Sleep Disorders: Insomnia, Sleep Apnea, Restless Leg Syndrome, Bruxism, Narcolepsy and Sleepwalking

1. Overview 12
1.1 Statement of Report 12
1.2 About This Report 12
1.3 Scope of the Report 13
1.4 Methodology 13
1.5 Executive Summary 14
1.6 U.S. Sleep Market 17
1.6.1 Sleep Drugs Market in the U.S. 17
1.6.2 U.S. Sleep Apnea Devices Market 18
1.6.3 U.S. Market for Mattresses and Other Related Products 18
1.6.4 Sleep Laboratories in the U.S. 19
1.6.4.1 Locate Sleep Centers in the U.S. 21
1.7 Future of Sleep Drugs 22
1.7.1 Sleep Drugs for Jet Lag and Shift Work 22
1.7.2 Sleep Drugs for Age-related Sleep Issues 23
1.7.3 Sleep Drugs for Those Who Cannot Sleep Through the Night 24
1.7.4 Sleep Drugs for Restless Leg Syndrome 24
1.7.5 Sleep Drugs for Insomnia 25
1.7.6 Sleep Drugs for Sleep Apnea 25

2. Introduction to Sleep Disorders 26
2.1 Sleep Disorders Overview 26
2.1.1 Sleep Facts from the U.S. 27
2.1.2 Consequences of Sleep Disorder Problems 27
2.2 Physiology of Sleep 27
2.2.1 Sleep Stages 28
2.2.2 Neutral Control of Sleep 29
2.3 Current Understanding of Sleep Disorders 29
2.3.1 Hypersomnia 30
2.3.1.1 Causes of Hypersomnia 30
2.3.1.2 Demographics of Hypersomnia 30
2.3.1.3 Treatment for Hypersomnia 31
2.4 Obstructive Sleep Apnea (OSA) 33
2.4.1 Causes of Sleep Apnea 33
2.4.2 Symptoms of Sleep Apnea 34
2.4.3 Demographics of Sleep Apnea 34
2.4.4 Diagnosis of Sleep Apnea 34
2.4.5 Treatments 35
2.4.5.1 Positional Therapy 35
2.4.5.2 Behavioral Therapy-Weight Loss 36
2.4.5.3 Oral Appliances 36
2.4.5.4 Surgery for Sleep Apnea 37
2.4.5.5 Nasal Continuous Positive Airway Pressure (CPAP) Therapy 37
2.4.5.6 Medications for Sleep Apnea 37
2.4.6 The National Ambulatory Medical Care Survey on Sleep Apnea 38
2.4.6.1 Age and Sleep Apnea in Men 41
2.5 Narcolepsy 42
2.5.1 Demographics of Narcolepsy 42
2.5.2 Causes of Narcolepsy 43
2.5.3 Symptoms of Narcolepsy 43
2.5.4 Diagnosis of Narcolepsy 43
2.5.5 Treatment for Narcolepsy 43
2.6 Insomnia 44
2.6.1 Causes of Insomnia 46
2.6.2 Symptoms of Insomnia 46
2.6.3 Demographics of Insomnia 47
2.6.4 Diagnosis of Insomnia 48
2.6.5 Insomnia and Obesity 48
2.6.6 Treatments for Insomnia 50
2.6.6.1 Behavioral Treatment for Insomnia 50
2.6.6.2 Treating Insomnia with Medications 50
2.6.6.3 Alternative Remedies for Insomnia 51
2.6.7 Insomnia Market 51
2.6.8 National Sleep Foundations' "Sleep In America Poll" 55
2.6.8.1 Benzodiazepines 56
2.6.8.2 The Short-term Gold Standard 56
2.6.8.3 Emerging Players 56
2.6.8.4 Insomnia Market Indicators 57
2.6.8.5 Newer Sedative Drugs for Insomnia in 2008 57
2.7 Restless Legs Syndrome 61
2.7.1 Demographics of RLS 62
2.7.2 Causes of RLS 62
2.7.3 Symptoms of RLS 63
2.7.4 Diagnosis of RLS 63
2.7.5 Treatments for RLS 64
2.7.5.1 Lifestyle Changes and RLS 64
2.7.5.2 Treating RLS with Pharmaceuticals 64
2.8 Circadian Rhythm Disorders 65
2.8.1 Causes of Circadian Rhythm Disorders 65
2.8.2 Symptoms 66
2.8.3 Demographics of Circadian Rhythm Disorders 66
2.8.4 Diagnosis of Circadian Rhythm Disorders 66
2.8.5 Treatments for Circadian Rhythm Disorders 67
2.9 Parasomnias 67
2.9.1 Nightmare Disorder 67
2.9.2 Sleep Terror Disorder 67
2.9.3 Sleep Walking Disorder 67
2.9.4 Demographics of Parasomnias 68
2.9.5 Causes and Symptoms of Parasomnias 68
2.9.6 Diagnosis 68
2.9.7 Treatment for Parasomnias 68

