1. Treatment of Sleep Associate disturbance in Allergy Diseases
Timothy J. Craig
Professor of Medicine and Pediatrics
Distinguished Educator
Penn State University

2. Presentation Overview
Allergic Rhinitis and Sleep Disturbance
Mechanisms of Sleep Disturbance in Allergic Rhinitis
Impact of AR-associated Sleep Disturbances
Effects of Allergic Rhinitis Therapies on Sleep and Quality of Life

3. conflicts of interest with this presentation
Merck- speaker, researcher, consultant
Astra-Zeneca- speaker
Teva- speaker
GSK- researcher

4. Allergic Rhinitis Adversely Impacts Sleep in Adults and Children/Adolescents
N=476 Adults/Adolescents/ Children with AR
N=221 Adolescents/ Children with AR
Patients with Moderate or Severe Impact (%)
Patients with Impact (%)
School/ Work Performance
Sleep
Daily Activities
School/ Work Performance
Normal Activities
Lifestyle
Sleep
O’Connor and Punekar. J Allergy Clin Immunol. 2006;117:S322. Abstract 1244.
Scadding and Punekar. EAACI Abstract Book. 2006;211. Abstract 741.

5. Allergic Rhinitis Symptoms are Associated with Sleep Complaints
Prevalence of Sleep Complaints in Patients with Allergic Rhinitis and Controls
Subjects with complaint (%)
Difficulty Falling Asleep
Nocturnal Awakening
Early Awakening
Nonrestorative Sleep
Feeling of Lack of Sleep
Snoring
ESS score >10 * * * * * * *
*P<0.001 vs controls.
Leger et al. Arch Intern Med. 2006;166:1744.

6. Allergic Rhinitis (AR) Symptoms are Associated with Sleep Disorders
Prevalence of Sleep Disorders in Patients with Allergic Rhinitis and Controls
Subjects with disorder (%)
Insomnia
Severe Insomnia
Sleep Apnea Syndrome
Hypersomnia *
7.6 fold increase of OSA in AR
*P≤0.003 vs controls.
Leger et al. Arch Intern Med. 2006;166:1744.

7. Allergic Patients Experience More Apnea/Hypopnea than Non-allergic Controls
Allergic patients had more apnea/hypopnea episodes than non-allergic controls
P<0.001
AHI=apnea/hypopnea index, determined as the total number of apnea and hypopnea episodes (assessed by polysomnography) divided by hours of sleep.
Stuck et al. J Allergy Clin Immunol. 2004;113:663.

8. Allergic Rhinitis is Associated with Increased Microarousals
Patients with rhinitis had 10 times more microarousals (average of 50) than controls (n=14)
Lavie et al. Acta Otolaryngol. 1981;92;529.

9. Microarousals in Allergic Rhinitis Correlate with Impaired Breathing
Microarousals Correlate with Impaired Breathing
Lavie et al. Acta Otolaryngol. 1981;92;529.

12. Similarities between the two
Obese man with severe OAS
Increase in IL-1
Increase in TNF
Increase in Il-6
Increase in T-helper 2 cytokines
Decrease in T-helper 1 cytokines
A young girl snoring and with rhinitis
Increase in IL-1
Increase in TNF
Increase in Il-6
Increase in T-helper 2 cytokines
Decrease in T-helper 1 cytokines

13. What is the Mechanism of Sleep Disturbance in Allergic Rhinitis?
Inflammatory components of the allergic response
Symptoms of allergic rhinitis
Nasal congestion
All three
Answer

14. Impact of Poor Sleep Delayed onset Sleep fragmentation
Impaired Social Functioning:
daytime fatigue/somnolence
Impaired performance
Impaired learning
Emotional/behavioral impact
Delayed onset
Sleep fragmentation
Arousals/microarousals
Sleep Disordered Breathing
Snoring
Obstructive Sleep Apnea
Associated Diseases:
Hypertension
Cardiovascular disease
Stroke
Diabetes
Psychological disorders

