October 23, 2007
Therapeutic Options for Reducing Sleep Impairment in Allergic Rhinitis, Rhinosinusitis, and Nasal Polyposis
By Storms, William Yawn, Barbara; Fromer, Leonard
Key words: Congestion - Nasal obstruction - Nasal polyposis - Rhinitis - Rhinosinusitis - Sleep ABSTRACT
Scope of literature search: Literature searches of Medline, Embase, and abstracts from medical/ scientific conferences were conducted for the period of 1995 through mid-2006 for primary and review articles and conference presentations about sleep disturbance related to allergic rhinitis, rhinosinusitis, and nasal polyposis. These searches also sought to identify articles examining how treatments for those diseases improved sleep and, consequently, patients' quality of life. Surveys of the impact of congestion on patients' quality of life and their sleep also were consulted. Clinical studies were selected for discussion if they were randomized, double-blind, and placebo-controlled. Limitations of this review include the absence of any direct comparisons of the effectiveness of different drugs on improving sleep and shortcomings in the statistical methods of the patient surveys.
Findings: Intranasal corticosteroids (INSs) are the most effective medication for reducing congestion in patients with inflammatory nasal conditions. There is a growing amount of evidence that a reduction in congestion with INSs is associated with improved sleep, reduced daytime sleepiness, and enhanced patient quality of life.
Conclusion: Relief of sleep impairment associated with inflammatory disorders of the nose and sinuses can be addressed with INS therapy.
Allergic rhinitis (AR), rhinosinusitis, and nasal polyposis are inflammatory disorders of the nose and sinuses that are commonly encountered in clinical practice. Sleep impairment is often a significant problem for patients with these conditions, and should be established and addressed. For example, in a population-based study of 5838 people (data on nasal congestion and sleep problems identified by questionnaire in 4927 participants and by objective laboratory measurement in 911), nearly 75% who either 'always' (> 15 nights per month) or Often' (5-15 nights per month) had nighttime rhinitis symptoms reported chronic nonrestorative sleep1. Similar results were seen in other studies which concluded that nasal congestion is a significant predictor of snoring and that congestion can lead to sleep fragmentation and deprivation, daytime tiredness, and altered behavioral patterns23. Sleep impairment is also reported by patients with rhinosinusitis and nasal polyposis4'5. The sleep disturbances experienced by patients with these conditions include difficulty going to sleep, snoring, interrupted sleep, sleep apnea, and hypopnea. Such disturbances, together with nocturnal symptoms such as congestion, sneezing, rhinorrhea, and pruritus, can reduce patient quality of life and lead to daytime sleepiness, fatigue, irritability, and decreased learning and productivity at school and work.
Congestion (nasal and sinus) is thought to be the main cause of sleep impairment and is a common, and the most bothersome symptom, of all three inflammatory disorders of the upper airways. Other factors that may play a role in causing sleep disturbance include other symptoms of these conditions, inflammatory mediators released as part of the underlying disease processes, and the effects of some of the medications used to treat these disorders.
Intranasal corticosteroids (INSs) improve the symptoms - especially congestion - of AR, rhinosinusitis, and nasal polyposis. In addition, INSs have been shown to improve patients' sleep and quality of life.