3. Drugs Used for Sleep Disorders 69
3.1 Estazolam 69
3.2 Flurazepam (Dalmane) 69
3.3 Temazepam 70
3.4 Triazolam 71
3.5 Zopiclone (Inovane) 71
3.6 Nonbenzodiazepine Hypnotics 72
3.6.1 Eszopiclone (Lunesta) 72
3.6.2 Zaleplon (Sonata) 73
3.6.3 Zolpidem (Ambien, Ambien CR) 74
3.7 Pineal Gland Hormones 76
3.7.1 Melatonin 76
3.7.2 Ramelteon (Rozerem) 76
3.8 Antihistamines 77
3.8.1 Benadryl (Diphenhydramine) 77
3.8.2 Doxylamine 77
3.9 Antidepressants 78
3.9.1 Amitriptyline (Elavil) 78
3.9.2 Nortriptyline (Pamelor) 79
3.9.3 Nefazodone (Serzone) 80
3.9.4 Trazodone (Desyrel) 80
3.9.5 Indiplon 81
3.9.6 Gaboxadol 81
3.9.7 Silenor 82
3.10 Other Substances 83
3.10.1 Lavender 83
3.10.2 Passion Flower 84
3.10.3 Ashwagandha 84
3.10.4 Catnip 86
3.10.5 Kava (Piper methysticum) 87
3.10.6 Valerian 89
3.11 Aromatherapy 90
3.12 Some OTC Sleep Gadgets in the Market 91
3.12.1 Dreamate™ 91
3.12.2 Anti-snoring Pillow 91
3.12.3 Nasal Dialators 92
3.12.4 Nasal Strips 92
3.12.5 Snore Stopper 92
3.12.6 SleepMate 93
3.12.7 Antisnor Therapeutic Ring 93
3.12.8 Ayurvedic Treatment for Insomnia 94
3.12.9 Yoga for Sleep Disorders 94
3.12.10 Meditation for Sleep Disorders 96
3.12.11 Hypnosis for Sleep Disorders 97
3.13 Homeopathic Treatment for Sleep Disorders 97
3.13.1 Belladonna 97
3.13.2 Nux vomica 98
3.13.3 Chamomilla 98
3.13.4 Gelsemium 99
3.13.5 Cannabis Indica 99

4. A Guide to Better Sleep 101
4.1 The Normally Required Sleep 101
4.2 Sleep and Driving 101
4.3 Tips to Avoid Drowsy Driving 101
4.4 Tips to Find whether One has Sleep Disorders 102
4.5 A Good Night's Sleep 102