15. Treatment Options

16. Treatment Options: Snoring Children

17. The approach to the child with concerns for having OSA

18. The affect of OSA and benefits of T+A on asthma

19. The affect of OSA and benefits of T+A on
poorly controlled asthma

20. Sleep apnea in children treated with topical budesonide nasal spray
Kheirandish-Gozal. Pediatrics 2008

21. Leukotrienes in tonsil tissue in children with sleep apnea (SA) and those with recurrent infection (RI)
LTB-4
LTC-4

22. Adenoid reduction with 16 weeks of montelukast therapy

23. Montelukast affect on sleep in children with sleep apnea compared with those receiving no therapy

24. Treatment Options for Rhinitis Associated With Sleep disordered Breathing

25. Treatment Considerations in Allergic Rhinitis: ARIA Guidelines
Congestion
Rhinorrhea
Itching/
Sneezing
Sleep
Intranasal steroids
Oral antihistamines
Intranasal antihistamines
Oral decongestants
Intranasal decongestants
Intranasal cromones
Anticholinergics
Antileukotrienes
Clinical Efficacy of Various Treatments for Allergic Rhinitis1,2
According to the US Allergy Report, “Corticosteroids are the most effective pharmacologic agents for treating allergic rhinitis.”1
Intranasal steroids are highly effective against all nasal symptoms, including nasal congestion, and have prolonged duration of action (up to 48 hours).
Intranasal steroids exert only local anti-inflammatory effects and are considered safer than their systemic counterparts.
1. The Allergy Report. American Academy of Allergy, Asthma, and Immunology, Inc
2. Van Cauwenberge et al. Allergy. 2000;55:116.
Bousquet et al. Allergy. 2003;58:192. Bousquet et al. Allergy. 2002;57:841. Van Cauwenberge et al. Allergy. 2000;55:116.

26. Intranasal Steroid Therapy in Patients with PAR Improves Sleep*
Change in Symptom Severity vs Baseline † † †
Congestion
Sleep Problems
Daytime Sleepiness
Daytime Fatigue
*Improvement in scores vs baseline was determined using the 0 (none) to 4 (greatly) scoring system in patient questionnaires.
†P≤0.05 vs placebo.
Hughes et al. Allergy. 2003;58:380.

27. Intranasal Steroid Therapy in Patients with PAR Improves Sleep‡
Symptom Score
Congestion*
Improved Sleep†
Improved Daytime Sleepiness†
Improved
Daytime Fatigue†
*Congestion scores were rated on the scale from 0=none to 4=severe.
† Improvement in sleep, daytime sleepiness, and daily fatigue scores vs baseline was determined using the 0 (none) to 4 (greatly) scoring system in patient questionnaires.
Craig et al. Allergy Asthma Proc. 2003;24:53.
‡P=0.04 vs placebo.

28. Intranasal Steroid Therapy in Patients with PAR Improves Congestion and Sleep*† †
Improvement in symptoms
per daily diary over 8 weeks
*Improvement in congestion and sleep vs baseline was determined using the 0 (none) to 4 (greatly) scoring system in patient questionnaires.
†P<0.05 vs placebo.
Craig et al. J Allergy Clin Immunol. 1998;101:633.

29. Intranasal Steroid Therapy Improves Symptoms, Sleep, and Quality of Life in Children with Allergic Rhinitis
Mansfield et al. Ann Allergy Asthma Immunol. 2004;92:240.

30. Intranasal Steroid Therapy Reduces Respiratory Disturbances in Children with Allergic Rhinitis
Mansfield et al. Ann Allergy Asthma Immunol. 2004;92:240.

31. Improvement of Epworth Sleepiness Scale: Budesonide vs Placebo
Difference=–3.85; P=0.02; SD=1.45.

32. Efficacy of Fluticasone Nasal Spray Compared With Placebo on AHI (Number Per Hour)15
Fluticasone
Placebo
Mixed/obstructive apnea/ hypopnea index (number per hour) 10 5
Pretreatment Posttreatment
Mixed/obstructive apnea/hypopnea index decreased from 10.7 ± 2.6 to 5.8 ± 2.2 (SE) in fluticasone group but increased from 10.9 ± 2.3 to 13.1 ± 3.6 in placebo group; P=0.4. AHI=apnea-hypopnea index. Brouillette RT, et al. J Pediatr. 2001;138:

33. MFNS-4 Pooled Phase III Trials in SAR*: Change in Ocular Symptoms
Mean Change in Daily rTOSS
Days
Days
1-15
1-15
Patients with Moderate to Severe Ocular Symptoms at Baseline (TOSS≥4)
All Patients
P<0.001
Mean Change in daily rTOSS from Baseline
Mean Change in daily rTNSS from Baseline
P=0.002
NASONEX® 4 Pooled Phase III Trials in SAR: Change in Ocular Symptoms
Total ocular symptom scores (TOSS) in phase III SAR studies with NASONEX® were evaluated on the 0-9 scale (0-3 scale for each of the 3 ocular symptoms: itching, redness, and tearing/watery eyes).
In the pooled analysis of 4 independent phase III trials of NASONEX® in SAR, the differences in the mean change in daily reflective TOSS from baseline for days 1-15 between the NASONEX® and placebo groups were 0.4 points in all patients (P<0.001) and 0.46 points in patients with moderate to severe ocular symptoms at baseline (TOSS≥4; P=0.002).
In the pooled analysis of 4 independent phase III trials of NASONEX® in SAR, daily reflective TOSS at days 1-15 in all patients were 1.33 points in the NASONEX® group and 0.93 points in the placebo group, whereas the corresponding values in patients with moderate to severe ocular symptoms at baseline (TOSS≥4) were 1.97 and 1.51 points for the NASONEX® and placebo groups.
The magnitude of TOSS benefit with NASONEX® in the pooled analysis of phase III trials in SAR cannot be compared with fluticasone furoate, because no such analyses were reported for fluticasone furoate.
Data on file, Schering Corporation, Kenilworth, NJ. Protocol No. C93-013, C93-184, C94-145, I
MFNS 200 µg OD (n=490)
Placebo (n=492)
MFNS 200 µg OD (n=298)
Placebo (n=307)
*C93013, C93184, C94145, I94001
TOSS=total ocular symptom scores.
Data on file, Schering Corporation, Kenilworth, NJ. Protocol No. C93-013, C93-184, C94-145, I
Submitted for AAAAI 2007 and publication.

34. Fluticasone Propionate: Ocular Effects in Analysis of Pooled Trials in SAR
Physician-Rated Ocular Symptoms at 14 Days*
TOSS
Itching
Tearing
Redness
Puffing
Mean change from baseline (points) †
*Each of the 4 ocular symptoms was rated on a visual analog scale (VAS).
†P<0.001 vs placebo.
DeWester et al. Allergy Asthma Proc. 2003;24:331.

35. Treatment Considerations in Allergic Rhinitis: ARIA Guidelines
Congestion
Rhinorrhea
Itching/
Sneezing
Sleep
Intranasal steroids
+++
++/+++
++++
Oral antihistamines
Intranasal antihistamines
Oral decongestants
Intranasal decongestants
Intranasal cromones
Anticholinergics
Antileukotrienes
Clinical Efficacy of Various Treatments for Allergic Rhinitis1,2
According to the US Allergy Report, “Corticosteroids are the most effective pharmacologic agents for treating allergic rhinitis.”1
Intranasal steroids are highly effective against all nasal symptoms, including nasal congestion, and have prolonged duration of action (up to 48 hours).
Intranasal steroids exert only local anti-inflammatory effects and are considered safer than their systemic counterparts.
1. The Allergy Report. American Academy of Allergy, Asthma, and Immunology, Inc
2. Van Cauwenberge et al. Allergy. 2000;55:116.
Bousquet et al. Allergy. 2003;58:192. Bousquet et al. Allergy. 2002;57:841. Van Cauwenberge et al. Allergy. 2000;55:116.

36. Oral Antihistamines Do Not Improve Sleep Latency and REM Sleep Duration
Sleep Latency Immediately After Treatment
REM Latency and Duration * * *
Time (min)
Sleep Onset Latency (min)
Placebo Fexo Chlor
*P≤0.05 vs placebo and fexofenadine.
N=18 healthy Japanese volunteers.
Boyle et al. Curr Med Res Opin. 2006;22:1343.

