Treatment of Insomnia for Clinicians

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1 Treatment of Insomnia for Clinicians Larry Pawluk, M.D., FRCPC Diplomate, American Board of Sleep Medicine Clinical Professor of Psychiatry, Sleep Medicine Program, University of Alberta

2 What is Insomnia? A complaint of: Difficulty falling asleep Difficulty staying asleep Poor quality sleep Associated with: Distress Impaired function

3 Insomnia And finally there was the sleepless night When I decided to explore and fight The foul, the inadmissible abyss, Devoting all my twisted life to this One task. - Vladimir Nabokov (from Pale Fire)

4 Insomnia: Daytime Complaints Fatigue, sluggishness Sleepiness Somatic complaints (aches & pains) Stress about poor sleep Mood disturbances Poor concentration Impaired performance

5 Insomnia: Consequences Decreased quality of life Increased healthcare costs Increased absenteeism Decreased productivity Increased risk for developing psychiatric disorders Increased accident risk Chesson A Jr. et al. SLEEP 2000;23. Sateia MJ et al. SLEEP 2000;23.

6 Insomnia: Prevalence Insomnia is the most common sleep complaint in the industrialized world Complaints in 30% to 40% Complaint with distress or impairment: 8% to 19% Sateia MJ et al. SLEEP 2000;23.

7 Major Risk Factors Previous history of insomnia Increasing age Female gender Psychiatric symptoms and disorders Medical symptoms and disorders

8 Management of Insomnia

9 Insomnia History Initiation vs. Maintenance vs. Early Morning Awakening Description Speed of onset and precipitant Temporal relationship to other symptoms Course and duration Exacerbating/alleviating factors

10 Insomnia History Typical Night Pre-bed routine and bedtime Sleep onset Number of awakenings and duration Final awakening Variation in schedule on weekends/vacations Daytime Naps Daytime Consequences Sleep Log/Diary Interview with bed partner

11 Insomnia Common Causes Most often there is more than one cause. Insomnia related to a psychiatric disorder makes up > 75% of primary or secondary diagnoses in insomniacs presenting to sleep centres (APA/NIMH DSM IV Field Trial).

12 Insomnia Common Causes Poor sleep hygiene Alcohol, nicotine, caffeine, substances Medications Psychiatric disorders Medical disorders Psychophysiological (Conditioned) insomnia Restless Legs Syndrome and Periodic Limb Movements Delayed Sleep Phase Syndrome

13 Dementia Schizophrenia Depression Anxiety Personality Psychosomatic Alcoholism Prevalence of Insomnia in Psychiatric Disorders (Weyerer and Dilling, 1991) # with insomnia

14 Insomnia Common Causes Clues suggestive of a psychiatric diagnosis Other psychiatric symptoms began in proximity to insomnia. Early morning awakening. Non-restorative sleep. Daytime fatigue/anergia. Feelings of hopelessness, helplessness; anhedonia. Agitation, worrying. Overwhelmed by or excessively focused on insomnia.

15 Common Causes Medical disorders» Neurological Insomnia Seizures, headache, Parkinsons, dementia, tumors, movement disorders.» Endocrinopathies Diabetes, hyperthyroidism, Addisons, Cushings.» Respiratory Obstructive Sleep Apnea, COPD, asthma, CF.» Pain Arthritis, various other.» GI GERD, PUD, inflammatory bowel disease.» Renal, Cardiac, IDs, Dermatological

16 Insomnia Common Causes Psychophysiological (Conditioned) insomnia» Largest category of non-psychiatric chronic insomnia.» May have obsessional or somatoform traits.» Features: Initiating factor= stressor in light sleeper. Insomnia develops life of its own after stressor diminishes. Excessive focus on poor sleep results in maladaptive associations promoting further wakefulness eg. clockwatching, ruminating, catastrophizing. Occasionally sleeps better away from home.