5. Sleep Laboratories 104

6. Profiles of Companies and Their Product Offering 107
6.1 Device Companies (CPAP and Other) 107
6.1.1 AEIOmed, Inc. and Product Offerings 107
6.1.2 Chad Therapeutics, Inc. and Product Offerings 108
6.1.3 Compumedics Ltd. and Product Offerings 113
6.1.4 Puritan Bennett (Covidien) and Product Offerings 122
6.1.5 ResMed Corporation and Product Offerings 135
6.1.6 Respironics, Inc. (Philips) 145
6.1.7 CleveMed and Product Offerings 153
6.1.8 SomnoMed Ltd. and Product Offerings 156
6.2 Pharmaceutical (Prescription and OTC) Companies 157
6.2.1 Acadia Pharmaceuticals, Inc. 157
6.2.1.1 Pimavanserin for the Treatment of Parkinson's Disease Psychosis 158
6.2.1.2 Pimavanserin as a Co-therapy for Schizophrenia 158
6.2.1.3 ACP-104 for the Treatment of Schizophrenia 158
6.2.1.4 Pimavanserin for the Treatment of Sleep Maintenance Insomnia 158
6.2.1.5 Neuropathic Pain 158
6.2.1.6 Glaucoma 158
6.2.2 Actelion Ltd. 160
6.2.2.1 Actelion's Tracleer® 164
6.2.2.2 Tracleer in Digital Ulcers 165
6.2.2.3 Actelion's Ventavis® 165
6.2.2.4 Actelion's Zavesca® 165
6.2.2.5 Actelion's Focus on Sleep and Sleep Disorders 165
6.2.2.6 The Orexin System 165
6.2.2.7 Almorexant in Clinical Development 165
6.2.3 Arena Pharmaceuticals, Inc. 166
6.2.3.1 Arena's R&D Programs 166
6.2.3.2 Arena Pharmaceuticals' Development Pipeline 167
6.2.3.3 Locaserin Hydrochloride for Obesity 168
6.2.3.4 APD125 for Insopmnia 168
6.2.4 Cephalon, Inc. 171
6.2.5 Eli Lilly and Company 174
6.2.5.1 Eli Lilly's Product Acquisitions, 2007 178
6.2.6 GlaxoSmithKline Plc 179
6.2.7 King Pharmaceuticals, Inc. and Product Offerings 188
6.2.7.1 King Pharmaceutical's R&D 192
6.2.7.2 King Pharmaceutical's Manufacturing 192
6.2.7.3 King Pharmaceutical's Financial Highlights 192
6.2.8 Neurogen Corporation 192
6.2.8.1 Neurogen's Insomnia Products 195
6.2.8.2 Positive Results in Phase IIb Studies in Chronic Insomnia 195
6.2.8.3 Positive Results in Phase IIb Studies with Adipiplon 195
6.2.8.4 Study 202-Primary Endpoint Sleep Maintenance 196
6.2.8.5 Study 203-Primary Endpoint Sleep Onset 196
6.2.8.6 Transient Insomnia 198
6.2.8.7 Study Results 198
6.2.8.8 Study Design 198
6.2.9 Neurocrine Biosciences, Inc. 199
6.2.9.1 Neurocrine's Pipeline-GnRH Antagonists 200
6.2.9.2 Corticotropin Releasing Factor (CRF1) Receptor Antagonists 201
6.2.9.3 Urocortin 2 for Congestive Heart Failure (CHF) 201
6.2.9.4 Neurocrine's Research Programs 201
6.2.9.5 Indiplon 201
6.2.10 Pfizer, Inc. and Product Offerings 202
6.2.10.1 Lipitor 204
6.2.10.2 Norvasc 204
6.2.10.3 Celebrex 204
6.2.10.4 Lyrica 204
6.2.10.5 Viagra 204
6.2.10.6 Xalatan/Xalacom 205
6.2.10.7 Zyrtec/Zyrtec D 205
6.2.10.8 Detrol/Detrol LA 205
6.2.10.9 Camptosar 205
6.2.10.10 Zyvox 205
6.2.10.11 Chantix/Champix 206
6.2.10.12 Geodon/Zeldox 206
6.2.10.13 Genotropin 206
6.2.10.14 Vfend 206
6.2.10.15 Sutent 207
6.2.10.16 Caudet 207
6.2.10.17 Zoloft 207
6.2.10.18 Zithromax/Zmax 207
6.2.10.19 Aricept 208
6.2.10.20 Replax 208
6.2.10.21 Revatio 208
6.2.10.22 Aromasin 208
6.2.10.23 Eraxis/Ecalta 209
6.2.10.24 Indiplon 216
6.2.10.25 Halcion (Triazolam) 217
6.2.11 Sanofi Aventis 217
6.2.11.1 Sanofi's Pharmaceutical Business in 2007 218
6.2.11.2 Sanofi's Human Vaccine Business in 2007 218
6.2.11.3 Ambien CR 222
6.2.11.4 Ambien 222
6.2.12 Schering-Plough Corporation 222
6.2.13 Sepracor, Inc. 227
6.2.14 SleepMed, Inc. 231
6.2.14.1 Home Sleep Disorders Sleep Laboratory Partnership Services 231
6.2.14.2 SleepMed's Self-test for Sleep Disorders 231
6.2.14.3 Sleepiness Scale 233
6.2.15 Somaxon Pharmaceuticals, Inc. 233
6.2.15.1 Silenor (Doxepin HCl Tablets)-A Successful Clinical Development Program 234
6.2.16 Takeda Pharmaceutical Company Ltd. 235
6.2.17 Takeda Pharmaceuticals North America, Inc. 242
6.2.17.1 Rozerem 243
6.2.18 Vanda Pharmaceuticals, Inc. 244
6.2.19 Wyeth 245
6.2.20 Valeant Pharmaceuticals, Inc. 250