This review summarizes the existing literature about the sleep- associated burden of AR, rhinosinusitis, and nasal polyposis, and examines how it can be managed effectively. Several electronic literature searches of Medline and Embase were conducted in November and December 2005 and in June and July 2006 to identify primary research and review articles addressing the impact on sleep of the three inflammatory nasal and sinus conditions, as well as the effectiveness of treatments for those conditions in improving patients' ability to sleep and quality of life. The references cited in relevant papers were reviewed for related articles. This search also sought to identify abstracts presented at the annual meetings of the American Academy of Allergy Asthma and Immunology, the American College of Allergy Asthma and Immunology, and the World Allergy Congress by searching supplements of the Journal of Allergy and Clinical Immunology, the Annals of Asthma, Allergy & Immunology, and Allergy and Clinical Immunology International, the journals which publish abstracts from the three congresses, respectively. The words allergic rhinitis, rhinosinusitis (also sinusitis), and nasal polyposis (also polyps) combined with the words sleep, sleep disturbance(s), and sleep impairment(s) were used as search terms. Other search terms included intranasal corticosteroids (also steroids), antihistamines, and immune response mediators with sleep; congestion and sleep; and quality of life and sleep. Searches also were conducted by the brand and generic names of the intranasal corticosteroids - Nasonex (mometasone furcate), Flonase (fluticasone propionate), Rhinocort (budesonide), Beconase or Vancenase (beclomethasone dipropionate), Nasacort (triamcinolone acetonide), and Nasalide or Nasarel (flunisolide) - coupled with the terms on sleep noted above. Both review and primary research papers were consulted, but primary papers were assigned a priority in selecting the data included in this manuscript.
The current burden of AR, rhinosinusitis, and nasal polyposis
Allergic rhinitis, rhinosinusitis, and nasal polyposis affect 2- 40% of the population in the USA and Europe, as shown in Table I6"14.
Congestion is a common, and the most troublesome, symptom of inflammatory disorders of the upper respiratory tract. Nasal congestion is a major symptom of AR, together with rhinorrhea, sneezing, and pruritus of the eyes, nose, and throat15. A large Internet survey of individuals with AR (adults and children) was conducted by an independent market research company, Roper Public Affairs Group of NOP World, New York, New York, on behalf of Schering-Plough Corporation, Kenilworth, New Jersey. Roper Public Affairs Group prepared the survey questions. Participants were part of the NOP World panel of consumers, recruited voluntarily through telephone surveys and Internet advertisements. Eligible individuals were asked to complete the Internet survey, which questioned respondents about the symptoms and effects of AR and its treatment. The survey found that 85% (margin of error +- 2%) of respondents experienced nasal congestion16. Of these respondents, 40% considered their nasal congestion to be severe, and 50% stated that congestion was the most bothersome of their symptoms. This result is similar to that of other patient surveys of adults and adolescents in which congestion (also referred to as a stuffy nose or a stuffy/blocked nose) was found to be the most frequently occurring symptom of AR and the one with the most impact on quality of life17'18.
Table 1. Prevalence of allergie rhinitis, rhinosinusitis, and nasal polyposis
Allergic rhinitis may also cause sinus congestion and blockage. A recent survey of allergy symptoms in the United States and five European countries (France, Germany, Italy, Spain, and the UK) was conducted by an independent market research company, Forbes Consulting Group, on behalf of Schering-Plough. The survey, which focused on patients' attitudes toward allergy suffering and approaches to allergy treatment, was administered by an online panel of people with allergy (adults and children). Respondents reporting both nasal and sinus congestion had the highest number of 'suffering days' per year across all countries19. The symptoms of AR display a circadian rhythm, increasing during the night and peaking in the early morning hours19"21. Fatigue and irritability, the most common morning complaints in this survey, reported by 31-59% and 26-58% of individuals, respectively, depending on the country19, may be a consequence of subjects' disturbed sleep during the previous night.
