z, Stanley N, Fairweather DB. A double-blind placebo-controlled investigation of the effects of fexofenadine, loratadine and promethazine on cognitive and psychomotor function. Br J Clin Pharmacol 1999;48:200 –206. 7. Craig TJ, Teets S, Lehman EB, et al. Nasal congestion secondary to allergic rhinitis as a cause of sleep disturbance and daytime fatigue and the response to topical nasal corticosteroids. J Allergy Clin Immunol 1998;101: 633– 637. 8. Flemons WW, Tsai W. Quality of life consequences of sleep-disordered breathing. J Allergy Clin Immunol 1997;99:S750 –756. 9. Scharf MB, Cohen AP. Diagnostic and treatment implications of nasal ob-
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
10.
11.
12.
13.
14.
15.
struction in snoring and obstructive sleep apnea. Ann Allergy Asthma Immunol 1998;81:279 –290. Barbe F, Pericas J, Munoz A, et al. Automobile accidents in patients with sleep apnea syndrome: an epidemiological and mechanistic study. Am J Respir Crit Care Med 1998;158: 18 –22. Teran-Santos J, Jimenez-Gomez A, Cordero-Guevara J, et al. The association between sleep apnea and the risk of traffic accidents. N Engl J Med 199; 340:847– 851. O’Hanlon JF, Ramaekers JG. Antihistamine effects on actual driving performance in a standard test: a summary of Dutch experience, 1989 –94. Allergy 1995;50:234 –242. Philpot EE, Brooker AE. Effects of sedating and nonsedating antihistamines on flying performance. Military Med 1993;158:654 – 660. Ramaekers JG, O’Hanlon JF. Acrivastine, terfenadine and diphenhydramine effects on driving performance as a function of dose and time after dose. Eur J Clin Pharmacol 1994;47: 261–266. Brookhuis KA, De Vries G, De Waard D. Acute and subchronic effects of the H1-histamine receptor antagonist ebastine in 10, 20, and 30 mg dose, and triprolidine 10 mg on car driving per-
VOLUME 84, APRIL, 2000
16.
17.
18.
19.
20.
21.
formance. J Clin Pharm 1993;36: 67–70. Nicholson AN, Turner C. Central effects of the H1-antihistamine cetirizine. Aviat Space Environ Med 1998;69: 166 –171. Kay GG, Berman B, Mockoviak SH, et al. Initial and steady-state effects of diphenhydramine and loratadine on sedation, cognition, mood, and psychomotor performance. Arch Intern Med 1997;157:2350 –2356. Tharion WJ, McMenemy DJ, Rauch TM. Antihistamine effects on the central nervous system, cognitive performance and subjective states. Neuropsychobiology 1994;29:97–104. Witek TJ, 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. Kerr JS, Dunmore C, Hindmarch I. The psychomotor and cognitive effects of a new antihistamine, mizolastine, compared to terfenadine, triprolidine and placebo in healthy volunteers. Eur J Clin Pharmacol. 1994;47:331–335. Rice VJ, Snyder HL. The effects of Benadryl and Hismanal on psychomotor performance and perceived performance. Aviat Space Environ Med 1993;64:726 –734.
