Somnolence,and Fatigue

Patients with allergic rhinitis, one of several inflammatory disorders of the upper respiratory tract, often suffer from impaired sleep. A recent survey of allergic rhinitis patients revealed that 68% of respondents with perennial allergic rhinitis and 48% with seasonal allergic rhinitis reported that their condition causes significant sleep disturbances. One of the major symptoms of the disorder, nasal congestion, in addition to such underlying disease processes as the release of inflammatory mediators, can cause the sleep impairment associated with allergic rhinitis.

The symptoms of allergic rhinitis include rhinorrhea, sneezing, pruritus of the eyes, nose, and throat, and nasal congestion. Nasal congestion stands as one of the most prominent and bothersome symptoms of the disorder, especially because it is linked to sleep-related problems associated with allergic rhinitis, such as sleep-disordered breathing, sleep apnea, and snoring.

The prevalence of inflammatory disorders of the upper respiratory tract make the sleep impairment associated with many of these disorders a common problem. Allergic rhinitis alone reportedly affects approximately 25% of the world’s population, and its prevalence has continued to climb. It has been estimated that the disorder affects 20 to 40 million people in the United States, which includes approximately 40% of the nation’s children. In Europe, the prevalence of allergic rhinitis is estimated as 23%.

Those who suffer from allergic rhinitis often cannot escape the socioeconomic burdens associated with living with the disorder. In 2000, patients spent over $6 billion on prescription medications for allergic rhinitis. Along with this overwhelming cost of treatment, patients must face the secondary cost of poor productivity, which stems from the negative impact of the disorder’s symptoms on patients’ lives, as well as the use of inappropriate therapies. The detrimental effect of allergic rhinitis on patients’ quality of life has been demonstrated by generic health-related quality of life questionnaires, such as the Medical Outcomes Study Short Form Health Survey (SF-36), and disease-specific measures, such as the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). This adverse impact on patients may result from the sleep impairment associated with the disorder. Although studies have shown that treatments for allergic rhinitis, particularly those that improve symptoms of nasal congestion, can improve patients’ sleep and quality of life, further research is needed to elaborate this limited existing data. This chapter explores the sleep impairment associated with allergic rhinitis and the adverse effects of disturbed sleep on patients’ quality of life. This chapter also examines how these effects are impacted by therapies that target the disorder’s underlying problems influencing sleep.

Evidence for sleep impairment in allergic rhinitis

Allergic rhinitis and other inflammatory disorders of the upper respiratory tract are generally associated with sleep impairment, daytime somnolence, and fatigue. Of the multiple symptoms of allergic rhinitis, nasal congestion, in particular, detrimentally affects sleep. The Allergic Rhinitis and its Impact on Asthma guidelines (Table Allergic rhinitis severity guidelines for the classification of allergic rhinitis.) serve to classify allergic rhinitis severity and provide a measure for this degree of sleep impairment. The sleep disturbances allergic rhinitis patients suffer from include microarousals and sleep-disordered breathing, which includes snoring to obstructive sleep apnea and/or hypopnea. Chronic excessive daytime sleepiness or fatigue has been demonstrated as more likely disturbances in patients with frequent nighttime symptoms than in those with rare or no such symptoms. Further examples illustrating that sleep impairment stands as a major concern for allergic rhinitis patients include a study showing that allergic rhinitis leads to snoring in children, and another study demonstrating that concomitant allergic rhinitis independently relates to difficulty sleeping and daytime sleepiness in bronchial asthma patients.

Table. Allergic rhinitis severity guidelines for the classification of allergic rhinitis.

Mechanisms of sleep impairment

Sleep impairment and quality of life

The Effects of Sleep Impairment

Patients with allergic rhinitis often must face adverse consequences of sleep disturbances, such as impaired cognitive function and decreased productivity and performance in the workplace. In children with allergic rhinitis, learning ability and school performance are afflicted.

Table. List of mediators contributing to daytime somnolence and fatigue (allergic rhinitis vs. severe sleep apnea).

Although symptoms of the disorder may lead to these consequences, the sleep impairment caused by allergic rhinitis is the likely cause of aggravation. Sleep-disordered breathing and sleep impairment have been known to correlate with decreased quality of life in the general population. Specifically, experimentally induced sleep fragmentation in healthy subjects leads to impaired mental flexibility and attention, increased daytime fatigue, and impaired mood. Children and adolescents with allergic rhinitis also suffer from impaired sleep, which results in problems doing schoolwork and poor school performance, compared to controls.