17 Insomnia Common Causes Restless Legs Syndrome and Periodic Limb Movements» Cardinal symptoms Unusual sensations exclusively in lower legs typically at bedtime often preventing sleep initiation. Accompanied by strong urge to move legs which alleviates the uncomfortable sensation. Once asleep, bed partner may notice lower leg jerking/kicking which may or may not be associated with brief cortical arousals.

18 Common Causes Insomnia Delayed Sleep Phase Syndrome» Shift of entire sleep period in a phase delayed direction.» Sleep initiation insomnia with difficulty awakening in the morning at times with morning daytime sleepiness.» Usually adolescents and young adults.» Disorder disappears when allowed to follow their preferred sleep schedule.» DDx includes mood disorders, substance abuse, poor sleep hygiene.

19 Clinical Presentation Predisposing, Precipitating and Perpetuating Factors

20 Assessment: Sleep/wake Diary

21 Assessment: Polysomnography Indications Suspect other sleep disorder Poor treatment response Atypical clinical presentation Not routinely indicated for the evaluation of insomnia Practice parameters for the evaluation of chronic insomnia. SLEEP 2000;23.

22 Treatment of Insomnia

23 Nonpharmacologic Therapy: Sleep Hygiene and Cognitive Behavioral Therapy (CBTI)

24 Cognitive Behavioral Therapy TECHNIQUE Sleep hygiene Stimulus control Sleep restriction Relaxation training Cognitive therapy Circadian rhythm entrainment AIM Promote habits that help sleep; provide rationale for instructions. Strengthen bed & bedroom as sleep stimulus Restrict time in bed to improve sleep depth & consolidation Reduce arousal & decrease anxiety Address maladaptive thoughts and beliefs that interfere with sleep. Reset or reinforce biological rhythm with light therapy and/or melatonin.

25 Behavioral Treatment: Sleep Hygiene Regularize sleep / wake schedule Avoid stimulants and stimulating behavior Establish relaxing bedtime routine Provide conducive sleep environment Limit daytime naps Reduce or eliminate alcohol, caffeine and nicotine Obtain regular exercise Avoid clock watching

26 Behavioral Treatment: Stimulus Control Use bed for sleep (and sex) Go to bed only when sleepy Get out of bed when unable to sleep Wake up at a consistent time (including weekends) Do not take daytime naps

27 Behavioral Treatment: Sleep Restriction (Consolidation) Determine average time asleep Set time in bed = time asleep Consistent wake-up time No daytime naps If time asleep > 90% of time in bed then increase time in bed (15-30 minutes) If time asleep < 80% of time in bed then decrease time in bed (15-30 minutes) Spielman AJ et al. SLEEP 1987;10.

Sleep Latency (Minutes) Nonpharmacologic Treatment Efficacy 90 80 70 60 50 40 30 20 10 Pre-treatment Post-treatment 0

28 Sleep Latency (Minutes) Nonpharmacologic Treatment Efficacy Pre-treatment Post-treatment 0 Stimulus Control Sleep Restriction Relaxation Sleep Hygiene Multi-component Adapted from Morin CM et al. Am J Psychiatry 1994;151.

29 Rating Percent Nonpharmacologic Therapy Efficacy 90 Sleep Efficiency CBT Relaxation Placebo Sleep Quality CBT Relaxation Placebo Adapted from Edinger JD et al. JAMA, 2001;285.

30 Nonpharmacologic Treatment: The Minimum Review sleep hygiene Limit time in bed Establish regular wake-up time Go to bed only when sleepy Get out of bed if unable to sleep

31 Pharmacotherapy: Indications Acute Stress Predictable Stress Chronic Insomnia Shift Work Jet Lag

32 Pharmacotherapy Benzodiazepines Newer GABA receptor agonists Antidepressants Antihistamines Melatonin Others

33 Pharmacotherapy: Benzodiazepine/GABA Receptor Agonists Benzodiazepines Non-benzodiazepines temazepam (Restoril ) triazolam (Halcion ) clonazepam (Rivotril) lorazepam (Ativan ) diazepam (Valium ) flurazepam (Dalmane ) zopiclone (Imovane ) zolpidem SL (Sublinox ) zaleplon (Starnoc )