37. Desloratadine: Effect on Ocular Symptoms in Patients with SAR
AM/PM Reflective Ocular Symptom Scores (2-Week Average)
Redness of Eyes
Tearing/
Watery Eyes
Itching/
Burning Eyes
Mean change from baseline * * *
Desloratadine 5 mg OD (n=172)
Placebo (n=174)
*P<0.05 vs placebo.
Meltzer et al. Clin Drug Invest. 2001;21:25. Data on File, Schering Corporation.

38. Treatment Considerations in Allergic Rhinitis: ARIA Guidelines
Congestion
Rhinorrhea
Itching/
Sneezing
Sleep
Intranasal steroids
+++
++/+++
++++
Oral antihistamines + ++
+++/++
Intranasal antihistamines
Oral decongestants
Intranasal decongestants
Intranasal cromones
Anticholinergics
Antileukotrienes
Clinical Efficacy of Various Treatments for Allergic Rhinitis1,2
According to the US Allergy Report, “Corticosteroids are the most effective pharmacologic agents for treating allergic rhinitis.”1
Intranasal steroids are highly effective against all nasal symptoms, including nasal congestion, and have prolonged duration of action (up to 48 hours).
Intranasal steroids exert only local anti-inflammatory effects and are considered safer than their systemic counterparts.
1. The Allergy Report. American Academy of Allergy, Asthma, and Immunology, Inc
2. Van Cauwenberge et al. Allergy. 2000;55:116.
Bousquet et al. Allergy. 2003;58:192. Bousquet et al. Allergy. 2002;57:841. Van Cauwenberge et al. Allergy. 2000;55:116.

39. Intranasal Antihistamines: Effect on Congestion and Sleep†
Improvement vs baseline over 8 weeks (score)*
*Improvement was determined using the 0 (none) to 4 (greatly) scoring system in patient questionnaires.
N=24 patients with perennial allergic rhinitis.
†P=0.041
Golden et al. Ann Allergy Asthma Immunol. 2000;85:53.

40. Treatment Considerations in Allergic Rhinitis: ARIA Guidelines
Congestion
Rhinorrhea
Itching/
Sneezing
Sleep
Intranasal steroids
+++
++/+++
++++
Oral antihistamines + ++
+++/++
Intranasal antihistamines
++/++
tiredness
Oral decongestants
Intranasal decongestants
Intranasal cromones
Anticholinergics
Antileukotrienes
Clinical Efficacy of Various Treatments for Allergic Rhinitis1,2
According to the US Allergy Report, “Corticosteroids are the most effective pharmacologic agents for treating allergic rhinitis.”1
Intranasal steroids are highly effective against all nasal symptoms, including nasal congestion, and have prolonged duration of action (up to 48 hours).
Intranasal steroids exert only local anti-inflammatory effects and are considered safer than their systemic counterparts.
1. The Allergy Report. American Academy of Allergy, Asthma, and Immunology, Inc
2. Van Cauwenberge et al. Allergy. 2000;55:116.
Bousquet et al. Allergy. 2003;58:192. Bousquet et al. Allergy. 2002;57:841. Van Cauwenberge et al. Allergy. 2000;55:116.

41. Oral decongestants compared to placebo and benefit on sleep and rhinitis

42. Oral decongestants compared to placebo and benefit on sleep and rhinitis

43. Treatment Considerations in Allergic Rhinitis: ARIA Guidelines
Congestion
Rhinorrhea
Itching/
Sneezing
Sleep
Intranasal steroids
+++
++/+++
++++
Oral antihistamines + ++
+++/++
Intranasal antihistamines
++/++
tried
Oral decongestants -
-/-
Intranasal decongestants
Intranasal cromones
Anticholinergics
Antileukotrienes
Clinical Efficacy of Various Treatments for Allergic Rhinitis1,2
According to the US Allergy Report, “Corticosteroids are the most effective pharmacologic agents for treating allergic rhinitis.”1
Intranasal steroids are highly effective against all nasal symptoms, including nasal congestion, and have prolonged duration of action (up to 48 hours).
Intranasal steroids exert only local anti-inflammatory effects and are considered safer than their systemic counterparts.
1. The Allergy Report. American Academy of Allergy, Asthma, and Immunology, Inc
2. Van Cauwenberge et al. Allergy. 2000;55:116.
Bousquet et al. Allergy. 2003;58:192. Bousquet et al. Allergy. 2002;57:841. Van Cauwenberge et al. Allergy. 2000;55:116.