Appendix 1: Sleep-related Disorders in the U.S. 254
Appendix 1.1: Sleep and Smoking 254
Appendix 1.2: Sleep and Alcohol Use 256
Appendix 1.3: Sleep and Physical Inactivity 256
Appendix 1.4: Sleep and Obesity 257

Appendix 2: Chronic Shift Work Sleep Disorder and Treatment with Modafinil 258

Appendix 3: Sleep Centers and Sleep Labs 261
Appendix 3.1: Tests Performed in the Sleep Laboratories 262

Appendix 4: Obesity 263
Appendix 4.1: U.S. Obesity Trends, 2007 264
Appendix 4.2: Economic Consequences of Obesity 267
Appendix 4.3: Childhood Overweight and Obesity 268
Appendix 4.4: Prevalence of Overweight and Obesity in a U.S. Pediatric Surgical Population 268

Appendix 5: Sleep Disorders and Sleep Deprivation 271
Appendix 5.1: Sleep Physiology 271
Appendix 5.2: Two Types of Sleep 271
Appendix 5.3: NREM and REM Sleep Cycles 272
Appendix 5.4: Four Stages of NREM Sleep 272
Appendix 5.5: Stage I Sleep 273
Appendix 5.6: Stage II Sleep 273
Appendix 5.7: Stages III and IV-Slow Wave Sleep 273
Appendix 5.8: REKM Sleep 273
Appendix 5.9: Sleep-Wake Regulation 274
Appendix 5.10: Sleep-generating System in the Brain Stem 274
Appendix 5.11: Wake-generating System in the Brain Stem 275
Appendix 5.12: Circadian Rythms 275
Appendix 5.13: Change of Sleep Patterns with Age 275
Appendix 5.14: Sleep Architecture in Young Children 275
Appendix 5.15: Sleep Architecture in Adolescents 276
Appendix 5.16: Sleep Architecture in Adults 276
Appendix 5.17: Gender Difference and Sleep Architecture 276
Appendix 5.18: Sleep Architecture in Elderly People 277

Appendix 6: American Sleep Association 278
Appendix 6.1: Clinical Trials 278
Appendix 6.2: Risks in Clinical Trials 278
Appendix 6.3: Ideas for Clinical Trials 278
Appendix 6.4: Sponsors of Clinical Trials 278
Appendix 6.5: Placebo 279
Appendix 6.6: Control Group 279
Appendix 6.7: Different Phases of Clinical Trials 279

Appendix 7: Deprived Sleep and Automobile Crashes in the U.S. 281
Appendix 7.1: Biology of Human Sleep and Sleepiness 281
Appendix 7.2: Crash Characteristics 281
Appendix 7.3: Countermeasures 282
Appendix 7.4: Panel Recommendations 282
Appendix 7.5: Sleepiness Impairs Performance 282
Appendix 7.6: Causes of Sleepiness/Drowsy Driving 282
Appendix 7.7: Sleep Restriction or Loss 283
Appendix 7.8: Job-related Sleep Restrictions 283
Appendix 7.9: Personal Demands and Lifestyle Choices 283
Appendix 7.10: Sleep Fragmentation 283
Appendix 7.11: Characteristics of Drowsy-driving Crashes 283
Appendix 7.12: The Problem Occurs during Late Night Hours 283
Appendix 7.13: Crashes Occur on a High-speed Road 286
Appendix 7.14: More Single Occupant Crashes 286
Appendix 7.15: Consumption of Alcohol Increases Drowsiness 286
Appendix 7.16: Population Groups at Highest Risk of Road Crashes 287