34 Hypnotic Pharmacokinetics Drug Onset of Action Elimination Half-Life (h) Typical Adult Dose Zolpidem SL min mg Zopiclone min mg Zaleplon min mg Temazepam min mg Triazolam min mg

35 Pharmacotherapy: Benzodiazepines Actions Side effects Hypnotic Anxiolytic Myorelaxant Anticonvulsant Sedation Anterograde amnesia Ataxia, falls Respiratory depression Tolerance, dependence, abuse

36 Benzodiazepine/GABA Receptor Agonists: Effects on Sleep Sleep continuity Sleep latency Awakenings Sleep Duration Slow Wave Sleep (BZs only) REM (BZs only) Duration and number of sleep spindles Periodic limb movements and associated arousals

37 Benzodiazepines: Rebound Insomnia Is related to dose and half-life Can be prevented by tapering dose Cannot easily be distinguished from return of original symptoms Does not predict future pill-taking behavior Varies among drugs May not be seen with some agents

38 Benzodiazepine/GABA Receptor Agonists: Clinical Approach Establish correct diagnosis Evaluate carefully for apnea, respiratory impairment, organic mental disorders, substance abuse history Choose drug with desired pharmacokinetic profile Use lowest effective dose Monitor side effects (e.g. fall risk, sedation) Aim for short-term, intermittent use Consider long-term use in carefully selected patients

39 Sublinox (zolpidem tartrate ODT): Product Profile Product Fast disintegrating, sublingual zolpidem tablet Characteristics Fast sublingual disintegration ( 2 minutes) For patients with difficulty swallowing or those who don t like to swallow pills or don t have access to water Ideal product profile for on demand treatment Next day residual effects comparable to oral formulation Product Monograph, Sublinox, Zolpidem tartrate orally disintegrating tablets. Montreal, Canada: MEDA Valeant Pharma Canada Inc.; 2011.

40 Mechanism of Action Subunit modulation of the GABA A receptor chloride channel macromolecular complex is hypothesized to be responsible for sedative, anticonvulsant, anxioytic, and myorelexant drug properties. The major modulatory site of the GABA A receptor complex is located on its alpha ( ) subunit and is referred to as the benzodiazepine (BZ) or omega ( ) receptor. Zolpidem has a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties It interacts with the GABA-BZ receptor complex and shares some of the pharmacological properties of the benzodiazepines. In contrast to the benzodiazepines, zolpidem in vitro binds the (ω1) receptor preferentially with a high affinity ratio of the alpha1/alpha5 subunits. Selective binding of zolpidem on the (ω1) receptor may explain: - the relative absence of myorelaxant and anticonvulsant effects in animal studies - the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem at hypnotic doses (vs. benzodiazepines) Product Monograph, Sublinox, Zolpidem tartrate orally disintegrating tablets. Montreal, Canada: MEDA Valeant Pharma Canada Inc.; 2011.

41 Incidence of Treatment-Emergent Adverse Experiences in Placebo- Controlled Clinical Trials with zolpidem tartrate lasting up to 35 nights (Percentage of patients reporting) Body System/ Adverse Event* Central and Peripheral Nervous System Zolpidem tartrate ( 10 mg) (N=152) Placebo (N=161) Drowsiness 8 5 Dizziness 5 1 Lethargy 3 1 Drugged feeling 3 - Lightheadedness 2 1 Depression 2 1 *Reactions reported by at least 1% of patients treated with oral zolpidem and at a greater frequency than placebo. Only dizziness and drugged feeling were reported with statistically significant differences Abnormal dreams 1 - Amnesia 1 - Sleep disorder 1 - Gastrointestinal System Diarrhea 3 2 Abdominal pain 2 2 Constipation 2 1 Respiratory System Sinusitis 4 2 Pharyngitis 3 1 Skin and Appendages Rash 2 1 Product Monograph, Sublinox, Zolpidem tartrate orally disintegrating tablets. Montreal, Canada: MEDA Valeant Pharma Canada Inc.; 2011.