44. Nasal Decongestant: Effect on Apnea-Hypopnea Index in Snorers* *
Apnea-Hypopnea Index
Control
Nasal Decongestant
Best Position
Nasal Decongestant + Best Position
N=20 asymptomatic male snorers.
*P≤0.03 vs control.
Braver and Block. Sleep. 1994;17:516.

45. Treatment Considerations in Allergic Rhinitis: ARIA Guidelines
Congestion
Rhinorrhea
Itching/
Sneezing
Sleep
Intranasal steroids
+++
++/+++
++++
Oral antihistamines + ++
+++/++
Intranasal antihistamines
++/++
tried
Oral decongestants -
-/-
Intranasal decongestants
Intranasal cromones
Anticholinergics
Antileukotrienes
Clinical Efficacy of Various Treatments for Allergic Rhinitis1,2
According to the US Allergy Report, “Corticosteroids are the most effective pharmacologic agents for treating allergic rhinitis.”1
Intranasal steroids are highly effective against all nasal symptoms, including nasal congestion, and have prolonged duration of action (up to 48 hours).
Intranasal steroids exert only local anti-inflammatory effects and are considered safer than their systemic counterparts.
1. The Allergy Report. American Academy of Allergy, Asthma, and Immunology, Inc
2. Van Cauwenberge et al. Allergy. 2000;55:116.
Bousquet et al. Allergy. 2003;58:192. Bousquet et al. Allergy. 2002;57:841. Van Cauwenberge et al. Allergy. 2000;55:116.

46. Treatment Considerations in Allergic Rhinitis: ARIA Guidelines
Congestion
Rhinorrhea
Itching/
Sneezing
Sleep
Intranasal steroids
+++
++/+++
++++
Oral antihistamines + ++
+++/++
Intranasal antihistamines
++/++
tried
Oral decongestants -
-/-
Intranasal decongestants
Intranasal cromones
+/+
Anticholinergics
Antileukotrienes
Clinical Efficacy of Various Treatments for Allergic Rhinitis1,2
According to the US Allergy Report, “Corticosteroids are the most effective pharmacologic agents for treating allergic rhinitis.”1
Intranasal steroids are highly effective against all nasal symptoms, including nasal congestion, and have prolonged duration of action (up to 48 hours).
Intranasal steroids exert only local anti-inflammatory effects and are considered safer than their systemic counterparts.
1. The Allergy Report. American Academy of Allergy, Asthma, and Immunology, Inc
2. Van Cauwenberge et al. Allergy. 2000;55:116.
Bousquet et al. Allergy. 2003;58:192. Bousquet et al. Allergy. 2002;57:841. Van Cauwenberge et al. Allergy. 2000;55:116.

47. Treatment Considerations in Allergic Rhinitis: ARIA Guidelines
Congestion
Rhinorrhea
Itching/
Sneezing
Sleep
Intranasal steroids
+++
++/+++
++++
Oral antihistamines + ++
+++/++
Intranasal antihistamines
++/++
tried
Oral decongestants -
-/-
Intranasal decongestants
Intranasal cromones
+/+
Anticholinergics
Antileukotrienes
Clinical Efficacy of Various Treatments for Allergic Rhinitis1,2
According to the US Allergy Report, “Corticosteroids are the most effective pharmacologic agents for treating allergic rhinitis.”1
Intranasal steroids are highly effective against all nasal symptoms, including nasal congestion, and have prolonged duration of action (up to 48 hours).
Intranasal steroids exert only local anti-inflammatory effects and are considered safer than their systemic counterparts.
1. The Allergy Report. American Academy of Allergy, Asthma, and Immunology, Inc
2. Van Cauwenberge et al. Allergy. 2000;55:116.
Bousquet et al. Allergy. 2003;58:192. Bousquet et al. Allergy. 2002;57:841. Van Cauwenberge et al. Allergy. 2000;55:116.