The major symptoms of rhinosinusitis and nasal polyposis include congestion/obstruction, nasal discharge or postnasal drip, facial pain/pressure, and, especially in individuals with nasal polyps, reduction or loss of sense of smell10'22. As in AR, congestion/ obstruction, including both nasal and sinus congestion, is typically the most problematic symptom22'23. For individuals with acute rhinosinusitis (ARS), symptoms generally last for up to 4 weeks, although recent information suggests they can persist (continuously or intermittently) for up to 12 weeks22. The most common causes of ARS are viral infection or allergic reaction, both of which induce an inflammatory response, leading to obstruction of the sinus ostia, retention of secretions, and bacterial invasion; these, in turn, produce the signs and symptoms characteristic of ARS and will have an effect on sleep24. Sleep impairment in AR, rhinosinusitis, and nasal polyposis
Allergic rhinitis adversely affects sleep25 in children26, adolescents17, and adults19. Children with AR are three times more likely to have disturbed sleep than unaffected children27. In the survey of allergy sufferers in the United States and five European countries, among the large proportion of patients who reported trouble falling asleep or getting enough sleep, up to 79% reported the problem as disruptive19. Both sleep-disordered breathing (snoring, sleep apnea, and/or hypopnea) and 'microarousals', which are brief awakenings that occur many times during the night, but of which patients are unaware, have been associated with AR; they are reviewed in Table 227'3'. These sleep disturbances may be the cause of daytime fatigue in AR patients. Sleep-disordered breathing in children, particularly snoring, is associated with an increased risk of obstructive sleep apnea syndrome32. In fact, nasal obstruction associated with AR and adenoidal hypertrophy causes children to breathe through their mouth and to snore while sleeping32. In a study involving children with snoring problems, McColley et al. found that 36% were sensitized to allergens, which is about three times higher than expected for the general pediatrie population. The frequency of obstructive sleep apnea in these subjects was about 50% greater than in the nonatopic group of children who snored. The authors reported an increased frequency of obstructive sleep apnea in children with AR and suggested an association between snoring and allergy32.
Patients with rhinosinusitis23'33 and nasal polyposis5 also experience sleep disturbances and fatigue. A recent study conducted in France found that the risk of sleep disturbance was more than doubled in patients with nasal polyposis compared with controls, and snoring was reported by a significantly greater proportion of people with nasal polyposis than by those without the condition34.
Table 2. Sleep disturbances associated with allergic rhinitis, rhinosinusitis, and/or nasal polyposis
The effects of sleep impairment
Sleep disturbances from AR, rhinosinusitis, and nasal polyposis can adversely affect cognitive function, daytime alertness, work or school performance, emotion, mood, and social interactions35'39. Daytime fatigue, difficulty concentrating, and decreased psychomotor performance are all commonly reported by individuals with AR37'39'40. Children with AR suffer from reduced learning ability and poor performance at school, compared with healthy children41'42. Adolescents with AR report difficulties getting a good night's sleep and problems doing their school work17, and children with snoring have poorer school performance than controls43. Sleep-disordered breathing (especially habitual snoring) in children has been associated with hyperactive and inattentive behavior similar to that seen in attention-deficit hyperactivity disorder27'44. The sleep disturbances seen in adult patients with seasonal AR (SAR) and perennial AR (PAR) have also been associated with reduced psychological well-being45.
Causes of sleep impairment
Is congestion the key factor in sleep impairment?
Congestion has been reported to be a significant factor in the sleep impairment and daytime fatigue associated with AR, rhinosinusitis, and nasal polyposis46"48. Nasal congestion (or nasal airway resistance) tends to increase when an individual lays down49. In addition, the normal circadian rhythm increases congestion during the late night and early morning2021. The combination of worsened congestion at night and increased congestion in the recumbent position may be additive, further aggravating sleep problems.
In the large Internet survey of more than 2000 individuals with AR mentioned earlier, approximately half of the respondents reported that nasal congestion woke them up during the night or made it difficult for them to fall asleep16. The adverse effects on sleep were greater among those with severe congestion than in those with mild or moderate congestion. Congestion was the symptom that adults (50%) and caregivers of children (65%) wanted most to prevent, and that was most likely to trigger a visit to a physician (54% and 69%, respectively)16 (Figure 1).
More objective studies have also demonstrated that the congestion associated with rhinitis and other upper respiratory tract disorders may lead to the onset or worsening of sleep disturbances, including obstructive sleep apnea50 and that congestion is a risk factor for habitual snoring1'5'. Indeed, allergic patients with congestion are almost twice as likely to have moderateto-severe sleep-disordered breathing as those without congestion1. Rhinorrhea and, to lesser degrees, pruritus and sneezing, can also interfere with sleep46'48'52.