A survey across five European countries using patients suffering from allergic rhinitis or urticaria showed that a considerable proportion of respondents reported snoring or poor sleep and not feeling rested in the morning. Of these respondents, 29% to 79%, and 28% to 56%, respectively, depending on the country, considered these problems either disruptive or extremely disruptive. Results from an Internet survey of 1322 individuals with rhinitis showed that both perennial and seasonal rhinitis interfered with sleep (68% and 51% of respondents, respectively) and daily routine (58% and 48%, respectively). Additionally, the sleep impairment suffered by allergic rhinitis patients has been linked to reduced psychological well-being, daytime fatigue, difficulty concentrating, and impaired psychomotor performance.

Measuring sleep impairment and impact on quality of life

Effects of therapy

Conclusion

The quality of life in patients with allergic rhinitis is detrimentally impacted by the sleep impairment associated with the disorder. One of the key causes leading to sleep disruptions and sleep-disordered breathing is nasal congestion, one of the most common and bothersome symptoms of allergic rhinitis. Recent research has led to the use of therapeutic agents that specifically target the nasal congestion associated with sleep impairment.

Intranasal corticosteroids stand as effective treatment that significantly reduces nasal congestion in allergic rhinitis. Clinical trials using this treatment suggest that this reduction in nasal congestion correlates with decreased sleep impairment, reduced daytime somnolence, and improved quality of life.

Further research is necessary to conclude definitively that intranasal corticosteroids hold the ability to improve sleep and quality of life in patients with allergic rhinitis. These studies should use sleep-related measures as primary endpoints and assess sleep parameters both subjectively and objectively, thus serving to identify the most effective therapies for alleviating the detrimental effects of sleep impairment associated with allergic rhinitis.

Evidence-based medicine

The hypothesis is that sleep and the consequences of poor sleep has been supported primarily by subjective assessments in studies where sleep-related outcomes stood as secondary endpoints. No controlled study has shown definitively that the reduction of nasal congestion, as measured by an objective instrument, correlates with improvement in daytime somnolence and fatigue or objective sleep measures. Despite this deficiency, a direct correlation between subjective improvement of congestion and sleep has been demonstrated. However, placebo-controlled, double-blinded, large randomized clinical trials that subjectively and objectively assess the outcomes of intranasal corticosteroid use on allergic rhinitis with impaired sleep, productivity, and daytime somnolence are needed.

To alleviate the symptom of sleep impairment in patients with allergic rhinitis, the mechanisms involved in this problematic issue must first be identified. Recent studies have proposed that the reduced sleep quality and daytime fatigue characteristic in allergic rhinitis patients may consequently arise from sleep impairment secondary to symptoms of the disorder, particularly nasal congestion, or to the effects of the disorder itself, such as the underlying pathophysiologic changes associated with allergic rhinitis leading to the release of cytokines and other inflammatory mediators.

Nasal Congestion

Nasal congestion, which results when the cavernous tissues of the nasal turbinates swell following dilation of the capacitance vessels, is a common and bothersome symptom that affects numerous allergic rhinitis patients. Its mechanism involves the reduction in the internal nasal diameter and the increase in airway resistance to nasal airflow, and the symptom can also cause nasal obstruction. Subjective clinical assessments of nasal congestion severity exist, as well as objective measures of nasal airflow, such as peak nasal inspiratory flow, assessments of airway resistance and conductance (rhinomanometry), and acoustic rhinometry, which assesses the volume and area of the nasal cavity by analyzing reflected sound waves.

The symptom of nasal congestion worsens at night and first thing in the morning, peaking at 6 AM, presumptively due to the posture change when an individual first lies down and to the normal decrease in serum cortisol levels overnight. The lower cortisol levels lead to greater nocturnal airway obstruction and may partially explain the large-amplitude circadian variation. These changes and others noted in Table Changes in early morning that may account for the circadian variation seen in allergic rhinitis may serve to explain why patients with inflammatory nasal conditions and nasal congestion often suffer from sleep impairment and daytime fatigue.

Results from an Internet survey of 2355 individuals with allergic rhinitis or the parents of children with allergic rhinitis further reinforced the complaints of those suffering from the disorder. Eighty-five percent of the respondents or their children reported experiencing nasal congestion, and 40% of all respondents, the greatest proportion of participants who rated the severity of various symptoms, considered their nasal congestion severe.

