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Devon A. Sherwood, PharmD, BCPP Assistant Professor UNE College of Pharmacy Clinical Psychopharmacology Specialist Spring Harbor Hospital Identify sleep stages and sleep cycles in a typical nights rest to relate how changes in these patterns affect sleep quality Differentiate various causes, classifications and presentations of insomnia Explain the importance of sleep hygiene and other non-pharmacologic therapies to help counsel patients with insomnia Compare therapeutic roles and pharmacokinetic profiles of hypnotic medications recommended in current guidelines Recognize inappropriate or contraindicated medications Advise patients' about potential adverse effects of insomnia treatments Which stage of sleep is when most parasomnias occur (eg. child bedwetting), and is known as restorative sleep characteristically seen by predominant delta waves on a polysomnograph? A. REM B. NREM Stage 1 C. NREM Stage 2 D. NREM Stage 3 E. NREM Stage 4 DR is a 42 yo male who is taking fluvoxamine for OCD. His physician wants to prescribe a sleep aid to help with antidepressant induced insomnia. Which sleep aid is contraindicated in this patient? A. Zaleplon B. Ramelteon C. Mirtazapine D. Diphenhydramine E. Suvorexant DR is a 42 yo male who is taking fluvoxamine for OCD. His physician wants to prescribe a sleep aid to help with antidepressant induced insomnia. Which agent would be the best choice in this patient? A. B. C. D. E. Eszopiclone Melatonin Trazodone Temazepam Suvorexant Nonrapid Eye Movement (NREM) Stage I - Theta waves Lightest sleep, easy to rouse Stage II – More theta waves, sleep spindles Deeper level of sleep Stage III – Increase in delta waves (20%) Deeper sleep Stage IV – Delta waves (50%) Deep sleep, difficult to rouse Rapid Eye Movement (REM) Frequent bursts of eye movement activity that occur Brain waves resemble Stage 1 (fast, low) Harder to wake than Stage 1 Kaplan V, Kaplan & Sadock’s Comprehensive Textbook of Psychiatry, 9th edition 2009; ch 20: 2150-2161. Which stage of sleep is when most parasomnias occur (eg. child bedwetting), and is known as restorative sleep characteristically seen by predominant delta waves on a polysomnograph? A. REM B. NREM Stage 1 C. NREM Stage 2 D. NREM Stage 3 E. NREM Stage 4 Develops within the first 2 years of life Involves a 24.2 – 25 hour internal clock Reset by external stimuli Primary – Conditions inherent to the mechanisms by which sleep is regulated Parasomnia Dyssomnia Insomnia Hypersomnia Secondary – Sleep disturbances consequently due to some other disorder Kaplan V, Kaplan & Sadock’s Comprehensive Textbook of Psychiatry, 9th edition 2009; ch 20: 2150-2161. Definition: Difficulty falling asleep, maintaining sleep, or not feeling rested despite a sufficient opportunity to sleep Epidemiology: 1/3 of US population reports insomnia 17% reported the symptoms to be serious SH is a 25yo BF who comes into you community pharmacy complaining she can’t sleep. She tells you she started having problems during this past semester in pharmacy school after exams. Upon questioning, the patient tells you she drinks “a lot” of caffeine and never goes to bed the same time every night since she stared school this past fall. She is requesting for something to help her sleep now that the problem is persisting into the next semester. Currently, her only medication is Fluoxetine (Prozac®) 60mg QHS. What other questions should you ask the patient before making a recommendation? What classification for insomnia is SH likely experiencing? What strategies could she implement to help her improve this condition? Patient Case What medications would you recommend for SH? Are there any drug interactions to be concerned with? Situational – stress, conflicts, jet lag Medical – cardiovascular, pain, respiratory, endocrine disorders, GI, neurologic, pregnancy Psychiatric – mood disorders, anxiety, substance abuse Pharmacologically Induced – anticonvulsants, central adrenergic blockers, diuretics, SSRI’s, steroids, stimulants Dipiro JT, Pharmacotherapy Inadequate Sleep Hygiene Psychophysiological Insomnia Sleep State Misperception Idiopathic Insomnia Kaplan V, Kaplan & Sadock’s Comprehensive Textbook of Psychiatry, 9th edition 2009; ch 20: 2150-2161. Short-Term (Acute) vs. Long Term (Chronic) Acute Insomnia: Overall, non-benzodiazepines (Z-drugs) or in specific patients