The suggestion that congestion is largely responsible for the disturbed sleep and daytime sleepiness associated with AR is further supported by data from treatment studies that have shown that relief of congestion reduces these problems5354. Indeed, it has been suggested that physicians should consider evaluation and treatment of this symptom for all patients diagnosed with a sleepdisordered breathing condition55.
Immune response mediators
Inflammatory mediators (specifically, histamine and cytokines) released during allergic reactions may have a role in the sleep impairment associated with AR, rhinosinusitis, and nasal polyposis. Brain histamine is associated with regulation of the sleep-wake cycle56. Increased levels of proinflammatory cytokines have been linked in polysomnography studies to an increased time to onset of rapid eye movement (REM) sleep and a shorter time in REM sleep57. These findings suggest that the mediators may directly effect the central nervous system, where the sleep-wake cycle is regulated, and could contribute to disturbed sleep and feelings of fatigue or sleepiness during the day56" 58. As with the symptoms of congestion, the levels of these inflammatory mediators peak during the early morning hours, which could explain the greater sleep disturbances during this period and the higher level of AR symptoms upon awakening2859. Treatments that reduce the nocturnal release or activity of inflammatory mediators may decrease central nervous system effects on sleep and, in turn, diminish the associated sleep impairment.
Figure 1. Effects of nasal congestion on sleep in allergic rhinitis'6. Results are expressed as a proportion of all survey respondents. Data were collected in response to the question: 'In what ways, if any, has the nasal congestion affected you/ your child during the night?'
Effects of therapy
Medication choices for patients with AR, such as second- generation or nonsedating antihistamines, intranasal ipratropium bromide, and INSs, have all been shown to improve health-related quality of life60, but they are not equally effective in reducing congestion and sleep impairment; indeed, some may even have adverse effects on sleep.
Nonsedating oral antihistamines (e.g. cetirizine, desloratadine, fexofenadine, levocetirizine, and loratadine) are widely used to treat AR, and effectively relieve nasal symptoms such as rhinorrhea, sneezing, and pruritus61. They are generally less effective in relieving congestion, although recent studies have shown some efficacy in reduction of congestion62"65. They are sometimes administered in combination with a decongestant for additional congestion relief8. Intranasal or oral decongestants can effectively reduce congestion, but may have adverse effects on sleep as a result of their stimulatory effects, and are also associated with systemic side effects, such as tachycardia and urinary retention61. Intranasal decongestants should not be used for prolonged periods because of the risk of developing rebound congestion (rhinitis medicamentosa)61. Antihistamine nasal sprays, such as azelastine, can reduce congestion in patients with rhinitis66, and recent studies have shown that this reduction is accompanied by improvements in sleep, ability to perform daily activities67, and quality of life68. It has been suggested that the efficacy of antihistamine nasal sprays, including their greater effectiveness in reducing congestion than oral antihistamines, and their rapid onset of effect, are due to their local action at the inflammatory site68'69. Most studies show that antihistamine nasal sprays are not as effective in relieving congestion as corticosteroid nasal sprays; e.g. in one randomized, controlled trial (N = 44), azelastine did not improve symptoms of congestion as well as flunisolide70. However, a recent study noted that the combination of azelastine plus fluticasone nasal spray improved congestion in patients with SAR to a greater extent than the individual therapies71. Antihistamine nasal sprays can also cause daytime drowsiness72.