22. Walsh JK, Muehlbach MJ, Schweitzer PK. Simulated assembly line performance following ingestion of cetirizine or hydroxyzine. Ann Allergy 1992; 69:195–200. 23. Goetz DW, Jacobson JM, Apaliski SJ, et al. Objective antihistamine side effects are mitigated by evening dosing of hydroxyzine. Ann Allergy 1991;67: 448 – 454. 24. Valk PJ, Simons RM, Struyvenberg PA, et al. Effects of a single dose of loratadine on flying ability under conditions of simulated cabin pressure. Am J Rhinol 1997;11:27–33. 25. Schweitzer PK, Muehlbach MJ, Walsh JK. Sleepiness and performance during three-day administration of cetirizine or diphenhydramine. J Allergy Clin Immunol 1994;94:716 –724. 26. Shanon A, Feldman W, Leikin L, et al. Comparison of CNS adverse effects between astemizole and chlorpheniramine in children: a randomized, double blind study. Dev Pharmacol Ther 1993;20:239 –246. Request for reprints should be addressed to: Howard M. Druce MD Clinical Associate Professor of Medicine Division of Allergy and Immunology UMDNJ—New Jersey Medical School 90 Bergen St, Suite 4700 Newark, NJ 07103
373
Seasonal allergic rhinitis and cognitive function BACKGROUND ISSUE One of our major goals as healthcare providers is to restore normal quality of life when impaired by disease. A prerequisite for this task is to understand the nature of the disease: signs and symptoms, natural history, and pathophysiology. In the case of allergic disease, our knowledge is incomplete and constantly growing. The cardinal symptoms of rhinitis are well known: sneezing, rhinorrhea, itchy watery eyes, and nasal obstruction. The effects of the primary pathology and these symptoms on the central nervous system are real, but subtle. Many patients complain of slowed thinking, memory problems, and difficulty sustaining attention during their allergy seasons. These effects have traditionally been attributed to adverse effects of allergy pharmacotherapy, as the effects of the disease on the CNS have not been adequately studied. The literature in this field to date consists of small studies with varied results.1– 4 THIS STUDY In this edition of the Annals, Marshall and colleagues report on the effect of symptomatic allergic reactions on a wider range of cognitive abilities.5 To provide a homogeneous subject group, patients all had classic ragweed-sensitive allergic rhinitis. Groups of patients and normal controls were studied in successive ragweed seasons, and out of season. Medications that might affect the CNS were excluded. Subjects rated their symptom severity to produce a total symptom discomfort score. A minimal score was needed to enter the study. For cognitive testing, all subjects were
VOLUME 84, APRIL, 2000
given an identical battery of assessment tests at the same time of day to control for the potential effects of diurnal variables. Eight tests were administered and a detailed description of each is provided in the manuscript. They covered areas of speed of cognitive processing, ability to divide and sustain attention, working memory and recent verbal memory. The authors concluded that during ragweed seasons, allergic patients experience subtle slowed speed of cognitive processing, but not deficits in attention and recent memory. Some patients also have difficulty in working memory. Recent verbal memory and motor speed were not affected. It is interesting to note that these objective observations differ from the subjects’ own initial observation at the beginning of the study where approximately half claimed difficulty paying attention, slowed thinking, and problems remembering things. The authors caution some limitations on making general conclusions from this study. Patients in this study underwent testing after only 4 days of significant rhinitis symptoms at the beginning of the ragweed season. They were off medications for only 4 days. Cognitive defects might have only become apparent after a long symptom experience. Second, the patients in this study had to be ragweed sensitive. It was not assessed if they had sensitivity to other allergens. It is possible that allergy to multiple substances confers a greater tendency to cognitive deficits. An additional possible variable is that there could be a learning or fatigue effect as all the tests were administered in the same sequence each time.
Although this study is relatively small, it highlights the need to study subjects with active symptomatic disease when measuring performance parameters. Yet, recent papers continue to evaluate the effects of drugs using populations of healthy volunteers.6 OTHER STUDIES Despite increasing number of papers in this area, there is no universal definition of what constitutes normal performance and what degree of impairment is either tolerable or not clinically significant. A statistical difference in a laboratory test may not translate into a clinically significant observation. Further, we do not know if there is a threshold level at which clinical significance appears. We are now appreciating that there are other confounding factors that also need to be measured. Examination of these variables should reinforce the need to revisit older performance measurement data. A recent study by Craig and colleagues published in 1998 claimed that daytime fatigue often attributed to adverse effects of medications may be due to nasal congestion and associated sleep fragmentation.7 Further, sleep disturbance and sleep apnea, which occur far more commonly than realized, are important causes of motor vehicle accidents.8 –11 Yet many studies have been published claiming adverse effects of antihistamines without evaluating subjects for sleep apnea syndrome. Allowing for limitations of current data with confounding variables, how should laboratory performance studies be interpreted?