Approximately 50% of the respondents reported that nasal congestion was their most bothersome symptom and that it woke them during the night and made it difficult to fall asleep. Twenty percent of adult respondents claimed that their bed partner’s sleep was adversely affected by their nasal congestion, and the degree of sleep impairment correlated with the severity of their congestion. Moreover, the survey revealed that nasal congestion negatively impacted the individuals’ or their children‘s emotions and ability to perform daily activities, all of which may result from the detrimental effects of nasal congestion on sleep.

Table. Changes in early morning that may account for the circadian variation seen in allergic rhinitis.

Studies on treatments for the nasal congestion associated with allergic rhinitis, such as one by Craig et al. on treatment with topical nasal corticosteroids, propose that the poor sleep and daytime somnolence characteristic of the disorder is predominantly attributed to the symptom of nasal congestion. Increased sleep apnea and transient arousals even occur when subjecting healthy individuals to nasal occlusion with a nose clip. Previous studies that objectively assessed the sleep patterns of allergic rhinitis patients demonstrated that their symptoms of nasal congestion led to increased microarousals and episodes of apnea at night. Subjective instruments, such as Juniper’s Nocturnal Rhinoconjunctivitis Quality of Life Questionnaire (NRQLQ), correlate with the objective findings noted on polysomnography Allergic rhinoconjunctivitis patients who complained of impaired sleep due to nighttime symptoms found nasal and sinus congestion to be among their most bothersome and troublesome symptoms.

A population-based study on the role of acute and chronic nasal congestion in sleep-disordered breathing, which used 4927 subjects with a history of nasal congestion and impaired sleep, showed that patients with frequent nocturnal rhinitis symptoms, compared to those with rare or no symptoms, were more likely to complain of habitual snoring, chronic nonrestorative sleep, and excessive daytime fatigue. Additionally, the study illustrated that subjects with allergic rhinitis — associated nasal congestion were 1.8 times more likely to suffer from moderate-to-severe sleep-disordered breathing, compared to subjects with allergic rhinitis and no reported nasal congestion. Rhinitis and other forms of nasal obstruction must be considered and treated in patients with primary sleep-associated breathing disorders as an adjunct to surgical and nonsurgical treatment. Topical nasal steroids may enhance compliance and effectiveness of continuous positive airway pressure especially, but not limited, to those patients with allergic rhinitis.

Immune Response Mediators

Histamine and cytokines are examples of inflammatory mediators released in the process of an allergic reaction, and such mediators may directly influence the central nervous system and result in the disturbed sleep daytime somnolence characteristic of allergic rhinitis. Histamine helps regulate the sleep-wake cycle and arousal; the higher levels of the cytokines interleukin (IL)-1(3, IL-4, and IL-10 seen in patients with allergies, compared with healthy individuals, correlate with increased latency to rapid eye movement sleep, decreased time in rapid eye movement sleep, and decreased latency to sleep onset. It is postulated that any such disruptions in rapid eye movement sleep may cause daytime fatigue, difficulty concentrating, and poor performance in allergic rhinitis patients. Inflammatory cells and mediators exhibit evident circadian variation, with its highest levels in the early morning hours, thus possibly explaining why the peak of allergic rhinitis symptoms frequently occurs upon waking and why nighttime sleep is detrimentally affected in the disorder. In addition, TNF, IL-1 and IL-6 are cytokines increased in allergic rhinitis and may cause fatigue and other nonspecific generalized symptoms typical of a flulike condition.

Studies on the subjective and objective measurements of sleep impairment and its influence on patients’ quality of life particularly emphasize the major impact of this problem in patients with such inflammatory nasal conditions as allergic rhinitis. In patients with this disorder, the majority of studies have used subjective measures, such as questionnaires or daily scoring of symptoms, sleep problems, daytime somnolence, and fatigue. Juniper’s Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) uses quality of life measures that are disease specific and includes a domain that assesses the effects of disease and/or treatment on patients’ sleep. Such questionnaires emphasize the problems and symptoms patients commonly complain of and seek help for and are thus more sensitive to alterations in patients’ quality of life than generic health-status questionnaires. The Nocturnal Rhinoconjunctivitis Quality of Life Questionnaire (NRQLQ) focuses on the functional impairments of patients with nighttime symptoms and assesses problems and symptoms during sleep time, as well as upon waking hours. The Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, Calgary Sleep Apnea Quality of Life Index, and the University of Pennsylvania Functional Outcomes of Sleep Questionnaire serve as general questionnaires that examine quality of sleep and daytime somnolence. However, the latter four questionnaires may be inadequate in their analysis of the mild-to-moderate sleep impairment characteristic of allergic rhinitis because they have less sensitivity.