Intranasal corticosteroids are the primary treatment option for patients with significant nasal congestion6''73'74. They are effective in relieving congestion associated with AR, ARS, and nasal polyposis10'73'75. Mometasone furoate, for example, has demonstrated efficacy in relieving congestion in all three conditions76"82. Mometasone alleviated congestion in patients with SAR81 and PAR80, nasal congestion and obstruction in nasal polyposis82, and was significantly more effective than amoxicillin or placebo in relieving congestion in patients with ARS77. Results from clinical studies have demonstrated that intranasal fluticasone propionate reduces congestion in patients with AR83, chronic rhinosinusitis84, and nasal polyposis8586. Additionally, it has been reported that sinus pain and pressure are reduced in patients with AR during treatment with fluticasone propionate87. Congestion in patients with AR is also reduced by the INS medications budesonide, flunisolide, and triamcinolone acetonide88'91. Intranasal budesonide has been shown to relieve congestion in patients with chronic rhinosinusitis or nasal polyps92'93.
Intranasal corticosteroids also have been used to treat children with enlarged tonsils and adenoids, which cause sleep apnea and disturbed sleep. Demain et al. administered beclomethasone 336 mug a day or placebo for 8 weeks to a small cohort (N = 17) of children with adenoidal hypertrophy and sleep apnea. Investigators found significant reductions in adenoidal hypertrophy and symptoms such as restless sleep and nasal congestion with INS therapy compared with placebo94.
Numerous small studies have indicated that alleviation of congestion with INSs may have beneficial effects on sleep, daytime sleepiness, and quality of life in patients with inflammatory upper respiratory tract disorders (Table 3)27,53,70,82,88,89,95-103 The sleep-related symptoms that elicit the greatest amount of patient complaints are daytime somnolence or sleepiness and fatigue27,52,88,89,95 and, to a slightly lesser extent, difficulty falling and then remaining asleep88'89. Treatment of adults or children with AR with INSs resulted in significant improvements in subjective assessments of sleep, daytime sleepiness, fatigue, and quality of life, compared with placebo or alternative treatments such as azelastine, although not all sleep-related problems were significantly improved in all studies.
Treatment with INSs also improves sleep and quality of life in patients with rhinosinusitis and nasal polyposis. In schoolchildren with symptomatic rhinitis or chronic rhinosinusitis, therapy with intranasal budesonide for at least 3 months reduced symptoms, improved performance at school and concentration, and decreased the number of sleepless nights (p
Table 3. Clinical studies of the effects of intranasal corticostiroids on sleep and/or quality of life in patients with allergic rhinitis, rhinosinusitis, and nasal polyposis
Table 3. Clinical studies of the effects of intranasal corticostiroids on sleep and/or quality of life in patients with allergic rhinitis, rhinosinusitis, and nasal polyposis
Intranasal corticosteroids are not associated with adverse effects on sleep, such as those observed with decongestants. Further, INSs are safe and well tolerated and, when used properly, exert their beneficiai effects without significant systemic effects104. The mild side effect profile of the INSs is related to intranasal administration placing the drug at the site of inflammation, thereby allowing therapeutic concentrations to be achieved in the nose. In addition, most of the INS is swallowed and undergoes first-pass metabolism in the liver without entering the systemic circulation73. When administered at recommended doses, INSs appear to have a negligible effect on the hypothalamic pituitary adrenal (HPA) axis of children or adults75,76,105,106. Clinical studies have assessed the potential effect of the INSs on HPA axis function using measurements such as knemometry107 (a sensitive noninvasive measure for evaluating lower leg growth), blood and urinary cortisol levels108, cosyntropin stimulation testing109, and stadiometry"0. Most studies concluded that INSs did not affect HPA axis function or have any impact on the rate of growth in children. In one of the few exceptions, lower leg growth velocity as measured by knemometry in children (n = 11) treated with budesonide (given at a high dose of 200 [mu]g BID) was significantly slower after 6 weeks than during a pretreatment run-in period (p
Long-term studies in children with AR have shown that mometasone furoate and fluticasone propionate do not adversely affect growth velocity109. Moreover, the INSs have been shown in long-term clinical studies not to cause nasal atrophy, and mometasone and fluticasone have been found to restore nasal mucosa to normal114"118.
