1 Insomnia August 9, 2017 Winnie Suen, MD, MSc, AGSFCindy Khamphaphanh Pharm.D. Candidate Chad Kawakami, PharmD, BCPS, CDE August 9, 2017 1

2 OBJECTIVES To understand Age-related changes in sleepCauses of sleep problems Office-based evaluation of sleep Sleep problem treatment options 2 2

3 How is insomnia defined?DSM-5 Difficulty in initiating or maintaining sleep or waking up too early, which is associated with daytime impairment (such as fatigue, poor concentration, daytime sleepiness, or concerns about sleep) Sleep problems must occur at least 3 times per week and (to meet chronic insomnia), must be present for 3 months.

4 Mr. Chen 66 year old man, recently retired engineer (6 months), mentions at the end of his appointment, that he is “up all night”, tired during the day, spends much of his time “resting.” It interferes with the couples‘ social activities. He saw a TV ad for a new sleeping pill and would like it to be prescribed to him. 11

5 What would you like to ask him next to figure out why he is not able to sleep?

6 Key History Questions DIAGNOSIS Are you satisfied with your sleep?Does sleep or fatigue interfere with daytime activities? Do others complain about unusual behaviors during sleep? (snoring, interrupted breathing, leg movements) Record- estimated amount of sleep, number of awakenings, time of morning awakening, when they got up, any symptoms at night, any medications or agents taken for sleep, time spent napping during the day 7 6

7 His Sleep Routine Wine with dinnerDozes watching TV, gets into bed at 10pm Lies awake for 2-3 hours Awakens at 4pm to urinate and can’t go back to sleep Get up 6am and “rests” on couch after breakfast Exercises in evening Rests on couch before dinner. Does not drink coffee or tea Denies leg discomfort, morning headaches …He has some difficulty falling asleep in the past, but never this bad. 12

8 Per his wife Snores lightly Hasn’t stopped breathingDoes not kick legs during sleep No major personality changes, but overall more “quiet” and withdrawn. 13

9 History & Physical PMH MEDICATIONS HTN GERD DepressionL knee arthritis MEDICATIONS Atenolol 100 mg qd Clonidine 0.2 mg bid Lisinopril 20 mg qd Ranitidine 75 mg qd Zoloft 50 mg po qd Tylenol 650mg po q6h prn 14

10 Key Physical Exam AreasInformed by the history taking Painful joints- examine joints Nocturia- examine cardiac, renal, prostate, or for diabetes Poor memory- assess mood and memory issues

11 History & Physical EXAM: BP 130/75 P 80 Weight 140 lb Ht 5’4”Alert, able to answer questions and carry on conversation without falling asleep. Rest of exam unremarkable except GDS=7/15. 14

12 Do you need to do any other investigations?

13 Key laboratory testingGuided by history and exam Polysomnography- when suspect sleep apnea (central, obstructive), narcolepsy or REM sleep behavior disorder In lab is gold standard Portable devices combining oximetry with HR, RR, nasal airflow may be promising (negative finding >> in lab) OSA common in older adults- morning HA, personality changes, poor memory, confusion, irritability Wrist activity monitors- estimate sleep vs wakefulness based on wrist movement Diagnosis of circadian rhythm sleep disorder

14 Basic Science: Normal Sleep PhysiologyDREAM DEEP SLEEP 3 14

15 Common changes with ageTrouble falling asleep= lower sleep efficiency Early awakening More daytime naps Early bedtime Less deep sleep 4 15

16 Primary Sleep Disorders5-20% Non-REM -PLMS (polysomnography; dopamine agonist) -RLS (Iron, dopamine angonist) Sleep Apnea Eval at Sleep lab CPAP 6 16

17 What could be possible causes of his insomnia?

18 Insomnia Medical Psychiatric Neurologic Environment/ Diet 5

19 Assessment/Plan A/P Medications Cough Arthritis Exercise in eveningAlcohol at night Exacerbated by depression and lifestyle changes in the context of recent retirement. 15