Appendix 8: Sleep-related Organizations 289
Appendix 8.1: American Sleep Apnea Association 289
Appendix 8.2: The American Sleep Association 289
Appendix 8.3: National Sleep Foundation 289
Appendix 8.4: National Center on Sleep Disorders Research (NCSDR) 289
Appendix 8.4.1: Research 289
Appendix 8.4.2: Training 290
Appendix 8.4.3: Technology Transfer 290
Appendix 8.4.4: Coordination 290
Appendix 8.5: American Academy of Sleep Medicines 290
Appendix 8.6: International Restless Leg Syndrome Study Group 290
Appendix 8.7: The Movement Disorder Society 291

INDEX OF FIGURES

Figure 1.1: Total Market for Leading Sleep Drugs, 2007 15
Figure 1.2: Sleep Product's Market Share, 2007 16
Figure 1.3: Percent Market Share of Leading CPAP Devices, 2008 16
Figure 1.4: U.S. Rx and OTC Sleeping Pills Market, 2003-2007 17
Figure 1.5: U.S. CPAP Sleep Apnea Devices Market, 2003-2007 18
Figure 1.6: U.S. Mattresses and Foundations Retail Market, 2003-2007 19
Figure 1.7: U.S. Sleep Lab Revenues, 2003-2007 19
Figure 1.8: Number of Accredited Sleep Labs in the U.S., 2003-2007 20
Figure 1.9: U.S. Growth of Sleep Center Beds, 2007-2009 21
Figure 1.10: Circadin's Effect on the Improvement in Quality of Sleep 24
Figure 2.1: Hours of Sleep in a Sample U.S. Population, 2008 26
Figure 2.2: Treatment Effects on Patients with Hypersomnia 32
Figure 2.3: Adults with Sleep Apnea Symptoms who Sought Medical Care in the U.S., 2006 34
Figure 2.4: Sleep Apnea Percentage by Medical Specialty as Reported by NAMCS 40
Figure 2.5: NAMCS Ages of Sleep Apnea Patients 40
Figure 2.6: Age-specific Prevalence of Obstructive Sleep Apnea Diagnosed 42
Figure 2.7: Prevalence of Sleep Aid Use by Age Group in the U.S., 1998-2006 44
Figure 2.8: Percentage of Sleep Aid Users Younger than 45 Years Old in the U.S., 1998-2006 45
Figure 2.9: Prevalence of Mental Health Diagnoses Made in First Sleep Aid Users by Provider Type 46
Figure 2.10: Common Symptoms of Insomnia 47
Figure 2.11: Insomnia Patient Population, 2007 48
Figure 2.12: Obesity Prevalence by Age and Sex in the U.S., 2005-2006 49
Figure 2.13: Prevalence of Obesity in U.S. Women by Age and Race/Ethnicity, 2005-2006 49
Figure 2.14: The Globally Growing Market for Insomnia, 2001-2006 52
Figure 2.15: Global Prescription for Insomnia Products, 2001-2006 53
Figure 2.16: Global Sales of Insomnia Drugs, 2007 54
Figure 2.17: Global Insomnia Market, 2005-2009 54
Figure 2.18: Frequency of Insomnia Symptoms in the U.S. Adult Population 55
Figure 2.19: U.S. Sleep Market-Under-Penetrated 56
Figure 2.20: U.S. Sleep Market Growth, 2009 57
Figure 2.21: Time to Sleep for RLS Sufferers 61
Figure 2.22: Times RLS Sufferers Woken at Night 62
Figure 2.23: RLS Sufferers Referred to Specialist by Country 63
Figure 3.1: Dalmane's Market, 2005-2007 70
Figure 3.2: Global Market for Lunesta, 2005-2007 73
Figure 3.3: Sonata's (Zaleplon) Sales, 2005-2007 74
Figure 3.4: Total Sales for Four Leading Brands of Sleeping Pills, 2007 75
Figure 3.5: WASO 82
Figure 5.1: Number of Accredited Sleep Labs in the U.S., 2003-2007 104
Figure 5.2: Sleep Monitoring Revenue Distribution by Provider Type in the U.S., 2006 105