Studies on allergic rhinitis that objectively assess sleep by using polysomnography are small in number. One such study observed 25 patients with seasonal allergic rhinitis and 25 healthy volunteers, all of whom underwent two consecutive nights of polysomnography before and during the pollen season, and results showed statistically significant differences between the two groups in sleep parameters, which included increases in the apnea index (number of apneas per hour), hypopnea index (number of hypopneas per hour), apnea-hypopnea index, snoring time, amount of rapid eye movement sleep, and sleep latency. However, parameter values fell within normal limits, preventing the changes from showing clinical relevance. Statistical significance was also reported in daytime sleepiness, which was subjectively measured using the Epworth Sleepiness Scale, in seasonal allergic rhinitis patients compared to healthy subjects. These results thus point toward a weak correlation between subjective and objective measures of sleep impairment.

Table. Disease-specific quality of life questionnaires and general measures of sleep quality.

Treatments aimed at reducing nasal congestion may alleviate sleep disturbances and daytime somnolence and consequently improve the quality of life in those who suffer from allergic rhinitis. However, the multiple treatments for the disorder vary in their efficacies.

Sedating antihistamines are contraindicated in patients who complain of daytime sedation, fatigue, and functional impairment; such treatment is also not recommended for most patients with allergic rhinitis. Common treatment for allergic rhinitis includes nonse-dating oral antihistamines, which alleviate nasal symptoms such as rhinorrhea, sneezing, and pruritus but may be less effective in reducing nasal congestion. Two studies by Murray et al. and Golden et al. suggest that treatment using oral or topical antihistamines result in improved sleep and quality of life. Oral decongestants are successful in improving nasal congestion but may impact sleep detrimentally because of their stimulatory effects and, additionally, may result in systemic side effects, such as tachycardia and urinary retention. Topical decongestants improve sleep in patients with nasal obstruction but should not be used for more than a few days, due to the risk of rhinitis medicamentosa, or “rebound” congestion. Data, although very limited, show that the anticholinergic agent ipratropium bromide may improve sleep and quality of life. However, ipratropium bromide appears to be unsuccessful in the relief of nasal congestion. Studies have shown that either leukotriene receptor antagonists as monotherapy or in combination with an antihistamine effectively improves sleep and quality of life in allergic rhinitis patients and in those who suffer from sleep-disordered breathing. Intranasal corticosteroids alleviate congestion and other nasal symptoms of allergic rhinitis and are used as first-line therapy when nasal obstruction is a predominant symptom in patients.

The Role of Intranasal Corticosteroids

Intranasal corticosteroids have been shown to relieve all the nasal symptoms of allergic rhinitis effectively including congestion. The effectiveness of intranasal corticosteroids in relieving nasal congestion may have a positive impact on sleep, daytime somnolence, and quality of life in patients who suffer from allergic rhinitis. Studies on adults and children with perennial allergic rhinitis support the hypothesis that intranasal corticosteroids decrease nasal congestion and subjective daytime sleepiness and fatigue, and improve sleep and quality of life. Further studies displayed efficacy in the improvement of nasal symptoms and quality of life, as well as verbal memory. Treatment was also proven to alleviate allergic rhinitis associated with Obstructive Sleep Apnea Syndrome (OSAS) and consequently to lead to both significantly lower frequencies of apnea/hypopnea episodes and subjective improvements in nasal congestion and daytime alertness, although snoring noise was unchanged.

Studies in allergic rhinitis patients using the RQLQ, NRQLQ, and the Pittsburgh Sleep Quality Index revealed that intranasal corticosteroid improves both nasal congestion and health-related quality of life, including sleep. These studies therefore support the notion that treatments focusing on the nasal symptoms of allergic rhinitis may reduce sleep impairment and improve patients’ quality of life.