20 What would you advise as next steps for treatment?

21 Plan #1 Improve Sleep hygiene Maintain regular rising and bed timeDo not go to bed unless sleepy Decrease or eliminate naps, unless necessary rest period Exercise daily but not immediately before bedtime Do not use bed for reading or watching TV Relax mentally before going to sleep; do not use bedtime as worry time If hungry, have a light snack, but avoid heavy meals at bedtime Limit or eliminate alcohol, caffeine, and nicotine, especially before bedtime 15 21

22 Plan #1 Improve Sleep hygieneWind down before bedtime and maintain a routine period of preparation for bed Control nighttime environment with comfortable temperature, quiet, darkness Try a familiar noise (fan, white noise) Wear comfortable bed clothing If unable to fall asleep in 30 minutes, get out of bed, perform soothing activity like listening to soft music, light reading Get adequate exposure to sunlight or bring light during the day 15 22

23 Plan #2 Remove offending medicine agents 15 23

24 Plan #3 Nonpharmacologic Interventions to Improve SleepSleep restriction Cognitive interventions Relaxation techniques progressive muscle relaxation Cognitive behavioral therapy combines stimulus control, sleep restrictions, cognitive interventions, with or without relaxation techniques; usually includes sleep hygiene 15 24

25 Plan #4 Pharmacologic therapy

26 Pharmacologic Treatment of Insomnia in the ElderlyCindy Khamphaphanh Pharm.D. Candidate Chad Kawakami Pharm.D., BCPS, CDE University of Hawai’i at Hilo The Daniel K. Inouye College of Pharmacy Pharmacologic Treatment of Insomnia in the Elderly

27 Approach to Pharmacologic Treatment1. Determine the underlying cause of insomnia Medical conditions (treat these appropriately first) Medication related 2. Treat on a short-term basis together with non-pharmacologic interventions 3. When starting a medication, “Start low and go slow.” 4. Monitor for side effects Medical conditions associated with insomnia include: BPH, CVD, CHF, COPD, Chronic Pain, Dementia, Depression, Malignancy, Parkinson’s Disease, Restless Leg Syndrome, Sleep apnea, Stroke, Thyroid Disease

28 Medications Contributing to InsomniaAntidepressants - SSRI, SNRI, MAOI Cardiovascular - alpha agonists/antagonists, beta-blockers, diuretics Decongestants - phenylephrine, pseudoephedrine Narcotic analgesics - codeine, oxycodone Pulmonary - albuterol, ipratropium, theophylline Stimulants - amphetamine derivatives, caffeine, methylphenidate, modafinil Others Antineoplastic agents Corticosteroids Nicotine Phenytoin Thyroid supplements EtOH Opiates disrupt REM and Non-REM stage 3 and 4 sleep. Opiates also worsen sleep apnea. Sedation is not sleep AD - activating Corticosteroids - increase cortisol Albuterol, pseudoephedrine - activating Alpha antagonists - linked to decreased REM Beta-blockers - increased night awakenings and nightmares through decreasing nighttime secretion of melatonin Antidepressants - unknown mechanism Diuretics - nighttime urination

29 Pharmacologic Treatment: OverviewFirst Line for Insomnia (Non-Geriatric): Hypnotic sedatives Sleep-onset insomnia Shorter-acting agents (e.g. zolpidem, zaleplon, triazolam) More rebound and withdrawal symptoms with discontinuation Sleep-maintenance insomnia Longer-acting agents (e.g temazepam, eszopiclone) More daytime carryover American Geriatrics Society recommends AGAINST the use of hypnotics as first line in older adults Sleep onset = problems initiating sleep

30 Sleep Medications: Geriatrics ApproachMelatonin Melatonin Receptor Agonist Ramelton Antidepressants Non-Benzodiazepines (Short-acting) Eszopiclone Zolpidem Zaleplon Benzodiazepines (Intermediate-acting) Temazepam Lorazepam (insomnia d/t anxiety or stress) Estazolam Suvorexant AE w/ hypnotic sedatives Caution in elderly w/ depression Risk rebound insomnia (reduce over weeks to months) Abuse w/ hx of alcohol or other sedative abuse Contraindications (alsohol or sedative abuse, use other sedatives, severe pulmonary failure or untreated sleep apnea, hepatic failure) Dose related (morning sedation, anterograde amnesia, anxiety, impaired balance or motor incoordination, increased risk of falls and hip fractures)