42 Sublingual zolpidem in early onset of sleep compared to oral zolpidem: polysomnographic study in patients with primary insomnia Staner L, et al. Curr Med Res Opin. 2010;26(6):

43 Study Design Randomized, double-blind, two-period, cross-over multi-centre study Polysomnographic study in patients with DSM-IV primary insomnia Powered to test for superiority of sublingual oral zolpidem compared to oral zolpidem on latency to persistent sleep Powered for at least as good as total sleep time and duration of wake after sleep onset Staner L et al. Curr Med Res Opin. 2010;26(6):

44 Results Sleep Initiation Latency to persistent sleep (min) Sleep onset latency (min) Baseline Sublingual zolpidem Oral zolpidem Treatment differences 84.54± ± ± (p=0.0 01) 72.30± ± ± (p<0.01) Latency to stage 1 (min) 61.07± ± ± (p<0.01) Staner L, et al. Curr Med Res Opin. 2010;26(6):

45 Results Sleep Continuity and Architecture Baseline Sublingual zolpidem Oral zolpidem Treatment differences SEI (%) 67.47± ± ± (p<0.05) TTA (min) ± ± ± (p<0.05) ST1 (min) 22.08± ± ± (p=ns) ST2 (min) ± ± ± (p<0.05) SWS (min) 51.65± ± ± (p=ns) REM (min) 70.44± ± ± (p=ns) RSL (min) 81.81± ± ± (p=ns) Sleep efficiency index and time spent in stage 2 were significantly higher with sublingual zolpidem Patients receiving oral zolpidem demonstrated significantly higher total time awake Staner L et al. Curr Med Res Opin. 2010;26(6):

46 Sublinox Contraindications Known hypersensitivity to zolpidem tartarte or to any of the inactive ingredients in the formulation Patients with significant obstructive sleep apnea syndrome and acute and/or severe impairment of respiratory function. Sublinox should not be given to patients with myasthenia gravis and in patients with severe hepatic impairment. Patients with a personal or family history of sleepwalking Elderly (longer half life) Not to be taken with alcohol Product Monograph, Sublinox, Zolpidem tartrate orally disintegrating tablets. Montreal, Canada: MEDA Valeant Pharma Canada Inc.; 2011.

47 COMPLEX SLEEP-RELATED BEHAVIOURS: Warning Complex sleep-related behaviours such as sleep-driving (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported in patients who have taken Sublinox. Other potentially dangerous behaviours have been reported in patients who got out of bed after taking a sedative-hypnotic and were not fully awake, including preparing and eating food, making phone calls, leaving the house, etc. As with sleep-driving, patients usually do not remember these events. Although complex sleep-related behaviours may occur with Sublinox alone at therapeutic doses, the use of alcohol and other CNS-depressants with Sublinox appears to increase the risk of such behaviours, as does the use of Sublinox at doses exceeding the maximum recommended dose. Product Monograph, Sublinox, Zolpidem tartrate orally disintegrating tablets. Montreal, Canada: MEDA Valeant Pharma Canada Inc.; 2011.

48 The Right Dose of Sublinox Sublinox recommended dose is 10 mg immediately before bedtime for adults Sublinox effect may be slowed by ingestion with food Dose adjustment needed when used with other CNS depressants The potential for drug interactions must always be considered. Sublinox course of treatment should not exceed 4 wks Product Monograph, Sublinox, Zolpidem tartrate orally disintegrating tablets. Montreal, Canada: MEDA Valeant Pharma Canada Inc.; 2011.

49 Administration Instructions Should be taken right before bed time. Should not be taken with or immediately after a meal. Should not be taken when drinking alcohol, or with other CNS depressants. Should be placed under the tongue, where it will disintegrate. Should not be chewed or swallowed and should not be taken with water. Maximum recommended dose of 10mg should not be exceeded. 1. Product Monograph, Sublinox, Zolpidem tartrate orally disintegrating tablets. Montreal, Canada: MEDA Valeant Pharma Canada Inc.; 2011.