Figure 5.3: U.S. Sleep Lab Revenues, 2003-2007 106
Figure 6.1: Chad's Business for the Six months ended September, 2006 and 2007 111
Figure 6.2: Chad's R&D Expenditure for the Six Months Ended September, 2006 and 2007 112
Figure 6.3: Chad's Business in Geographic Region/Country for Six Months Ended September, 2007 112
Figure 6.4: Compumedics' Revenue, 2003-2008 113
Figure 6.5: Compumedics' R&D Expenditure, 2007 and 2008 114
Figure 6.6: Compumedics' Business Revenue from the U.S., 2003-2008 115
Figure 6.7: Compumedics' Global Sleep Diagnostic Market, 2008 115
Figure 6.8: Compumedics' Global Brain Research Market, 2008 116
Figure 6.9: Compumedics' Global Neurodiagnostics Market, 2008 116
Figure 6.10: Compumedics' Global Neuromedical Supplies Market, 2008 117
Figure 6.11: Compumedics' Global Doppler Ultrsound Market, 2008 117
Figure 6.12: Covidien's Medical Device Business Sales, 2005-2007 124
Figure 6.13: Covidien's Pharmaceutical Products Business Sales, 2005-2007 124
Figure 6.14: Covidien's Imaging Solutions Business Sales, 2005-2007 125
Figure 6.15: Covidien's Medical Supplies Business Sales, 2005-2007 125
Figure 6.16: Covidien's Retail Products Business Sales, 2005-2007 126
Figure 6.17: Covidien's Net Sales by Geographic Area, 2005-2007 126
Figure 6.18: Covidien's R&D Expenditure, 2005-2007 127
Figure 6.19: ResMed's Percent Net Revenue from North and Latin America, 2006-2008 137
Figure 6.20: ResMed's Percent Net Revenue from Europe, 2006-2008 138
Figure 6.21: ResMed's Percent Net Revenue from Asia Pacific, 2006-2008 138
Figure 6.22: Number of Employees in ResMed and its Subsidiaries, 2008 139
Figure 6.23: ResMed's Consolidated Statement of Income Data, 2004-2008 139
Figure 6.24: ResMed's R&D Expenditure, 2004-2008 140
Figure 6.25: Respironics' Business, 2006 and 2007 146
Figure 6.26: SomnoMed's OSA Global Market Size Projection, 2007 and 2008 156
Figure 6.27: Growth Projection for SomnoMed MAS, 2005-2010 157
Figure 6.28: Acadia's Revenue, 2003-2007 159
Figure 6.29: Acadia's R&D Expenses, 2003-2007 160
Figure 6.30: Actelion's Sales Revenue from Three of its Brands, 2007 161
Figure 6.31: Actelion's Revenue, 2007-2008 162
Figure 6.32: Actelion's Net Revenues and Net Income, 2006 and 2007 162
Figure 6.33: Actelion's Sales Revenue, 2006-2008 163
Figure 6.34: Arena's Research Expenditure, 2005-2007 169
Figure 6.35: Arena's Revenue, 2003-2007 170
Figure 6.36: Arena's Revenue from Partnered Programs, 2005-2007 170
Figure 6.37: Provigil Sales Revenue, 2007 171
Figure 6.38: Cephalon's Percent Net Sales of Provigil, Fentora and Actiq, 2007 172
Figure 6.39: Cephalon's Consolidated Total Revenue, 2003-2007 173
Figure 6.40: Cephalon's R&D Expenditure, 2006-2007 173
Figure 6.41: Cephalon's Total Sales Revenue of Products by Segment, 2007 174
Figure 6.42: Eli Lilly's Products Launched this Decade Contributed $6.0 Billion, 2007 175
Figure 6.43: Eli Lilly's Six Products Exceeded $1.0 Billion in Net Sales, 2007 175
Figure 6.44: Eli Lilly's Growth Across Therapeutic Areas, 2007 176
Figure 6.45: Eli Lilly's Gross Margin, 2003-2007 177
Figure 6.46: Eli Lilly's Increased R&D Investment, 2003-2007 177
Figure 6.47: GSK's Top Five