with comorbidities sedative antidepressants are preferred Eszopiclone, zolpidem, and suvorexant may improve short-term global and sleep outcomes for adults with insomnia disorder Caution even in short-term treatment, as pharmacotherapies for insomnia may cause cognitive and behavioral changes and have been associated with infrequent but serious harms Wilt T, et al. Pharmacologic Treatment of Insomnia Disorder: An Evidence Report for a Clinical Practice Guideline by the American College of Physicians. Annals of Internal Medicine 2016: 165(2) Chronic Insomnia: CBT is 1st line therapy If CBT unsuccessful, weigh risk vs. benefit of medications as evidence of benefit is weak Comparative effectiveness and long- term efficacy of pharmacotherapies are still not established Qaseem A, et al. Management of Chronic Insomnia Disorder in Adults: A clinical Practice Guideline from the American College of Physicians. Annals of Internal Medicine 2016: 165(2). Wilt T, et al. Pharmacologic Treatment of Insomnia Disorder: An Evidence Report for a Clinical Practice Guideline by the American College of Physicians. Annals of Internal Medicine 2016: 165(2) Cognitive behavioral therapy Stimulus control Sleep hygiene Relaxation therapy Light therapy Sleep deprivation Up to 80% of people with insomnia treated nonpharmacologically have a positive response. Maintain regular hours of bedtime and arising Do not eat heavy meals before bedtime Avoid napping during the daytime Exercise daily Avoid “clock watching” Minimize cigarette smoking and caffeine before bedtime Release worrisome thoughts before bedtime Make the bedroom comfortable Avoid alcohol as a sleep aid Valerian Root Melatonin Kava Kava (not recommended) Diphenhydramine and Doxylamine [Rx hydroxyzine pamoate (Vistaril®)] Branded as several products Diphenhydramine: Benadryl, Diphenhist, Unisom Gelcaps, Nytol, Simply Sleep, Sleepinal, Sominex, Twilite, Tylenol PM Doxylamine: Good Sense Sleep Aid, Unisom Sleep Tabs MOA – competes with histamine for H1receptor sites; also Ach effects Problems with antihistamines: Tolerance Hangover Barbiturates Chloral Hydrate Antidepressants Trazodone Mirtazapine Amitryptiline Doxepin Preferred for treating: Antidepressant Induced Insomnia Insomnia due to depression or anxiety symptoms Generally low doses work best and have minimal to no side effects Trazodone most widely used Monitor Mirtazapine for ADR Weight gain, HTN, Diabetes Mellitus Silenor® ultra-low-dose brand (doxepin 3mg or 6mg) vs. generic doxepin 10mg Zolipidem (Ambien®, Intermezzo®, others) Zaleplon (Sonata®) Eszopiclone (Lunesta®) All have same MOA: Selectively act on BZD1 receptor FDA Black Box Warning: Abnormal thinking, behavioral changes and complex behaviors: May include “sleep-driving” Any new onset behavioral changes need evaluation As effective as BZD hypnotics with little effect on sleep stage Not associated with tolerance or rebound after 35 days of use Due to MOA which selectively acts on BZD1 receptor: Minimal anxiolytic effects No muscle relaxant or anticholenergic effects Ambien®, Ambien CR®, Intermezzo®, Edular®, Zolpimist® Packaage Inserts Dose for Men: Zolpidem IR or Edular® SL : 5 to 10 mg (max 10 mg) Ambien CR: 6.25 to 12.5mg (max 12.5 mg) Intermezzo® SL: 3.5 mg (max 3.5 mg) Dose for Women: Zolpidem IR or Edular® SL : 5 mg (may increase to max 10mg) Ambien CR: 6.25 mg (may increase to max 12.5mg) Intermezzo® SL: 1.75 mg (may increase to max 3.5mg) Elderly & hepatically impaired = lowest doses only PK: T½ = 2.5h Duration of action (sleep effects) = 6 - 8 hours No significant rebound insomnia, withdrawal symptoms, daytime anxiety or daytime sedation No psychomotor impairment, or memory impairment Most common SE are dizziness, HA, and somnolence Sonata® package insert Dose: 10 mg nonelderly adults 5 mg elderly PK: Rapid onset, short duration of effects T½ = 1 hour Duration = 3 hours FDA approved for long term use No evidence of tolerance throughout 6 months of nightly use Most common side effects are unpleasant taste, headache and somnolence Dosing: 2 mg qhs in nonelderly patients, then increase to 3 mg if necessary 1 mg qhs in elderly, severely hepatic impairment, or concurrently administered potent CYP 3A4 inhibitors PK: T½ = 6 h Duration = 7 - 8 hours NO evidence of abuse or dependence OR impaired daytime wakefulness MOA: Melatonin receptor agonist with high affinity for MT1 and MT2 and