371
LABORATORY PERFORMANCE STUDIES Surrogate endpoints always invite controversy, as translation into real life situations is difficult at best. As one author in the field concluded: no psychometric test or battery of tests has ever been shown to predict the affect of drugs on actual performance or behavior in real life.12 Laboratory studies showing an effect on performance based on objective measures also typically show a subjective response (ie, the subject reports feeling sleepy). Although the subjective report of sleepiness is often viewed as a negative, in real-world situations this subjective awareness can motivate subjects to heighten vigilance and take corrective action. For example, a study designed to compare the effects on flying performance of a second-generation antihistamine, (terfenadine), two first-generation antihistamines (chlorpheniramine and diphenhydramine), and placebo showed no significant differences in flight performance among 12 pilots evaluated. Although some pilots reported adverse effects, all compensated and flew well.13 Most studies showing performance effects after taking antihistamines have evaluated healthy volunteers rather than persons taking the drug for its intended use.14,15,18 –27 The value of data from studies that looked at healthy volunteers taking higher than usual doses of classical antihistamines at unlikely schedules is questionable. Psychometric studies of healthy volunteers might not be as predictive as clinical studies of patients with allergic rhinitis. Few comparisons of first-generation and second-generation antihistamines looked at sedative effects in persons with allergic rhinitis.1–3,25–26 Those that did often failed to control the patient groups carefully for severity of disease and concomitant treatment.14 –26 Accordingly, the possibility exists that different results would be obtained when the performance impairment caused by the symptoms is factored in. Most laboratory studies that showed effects were designed to maximize the
372
probability of detecting an effect by taking measurements at a time when maximal blood concentrations are expected to occur, typically 1 to 3 hours after drug administration. This could represent an unfair comparison, as sedation or performance impairment would be at peak for one drug under study and might not be for the comparator. The best method of determining performance impairment with antihistamines would involve dosing schedules designed to achieve steady state. Dosing strategies also make it difficult to interpret the results of many of these studies. For example, in virtually all studies in adults, diphenhydramine has been used as a positive control, and has been frequently administered in doses that are typically used in sleep aids (ⱖ50 mg). Diphenhydramine as an oral antihistamine is supplied in 25-mg doses. Yet, no studies in adults have been published that evaluated the sedative effects at this dose. In fact, some studies show no difference for diphenhydramine from placebo for performance variables when measured at times other than when peak blood concentration occurs after a first dose.21,25 IMPLICATIONS Patients who suffer from allergies can be in a double jeopardy situation when it comes to taking medication throughout the season. Although there may be relief of symptoms, the price in terms of convenience, expense and adverse effects may be a less attractive proposition than suffering from the untreated disease. With appropriate education, allergy sufferers should be allowed to choose from a variety of therapeutic options that suit their lifestyle. Any therapeutic intervention requires a benefit risk analysis, which may vary depending on the individual, the severity of symptoms, and overall lifestyle. The intervention should be evaluated for efficacy as well for potential adverse effects. Balance is needed to complete the equation. Further studies performed on wellcontrolled and balanced groups of al-
lergic individuals will help us understand better the real-world place for specific allergy therapies. HOWARD M DRUCE, MD Clinical Associate Professor of Medicine Division of Allergy and Immunology UMDNJ-New Jersey Medical School Newark, New Jersey REFERENCES 1. Burns M, Shanaman JE, Shellenberger CH. A laboratory study of patients with chronic allergic rhinitis: antihistamine effects on skilled performance. J Allergy Clin Immunol 1994;93: 716 –724. 2. Vuurman EFPM, van Veggel, Uiterwijk MMC, et al. Seasonal allergic rhinitis and antihistamine effects on children’s learning. Ann Allergy 1993;71: 121–126. 3. Vuurman EFPM, van Veggel LMA, Sanders RL, et al. Effects of Semprex-D and diphenhydramine on learning in young adults with seasonal allergic rhinitis. Ann Allergy Asthma Immunol 1996;76:247–252. 4. Marshall PS, Colon EA. Effects of allergy season on mood and cognitive function. Ann Allergy 1993;71: 251–258. 5. Marshall PS, O’Hara C, Steinberg P. Effects of seasonal allergic rhinitis on selected cognitive abilities. Ann Allergy Asthma Immunol 2000;84: 403– 410. 6. Hindmarch I, Shamsi Z, Stanley N, Fairweather DB. A double-blind placebo-controlled investigation of the effects of fexofenadine, loratadine and promethazine on cognitive and psychomotor function. Br J Clin Pharmacol 1999;48:200 –206. 7. Craig TJ, Teets S, Lehman EB, et al. Nasal congestion secondary to allergic rhinitis as a cause of sleep disturbance and daytime fatigue and the response to topical nasal corticosteroids. J Allergy Clin Immunol 1998;101: 633– 637. 8. Flemons WW, Tsai W. Quality of life consequences of sleep-disordered breathing. J Allergy Clin Immunol 1997;99:S750 –756. 9. Scharf MB, Cohen AP. Diagnostic and treatment implications of nasal ob-
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
10.