48. Leukotriene Receptor Antagonists: Effect on Congestion and Sleep in Patients with SAR
Improvement in Total and Individual Nighttime Symptoms Over Placebo
Total nighttime symptoms
Difficulty going to sleep
Nighttime awakenings
Congestion on awakening * *
Improvement over Placebo
Loratadine 10 mg (n=602)
Montelukast 10 mg (n=348)
Percentage improvements over placebo were modest for both total and individual nighttime symptoms
*P≤0.003 vs placebo.
All symptoms were scored on a scale from 0 (best) to 3 (worst).
Philip et al. Clin Exp Allergy. 2002;32:1020.

49. Leukotriene Receptor Antagonists: Ocular Effects in Patients with SAR
Improvement in Total and Individual Daytime Eye Symptoms Over Placebo
Total daytime eye symptoms
Tearing
Pruritus
Redness * *
Improvement over Placebo
Loratadine 10 mg (n=602)
Montelukast 10 mg (n=348)
Percentage improvements over placebo for both total and individual daytime eye symptoms were greater with loratadine
*P≤0.001 vs placebo.
All symptoms were scored on a scale from 0 (best) to 3 (worst).
Philip et al. Clin Exp Allergy. 2002;32:1020.

50. Montelukast for sleep disturbance associated with rhinitis
Santos et al. Allergy and Asthma Proceedings

51. Treatment Considerations in Allergic Rhinitis: ARIA Guidelines
Congestion
Rhinorrhea
Itching/
Sneezing
Sleep
Intranasal steroids
+++
++/+++
++++
Oral antihistamines + ++
+++/++
Intranasal antihistamines
++/++
tried
Oral decongestants -
-/-
Intranasal decongestants
Intranasal cromones
+/+
Anticholinergics
Antileukotrienes
Clinical Efficacy of Various Treatments for Allergic Rhinitis1,2
According to the US Allergy Report, “Corticosteroids are the most effective pharmacologic agents for treating allergic rhinitis.”1
Intranasal steroids are highly effective against all nasal symptoms, including nasal congestion, and have prolonged duration of action (up to 48 hours).
Intranasal steroids exert only local anti-inflammatory effects and are considered safer than their systemic counterparts.
1. The Allergy Report. American Academy of Allergy, Asthma, and Immunology, Inc
2. Van Cauwenberge et al. Allergy. 2000;55:116.
Bousquet et al. Allergy. 2003;58:192. Bousquet et al. Allergy. 2002;57:841. Van Cauwenberge et al. Allergy. 2000;55:116.

52. Effect of Therapies for Allergic Rhinitis on Sleep and Quality of Life: Summary
Intranasal steroids provide significant relief of congestion and ocular symptoms and improve sleep in patients with allergic rhinitis
Non-sedating antihistamines and leukotriene receptor antagonists provide modest improvements in congestion, ocular, and nighttime symptoms
Decongestants effectively reduce congestion, but have minimal affect on sleep-disordered breathing

53. Allergic rhinitis is associated with impaired sleep
Adverse Impact of Allergic Rhinitis on the Patient Quality of Life-Focus on Sleep: Conclusions
Allergic rhinitis is associated with impaired sleep
Sleep impairment in allergic rhinitis can be caused by
Inflammatory mediators
Nasal symptoms, primarily congestion and rhinorrhea
Ocular symptoms
Impaired sleep adversely affects performance, productivity and social functioning, and increases the risk of associated diseases
Intranasal steroids effectively target inflammation and relieve symptoms to provide improved sleep

54. Thank you Stephanie Teets Stan Golden Josh Berlin Sujani Kukumanu
Katherine Hughs
Casey Glass
Joel Torretti
Faina Gurevich
Wenxin Wei
Jeff McCann
Chris Hanks
Carah Santos
Niti Sardana

55. Questions
Have a great day.