50 Antidepressants: Rationale No antidepressant is FDA/HPB-approved for treatment of insomnia Some antidepressants have sedative, sleeppromoting effects Some insomnia patients have symptoms of depression or anxiety Low risk of abuse, but psychological dependence occurs

51 Antidepressants: Sleep Effects Sleep Continuity REM Sleep SWS Comments Tricyclic to to to apnea, PLMS SSRI SNRI to to Variable effects on insomnia; may PLMS; eye movements in NREM Trazodone to to to Carry-over sedation Mirtazapine Sedation is inversely related to dose

52 Pharmacotherapy: Antihistamines Mechanism of action H1 receptor antagonism Variable antagonism of cholinergic, serotonergic, adrenergic receptors Adverse effects Sedation, grogginess Dry mouth Psychomotor impairment Delirium

53 Ordinal Rating Scale Antihistamines: Sleep Efficacy p<.01 p<.01 p<.001 p< Sleep Latency Number of Awakenings Diphenhydramine 50mg Adapted from Rickels K et al. J Clin Pharmacol 1983;23. Sleep Duration Placebo Sleep Quality

54 Pharmacotherapy: Melatonin Naturally occurring hormone secreted during darkness at night Broad range of physiological effects Inconclusive findings concerning sleep promotion in insomnia May be most useful in shifting circadian phase e.g. delayed sleep phase syndrome

55 Other Pharmacologic Agents Tryptophan Valerian HRT

56 Pharmacologic Treatment: Approach Select appropriate medication Use lowest effective dose Use at bedtime Duration of therapy Use as needed for 2 to 4 weeks Reduce dose as tolerated Intermittent use suggested Reassess and adjust approach Combine with behavioral strategies

59 Insomnia Case 1 40 year old female teacher Unable to sleep for 5 years with worsening over 3 months Appears anxious Worries she will lose job due to lack of sleep

60 Insomnia Case 1 Evaluation 1. Description» Initiation insomnia for 5 yrs; abrupt worsening X 3 months with EMW» Typical noc:» BT 10 pm, sleep onset 3 hrs (toss and turn, check clock, ruminates, ++ focussing on need to sleep), EMW ~ 5 am» Sleep diary confirms

61 Insomnia Case 1 Evaluation 2. Common Causes» Sleep hygiene incl. EtOH caffeine, substances: marks late» Meds: occas. Antihistamine to sleep» Medical: nil reported» Psychiatric: sx of depression and anxiety, a few neuroveg. features, no suicidal ideation» Psychophysiol: 5 yr hx of ++focus on sleep, check clock, ruminating» RLS: no Circadian: no

62 Insomnia Case 1 Diagnoses: Major Depression with anxiety component Sleep hygiene factor: works til bedtime Psychophysiological insomnia component

63 Insomnia Case 1 Treatment Treat mood/anxiety disorder first:» Antidepressant with anxiolytic properties» Supportive therapy» Review sleep hygiene principles eg. wind down before bed

64 Insomnia Case 1 Treatment (cont.) After 2 months EMW and most depressive/anxiety symptoms improve but sleep initiation problem continues: Address conditioned component:» Behavioral strategies: hide clock, stimulus control, sleep consolidation» Cognitive restructuring: address maladaptive assumptions

65 Insomnia Case 1 Treatment (cont.) If required:» Use short acting hypnotic for agreed upon period to help break cycle» If subsequent use required, use intermittently

66 Insomnia Case 1 40 year old female teacher Unable to sleep for 5 years with worsening over 3 months Appears anxious Worries she will lose job due to lack of sleep

Insomnia. Learning Objectives. Disclosure 6/7/11. Research funding: NIH, Respironics, Embla Consulting: Elsevier

Insomnia. Learning Objectives. Disclosure 6/7/11. Research funding: NIH, Respironics, Embla Consulting: Elsevier Insomnia Teofilo Lee-Chiong MD Professor of Medicine National Jewish Health University of Colorado Denver School of Medicine Learning Objectives Learn about the causes of transient and chronic Learn how