selectivity over the MT3 receptor No affinity for GABA receptors Side effects include fatigue, dizziness, drowsiness Dose: 8 mg qhs PK: T½ = 1-2.6 h 2-5 hours (active metabolite) Metabolized by CYP 1A2 – watch for DDI’s! Quick onset and duration of action Median peak concentration occurs at 0.75 h DR is a 42 yo male who is taking fluvoxamine for OCD. His physician wants to prescribe a sleep aid to help with antidepressant induced insomnia. Which sleep aid is contraindicated in this patient? A. Zaleplon B. Ramelteon C. Mirtazapine D. Diphenhydramine E. Suvorexant Five BZD are FDA approved for insomnia: Estazolam, Flurazepam, Quazepam, Temazepam, Triazolam MOA of BZD: Nonselectively binds to BZD receptors Increase stage 2 sleep, decrease stage 1 and 4 sleep – Do not decrease REM sleep Increase total sleep time Decrease latency to sleep onset and number of awakenings Benzodiazepines Used for Insomnia Micromedex® 2016 Orexin receptor antagonist Approved for insomnia with sleep onset and/or sleep maintenance difficulties The orexin neuropeptide signaling system is a central promoter of wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress wake drive. Use the lowest dose effective Dose = 10 mg po within 30 minutes of bedtime No more than once per night At least 7 hours remaining before planned awakening If the 10 mg dose is well- tolerated but not effective, increase dose not to exceed 20 mg once/night Time to effect may be delayed if taken with or soon after a meal CYP 3A4 DRUG INTERACTION! Dose = 5mg if moderate interaction, 10mg maximum AVOID use with strong CYP 3A4 inhibitors DR is a 42 yo male who is taking fluvoxamine for OCD. His physician wants to prescribe a sleep aid to help with antidepressant induced insomnia. Which of the following medications would be the best choice in this patient? A. B. C. D. E. Eszopiclone Melatonin Trazodone Temazepam Suvorexant Diagnosis Insomnia has a high prevalence – Usually an underlying problem, not a primary disorder CBT & Sleep Hygiene first! Nonpharmacologic treatment first, then pharmacologic therapies Appropriate Drug Selection Pharmacokinetics Drug-drug interactions Drug-disease interactions SH is a 25yo BF who comes into you community pharmacy complaining she can’t sleep. She tells you she started having problems during this past semester in pharmacy school after exams. Upon questioning, the patient tells you she drinks “a lot” of caffeine, never goes to bed the same time every night since she stared school this past fall. She is requesting for something to help her sleep now that the problem is persisting into the next semester. Currently, her only medication is Fluoxetine (Prozac®) 60mg QHS. What other questions should you ask the patient before making a recommendation? What classification for insomnia is SH likely experiencing? What strategies could she implement to help her improve this condition? Patient Case What medications would you recommend for SH? Are there any drug interactions to be concerned with? www.vectorstock.com CE Test Questions: Which of the following medication can effect the sleep cycle (ie. increase or decrease any stage of sleep)? SELECT ALL THAT APPLY: A. estazolam B. triazolam C. temazepam D. eszopiclone E. zaleplon CE Test Questions: Which of the following is NOT associated with next day hangover? A. B. C. D. E. diphenhydramine (Unisom) quazepam (Doral) suvorexant (Belsomra) ramelteon (Rozerem) zaleplon (Sonata) CE Test Questions: KZ is a 45yo BF who travels often. The physician would like help her sleep flying across the country. She has no comorbidities or current medications. The physician specifically asks if you know of a medication that only lasts a few hours, so she will not have any residual effects. Which of the following would be BEST CHOICE to give KZ at this time? A. B. C. D. E. eszopiclone zaleplon doxylamine temazepam valerian root CE Test Questions: TE is a 48yo WM complaining of trouble falling asleep. He reports this started last week when he began taking Wellbutrin XL® (bupropion) 150mg po QAM for depression. He has no comorbidities or other medications. Considering TE’s trouble falling asleep is likely due to his new antidepressant medication, which of the following medications used for insomnia would be best to recommend? A. B. C. D. E. Trazodone Imipramine Zolpidem Temazepam Ramelteon Devon A. Sherwood, PharmD, BCPP [email protected]