31 Sleep Medications: MelatoninRX: prolonged release (Circadian) 2mg two hrs before bed improved sleep and alertness in patients >55yo OTC: short acting dietary supplement Little to no effect (no clinically meaningful benefit) Headache, back pain, nasopharyngitis, arthralgia Do not use in hepatic impairment, autoimmune disease, LAPP lactase deficiency or glucose-galactose malabsorption

32 Sleep Medications: Melatonin Receptor AgonistRamelteon (Rozerem) Consider in patients w/ hx of substance abuse disorder who prefer not to use scheduled drug Contraindicated w/ fluvoxamine No significant rebound insomnia or withdrawal Avoid taking immediaely after meal d/t delayed onset American Geriactrics Society recommends against using BZD or other sedative hypnotics in older adults and first line

33 Sleep Medications: AntidepressantsAntidepressants: Recommended after treatment failures or when comorbid depression present Trazodone Moderate orthostatic effects (administer with food) Effective for insomnia w/ or w/o depression Headache, dizziness, nausea, priapism Mirtazapine Increased appetite, weight gain, headache, dizziness Effective for insomnia w/ depression Doxepin (FDA approved) Sinequan 25 mg - 75 mg (antidepressant – do not use) vs. Silenor mg at bedtime (insomnia) Silenor has the same sedation profile as Sinequan minus the toxicity Little rebound insomnia No specific preferred agent No specific agent preferred (Doxepin is MOST anticholingergic) Low dose sedating AD alone not adequate tx of MDD w/ insomnia Only moderate effect

34 Sleep Medications: Non-BZD Hypnotic SedativesZolpidem (Ambien, Ambien CR) Tab, ER, sublingual, oral spray No rebound insomnia when abruptly discontinued Avoid taking immediately after meal d/t delayed onset Zaleplon (Sonata) No withdrawal symptoms, daytime anxiety, sedation, or psychomotor impairment Rebound insomnia more likely w/ higher doses Eszopiclone (Lunesta) Metallic aftertaste and headache Avoid with high-fat meal d/t delayed onset Non-BZD compared to BZD appear to be equally effective CNS depression w/ sedative but no anxiolytic effects Beer’s Criteria – Increase risk for falls BZD and non-BZD appear equally effective Drug Class Effect CNS depression w/ sedative but NO anxiolytic effects Enhanced inhibition of GABA Less abuse potential than BZD No withdrawarl or tolerance Reduce sleep onset latency and increase total sleep time in chronic insomnia

35 Sleep Medications: BZD Hypnotic SedativesTemazepam* Lorazepam Estazolam Triazolam Avoid in elderly: Increased risk of falls Psychomotor impairment Cause CNS depression with sedative and anxiolytic effects Risk of withdrawal and tolerance Temazepam is better option of BZD if appropriately dosed (less cognitive and behavioral SE?) Cause CNS depression with sedative and anxiolytics effects Enhance inhibitory effect of GABA Reduce sleep onset latency by 15 mins and may increase total sleep time in chronic insomnia FALLS: risk highest in first 2 weeks, half life didn’t matter

36 Sleep Medications: Novel DrugsSuvorexant (Belsomra) Novel orexin receptor antagonist - block binding of orexin neuropeptides to receptors suppressing wake drive. Usual dose: 10mg - 30 mins before bedtime; may increase to max 20mg Due to less side effects, consider in elderly before hypnotics Most common side effect is mild-to-moderate daytime somnolence No withdrawal or rebound insomnia when abruptly discontinued No dosage adjustment for renal impairment and mild - moderate hepatic impairment Avoid taking immediately after meal d/t delayed onset Try before BZD (no definite place in therapy)