CIRCADIAN RHYTHMS:
TIMING OF TREATMENT AFFECTS RHINITIS

CHICAGO-- The body's circadian rhythms have a major influence on allergic rhinitis--including its symptoms, diagnosis, and treatment. "In epidemiologic studies, for example, sneezing, rhinorrhea, and other symptoms have shown marked circadian variation in 75% to 85% of individuals with this condition," said Michael H. Smolensky, PhD. Rhinitis is typically at its worst in the morning, decreases during the day, and worsens again in the evening and during sleep.

If circadian rhythms play an important role in regulating the severity and variations of symptoms, what are the implications for diagnosis and treatment? Dr. Smolensky, who is director of the Memorial-Hermann Center for Chronobiology and Chronotherapeutics and professor of environmental physiology at the University of Texas School of Public Health in Houston, discussed these issues at the recent annual meeting of the American College of Allergy, Asthma, and Immunology.

SYMPTOMS WORSE AT NIGHT

Up to 85% of allergic rhinitis patients report nighttime symptoms that cause sleep disturbance, which subsequently leads to daytime fatigue, mood alterations, reduced productivity, and work or school absences, Dr. Smolensky recently told RESPIRATORY REVIEWS. Plasma cortisol is a vital factor in the development of nighttime symptoms. "Cortisol levels are highest in the morning and lowest during sleep," explained Dr. Smolensky. "When cortisol is low, allergic inflammation exacerbates, causing congestion and interfering with sleep."

The menstrual cycle also influences allergic rhinitis in some women. This may have an impact on the accurate diagnosis of allergen sensitivities. "Moreover, there is about 25% variability in skin reactivity over the menstrual cycle," said Dr. Smolensky, "with reactivity being lowest around the expected time of ovulation and highest around the end of the cycle and during menstruation."

Circadian rhythms may also influence the results of diagnostic skin tests for allergic rhinitis. Skin test results are more likely to be false negative in the morning than in the late afternoon or early evening, according to Dr. Smolensky.

Seasonal variation in allergic rhinitis is also well documented. In a multicenter French study of 765 allergic rhinitis patients, sneezing was most problematic in March and April, whereas rhinorrhea and congestion were most problematic in January and February.[1] Annual rhythms in total and specific immunoglobulin E levels and other aspects of immune function may help to explain these findings, Dr. Smolensky suggested.

TIMING THERAPY FOR OPTIMAL RESULTS

Allergic rhinitis treatment is safest and most effective when timed to circadian variations. "You can optimize the therapeutic effects of a once-daily, nonsedating antihistamine by giving it before bedtime to control overnight exacerbations," explained Dr. Smolensky. This strategy also reduces morning and early afternoon symptoms.

Some of the strongest data to support this approach come from a decade-old French study of nearly 100 allergic rhinitis patients.[2] As part of the double-blind, placebo-controlled, crossover trial, subjects took 10 mg of a once-daily nonsedating antihistamine in the morning or at bedtime. The evening dose was better at controlling overnight exacerbations, as well as morning and early afternoon symptoms, the study found.

Although effective for severe allergic rhinitis, oral corticosteroid treatment requires proper timing to minimize the risk of adrenal suppression and a subsequent drop in plasma cortisol levels. This has been recognized for nearly 40 years.

For example, a study published in the 1960s found that giving 8 mg/d of oral triamcinolone in four divided doses led to marked adrenal suppression after 8 days.[3] This did not occur when the same subjects took the entire 8 mg in the morning at the start of the daily activity period, when the concentration of plasma cortisol is highest and the hypothalamic-pituitary-adrenal access is least vulnerable to suppression by synthetic corticosteroid.

"What we have also learned is that the later the timing of tablet synthetic steroids after 3 in the afternoon--that is, eight to nine hours after waking in the morning--the greater the risk of inducing adrenal suppression," added Dr. Smolensky.

Studies in asthma patients also show that therapeutic results from tablet corticosteroid treatment can be enhanced with short courses of early afternoon (about 3 PM) dosing. Physicians should therefore prescribe morning oral corticosteroid therapy for severe allergic rhinitis; if necessary, they may try early afternoon dosing.

LOW LEVEL OF AWARENESS

Research on the role of circadian rhythms in allergic rhinitis is not new, yet many general practitioners are largely unaware of it, according to Dr. Smolensky. In 1996, he conducted a survey to determine general practitioners' knowledge of the role of circadian rhythms in clinical medicine.

Respondents were, for the most part, surprised that these rhythms play a role in sleep and conditions such as hypertension, cardiovascular disease, and angina pectoris. "It's interesting that only 50% realized there could be a circadian rhythm in the symptom intensity of allergic rhinitis," Dr. Smolensky said. Only 26%, he noted, were aware that circadian variations contribute to nighttime asthma exacerbations. In addition, only 24% of the surveyed doctors were aware that allergy symptoms are worst in the morning; only 26% knew that asthma is worst between midnight and 6 AM.[4]

Because of this widespread lack of awareness, education is necessary to inform physicians about the importance of circadian rhythms in allergic rhinitis and other conditions. This information will help them maximize the benefits of therapy in patients with rhinitis.

--Timothy Begany

References
1. Reinberg A, Gervais P, Levi F, et al. Circadian and circannual rhythms of allergic rhinitis: an epidemiologic study involving chronobiologic methods. J Allergy Clin Immunol. 1988;81:51-62.
2. Reinberg A, Gervais P, Ugolini C, et al. A multicentric chronotherapeutic study of mequitazine in allergic rhinitis. Annu Rev Chronopharmacol. 1986;3:441-444.
3. Grant SD, Forsham PH, Di Raimondo VC. Suppression of 17-hydroxycorticosteroids in plasma and urine by single and divided doses of triamcinolone. N Engl J Med. 1965;273:1115-1118.
4. Smolensky MH. Knowledge and attitudes of American physicians and public about medical chronobiology and chronotherapeutics: findings of two 1996 Gallup surveys. Chronobiol Int. 1998;15:377-394.

Suggested Reading
Smolensky MH, Lamberg L. The Body Clock Guide to Better Health. New York, NY: Henry Holt & Co; 2000.