Seasonal allergic rhinitis (hay fever) affects 10-15% of people in the UK, and millions of patients rely on OTC medicines for treatment. The symptoms of allergic rhinitis occur after an inflammatory response involving the release of histamine, which is initiated by allergens being deposited on the nasal mucosa. Allergens responsible for seasonal allergic rhinitis include grass pollens, tree pollens and fungal mould spores. Perennial allergic rhinitis occurs when symptoms are present all year round and is commonly caused by the house dust mite, animal dander and feathers. Some patients may suffer from perennial rhinitis, which becomes worse in the summer months.

Age

Symptoms of allergic rhinitis may start at any age, although its onset is more common in children and young adults (the condition is most common in those in their twenties and thirties). There is frequently a family history of atopy in allergic rhinitis sufferers. Thus, children of allergic rhinitis sufferers are more likely to have the condition. The condition often improves or resolves as the child gets older. The age of the patient must be taken into account if any medication is to be recommended. Young adults who may be taking examinations should be borne in mind, because treatment that may cause drowsiness is best avoided in these patients.

Duration

Sufferers will often present with seasonal rhinitis as soon as the pollen count becomes high. Symptoms may start in April when tree pollens appear and the hay fever season may start 1 month earlier in the south than in the north of England. Hay fever peaks between the months of May and July, when grass pollen levels are highest and spells of good weather commonly cause patients to seek the pharmacist’s advice. Anyone presenting with a summer cold, perhaps of several weeks’ duration, may be suffering from hay fever. Fungal spores are also a cause and are present slightly later, often until September.

People can suffer from what they think are mild cold symptoms for a long period, without knowing they have perennial rhinitis.

A useful classification of allergic rhinitis is:

Intermittent. Occurs less than 4 days/week or for less than 4 weeks

Persistent. Occurs more than 4 days/week and for more than 4 weeks

Mild. All of the following – normal sleep; normal daily activities, sport, leisure; normal work and school; symptoms not troublesome

Moderate. One or more of the following – abnormal sleep; impairment of daily activities, sport, leisure; problems caused at work or school; troublesome symptoms

Homeopathy is a form of traditional medicine that has been used for more than 150 years and is growing in popularity throughout the world. Despite their widespread use over many years, there have been few extensive clinical studies to assess the clinical benefits of traditional homeopathic therapies. Homeopathic drugs consist of mixtures of natural extracts that have a pharmacologic effect that mimics the illness they are intended to treat. For example, a homeopathic treatment for fever would contain extracts that in high concentrations would induce fever. However, when used in homeopathic preparations, these extracts are very highly diluted, almost to the point where none of the original extract remains – only the “imprint” of the extract. These dilutions are believed to combat selected illnesses while being essentially devoid of side effects.

Just how effective homeopathic preparations are is the subject of extensive debate. In one meta-analysis of published clinical studies of homeopathic medicines, a trend indicating greater effectiveness than placebo was observed, but this analysis was limited by a variety of study design constraints.

Several homeopathic combinations are available over the counter for the management of allergic conditions. In an attempt to determine the effectiveness of one such product, James DeMasi and colleagues treated patients affected by seasonal allergic rhinitis with a homeopathic product containing red onion, eye bright, and nux vomica, among other ingredients. All of these materials were identified in the Homeopathic Pharmacopoeia as being appropriate for the treatment of allergies. Patients were treated for one week (according to the instructions on the product label). After a washout period, they received a control homeopathic preparation that was designed to treat gastrointestinal hyperacidity rather than allergy.

Seven patients were evaluated in the study. The results indicated that symptoms of allergy, based on a daily history kept by the patients, remained constant throughout the study (symptom scores of 22.8 at baseline, 22.0 after the “active” treatment, and 21.8 after the “control” treatment). Pollen counts were performed during the study and did not vary enough to affect the results.

The daily history kept by each patient also provided information about gastrointestinal symptoms. The investigators thought that if homeopathic agents really did mimic underlying diseases, some patients would have noted an increase in gastric symptoms after their use. However, this was not observed.

Dr. DeMasi was prompt to acknowledge that this study was very preliminary and that the results should be interpreted cautiously. Most important, the study was very small, with only seven patients being evaluated. Furthermore, the combination of natural extracts may not have been the most effective mixture available. He also noted that the medications were very well tolerated by the patients, with no significant adverse events being observed during the study.

He encouraged other researchers to continue his investigation using larger study groups and, perhaps, other types of homeopathic treatments.