11.
12.
13.
14.
15.
struction in snoring and obstructive sleep apnea. Ann Allergy Asthma Immunol 1998;81:279 –290. Barbe F, Pericas J, Munoz A, et al. Automobile accidents in patients with sleep apnea syndrome: an epidemiological and mechanistic study. Am J Respir Crit Care Med 1998;158: 18 –22. Teran-Santos J, Jimenez-Gomez A, Cordero-Guevara J, et al. The association between sleep apnea and the risk of traffic accidents. N Engl J Med 199; 340:847– 851. O’Hanlon JF, Ramaekers JG. Antihistamine effects on actual driving performance in a standard test: a summary of Dutch experience, 1989 –94. Allergy 1995;50:234 –242. Philpot EE, Brooker AE. Effects of sedating and nonsedating antihistamines on flying performance. Military Med 1993;158:654 – 660. Ramaekers JG, O’Hanlon JF. Acrivastine, terfenadine and diphenhydramine effects on driving performance as a function of dose and time after dose. Eur J Clin Pharmacol 1994;47: 261–266. Brookhuis KA, De Vries G, De Waard D. Acute and subchronic effects of the H1-histamine receptor antagonist ebastine in 10, 20, and 30 mg dose, and triprolidine 10 mg on car driving per-
VOLUME 84, APRIL, 2000
16.
17.
18.
19.
20.
21.
formance. J Clin Pharm 1993;36: 67–70. Nicholson AN, Turner C. Central effects of the H1-antihistamine cetirizine. Aviat Space Environ Med 1998;69: 166 –171. Kay GG, Berman B, Mockoviak SH, et al. Initial and steady-state effects of diphenhydramine and loratadine on sedation, cognition, mood, and psychomotor performance. Arch Intern Med 1997;157:2350 –2356. Tharion WJ, McMenemy DJ, Rauch TM. Antihistamine effects on the central nervous system, cognitive performance and subjective states. Neuropsychobiology 1994;29:97–104. Witek TJ, 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. Kerr JS, Dunmore C, Hindmarch I. The psychomotor and cognitive effects of a new antihistamine, mizolastine, compared to terfenadine, triprolidine and placebo in healthy volunteers. Eur J Clin Pharmacol. 1994;47:331–335. Rice VJ, Snyder HL. The effects of Benadryl and Hismanal on psychomotor performance and perceived performance. Aviat Space Environ Med 1993;64:726 –734.
22. Walsh JK, Muehlbach MJ, Schweitzer PK. Simulated assembly line performance following ingestion of cetirizine or hydroxyzine. Ann Allergy 1992; 69:195–200. 23. Goetz DW, Jacobson JM, Apaliski SJ, et al. Objective antihistamine side effects are mitigated by evening dosing of hydroxyzine. Ann Allergy 1991;67: 448 – 454. 24. Valk PJ, Simons RM, Struyvenberg PA, et al. Effects of a single dose of loratadine on flying ability under conditions of simulated cabin pressure. Am J Rhinol 1997;11:27–33. 25. Schweitzer PK, Muehlbach MJ, Walsh JK. Sleepiness and performance during three-day administration of cetirizine or diphenhydramine. J Allergy Clin Immunol 1994;94:716 –724. 26. Shanon A, Feldman W, Leikin L, et al. Comparison of CNS adverse effects between astemizole and chlorpheniramine in children: a randomized, double blind study. Dev Pharmacol Ther 1993;20:239 –246. Request for reprints should be addressed to: Howard M. Druce MD Clinical Associate Professor of Medicine Division of Allergy and Immunology UMDNJ—New Jersey Medical School 90 Bergen St, Suite 4700 Newark, NJ 07103
373