Many people with inflammatory disorders of the upper airways do not see a physician, choosing instead to treat themselves with over- the-counter (OTC) products119'120 such as isotonic/hypertonic saline as a nasal douche; sedating antihistamines such as diphenhydramine, brompheniramine, and chlorpheniramine; and decongestants. The most common oral decongestants vary in efficacy; pseudoephedrine and phenylpropanolamine are effective, but phenylephrine undergoes first- pass metabolism, rendering it considerably less effective at currently recommended doses. Because pseudoephedrine is no longer available as an OTC product, people seeking relief may opt for the less appropriate phenylephrine121. It is important to determine whether patients are using those products or herbal preparations to treat their symptoms, because they may adversely affect sleep.
The anticholinergic agent ipratropium bromide improves rhinorrhea, but usually does not relieve congestion61. Nevertheless, there is some evidence that sleep and quality of life improve during treatment with ipratropium bromide in patients with AR97. A few studies in patients with AR or sleep-disordered breathing have shown an improvement in sleep and quality of life following therapy with a leukotriene receptor antagonist122'123 or a combination of an antihistamine and a leukotriene receptor antagonist124. However, leukotriene receptor antagonists alone or in combination with antihistamines are not as effective as INSs in reducing congestion or improving quality of life in AR patients125'126.
Surgical treatment can improve congestion and quality of life in patients with nasal polyposis127'128 or chronic rhinosinusitis10129. However, nasal polyps tend to recur, and surgery is indicated for chronic rhinosinusitis/nasal polyposis only when conservative, medical treatment, such as INS administration, has failed.
Several limitations of this review should be acknowledged. First, randomized, placebo-controlled, blinded clinical trials comparing the effectiveness in reducing sleep disturbances of the drugs for the three upper respiratory diseases have not been conducted. Comparisons across different classes of drugs (e.g. antihistamines versus INSs) in improving congestion have been reported, but the efficacy of the different INSs in reducing sleep disturbances has not been compared.
second, the Roper survey cited above has some inherent limitations. Only people with nasal congestion could participate, people with more troublesome symptoms may have been more motivated to respond, and the survey was limited to people with Internet access. Consequently, people with symptoms (e.g. rhinorrhea, itching) that were more severe than congestion may have been excluded from the survey. Finally, AR was self-reported and not confirmed by a physician's diagnosis, so the survey may have included people with rhinitis that did not derive from an allergic reaction16.
Allergic rhinitis has a significant adverse impact on patients' lives through sleep impairment. Effectively treating congestion, which is associated with sleep disturbances, could be the key to reducing needless patient suffering. Intranasal corticosteroids are the most efficacious treatments for nasal congestion. Moreover, data on sleep-related endpoints from clinical trials with INSs indicate that alleviation of congestion is associated with a trend toward improved sleep, reduced daytime fatigue, and improved quality of life. The effectiveness of INSs in relieving sleep impairment and improving quality of life in AR, rhinosinusitis, and nasal polyposis needs to be confirmed in further studies. The use of INSs could help to ensure optimal management of all aspects of these bothersome conditions.
Declaration of interest: This study was funded by the Schering- Plough Corporation. None of the authors received any payment for this manuscript. Editorial support in the preparation of this manuscript was provided by Gardiner Caldwell-London and Adelphi Eden Health Communications.
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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com
Paper CMRO-3879_4, Accepted for publication: 29 June 2007
Published Online: 30 July 2007
William Storms(a), Barbara Yawn(b) and Leonard Fromer(c)
a The William Storms Allergy Clinic, Colorado Springs, CO, USA
b Department of Primary Care Research, Olmsted Medical Center, Rochester, MN, USA
c David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Address for correspondence: Leonard Fromer, David Geffen School of Medicine at UCLA, 15525 Hamner Drive, Los Angeles, CA 90077, USA. Tel.: +1 310 383 8168; Fax: +1 310 471 5392; [email protected]
Copyright Librapharm Sep 2007
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