Anjali Ahn, MD Beth Israel Deaconess Medical Center aahn1@bidmc.harvard.edu May 1, 2015
Ms G. is a 50yo female Boston police officer presents with chief complaint: I ve never been a good sleeper! Where do you start? Let s discuss the components of a good sleep history
Chronology of sleep problem Sleep routine Daytime symptoms Comorbid conditions and symptoms Daytime factors
Difficulty falling asleep or staying asleep or both? When did it start and what was going on at that time? What was your sleep like before your sleep issues started? What interventions or medications have you tried already to help with your sleep?
History of her sleep problems: Ms G. has had sleep onset insomnia for 30 yr. Only DFA, no DMS. She recalls sleeping well when she was in college. In the past, she has tried trazodone (ineffective), lorazepam (groggy/ineffective), clonazepam (groggy/ineffective), doxepin (doesn't recall), propranolol (doesn't recall effect), ambien (did not like). She currently uses sonata 10mg which does not help. Uses 3x per week. Has script for lunesta 1mg which she will use on the alternate nights (also ineffective).
What is the range of bedtimes (WD, WE)? What is the range of rise times (WD, WE)? How long does it take to fall asleep? How often do you wake up? Can you get back to sleep? What do you do typically prior to bed? After MNA? Where do you sleep and with whom? How do you feel when you are up in the middle of the night?
Sleep Routine: Ms G. takes sleep meds around 9p. Reads and gets in bed around 10p. Continues to read. Does not feel sleepy at this time at all. Will read for most of the night. No clock, tv, computer, phone. Keeps room dark and clean. May not fall asleep until near dawn. OOB 6:30-7am. Rarely OOB 8:30am. She admits that she is very alert or on guard at night and finds it hard to relax and will wake to the slightest noise. She lives alone but has 4 dogs. The dogs sleep in the bedroom with her. She does feel safer having her dogs with her.
Sleep Routines (continued): How does she feel at night? Suspect hypervigilance: Her father was physically abusive to her mother and her. She then worked 30 yr on the street as a Boston police officer and only in the last yr, has she taken a office position in the police force. It is a "toxic job" but she still loves it and looks forward to going to work.
Are you sleepy during the day? Do you doze unintentionally or nap? Or just tired/fatigued? Very unusual for pure insomniacs to be able to doze/nap. Irritable, mood changes? Does you mood completely improve after a good night s rest? There has to be daytime impairment to make a diagnosis of insomnia.
Daytime symptoms: Ms G. is exhausted and tired But she can t doze off and can t nap.
Caffeine use? How much and when? Alcohol use? Tobacco or illicits? Physical activity? Daytime structure? These daytime habits along with sleep-wake schedule, prebt routine and sleep environment help defines the term sleep hygeine.
Daytime factors Drinks 1 coffee in am, no etoh, no tobacco/illicits Works 9:30a-6:30p and overtime to 8pm twice a wk
H/o mood disorders? Early morning awakenings in depression Ruminations/worry in anxious patients Compulsive prebt routines in OCD patients Hypervigilance in PTSD patients Sxs or suspicion of sleep disordered breathing? Snoring, witnessed apnea, nocturia, obesity, morning headaches Sxs of restless leg syndrome? Leg twitching or kicking, urge to move legs, relief with movement, diurnal variation, antidepressant use Sxs of circadian rhythm disturbance? Strong morning or evening preference, preferred sleep schedule on weekends or vacations
Comorbid conditions and sxs: History of OSA, on PAP therapy and uses faithfully Checked her compliance in office using PAP 5-6 hr per night Dx of OCD and PTSD
Medical conditions Chronic pain syndromes Diabetes (nocturia, neuropathy) BPH Serious cardiopulmonary conditions GERD Menopausal symptoms Medications that can fragment sleep Diuretics > nocturia Beta blocker can cause nightmares, can cause fatigue Many antidepressants suppress REM sleep, result in sleep fragmentation, aggravate RLS or RBD
Patient reported complaint of difficulty initiating or maintaining sleep SOL > 30 min or WASO > 30 min 1 Objective measures (PSG/actigraphy) show sig overlap btw insomniacs and good sleepers 2 Many patients with insomnia overestimate SOL and WASO and underestimate sleep duration altered perception 3 Sxs occur despite adequate opportunity Sxs produce a deficit in daytime function Buysse DJ JAMA 2013, 1 Lichstein KL, Behav Res Ther 2003, 2 Rosa RR, Psychosom Med 2000, 3 Edinger JD Sleep Me
ICSD-1 & ICSD-2 subtyped primary & secondary (comorbid) Subtyped primary insomnia into psychophysiologic, idiopathic and paradoxical ICSD-3 represents marked departure from this nosology Vast majority of insomnia subtypes share characteristics regardless of whether primary or comorbid Typically all are assoc with maladaptive cognitions and behaviors Treatment approaches are same regardless of subtype or comorbidity Diag reliability and validity have been challenged ICSD-3 elected to consolidate all insomnia subtypes Sateia MJ Chest 2014
ICSD-3 general criteria for insomnia diagnosis A report of sleep initiation or maintenance problems Adequate opportunity & circumstances for sleep Daytime consequences Symptoms at least 3x per week ICSD-3 Insomnia Diagnoses Chronic insomnia disorder >3 months duration Short-term insomnia disorder Other insomnia disorder Sateia MJ Chest 2014
Slide borrowed from Suzie Bertisch, MD
Prevalence ~ 10-20% in the general population Based on predominant symptom (DFA or DMS) Prevalence of sleep maintenance sxs 50-70% Prevalence of sleep onset sxs 35-60% Prevalence of nonrestorative sleep 20-25% Multiple sleep sxs more common Morin CM Can J Psych 2011, McCrae CS Sleep Med Rev 2001, Buysse DJ JAMA 2013
Depression, female sex, older age, lower SES, comorbid medical/psych disorders, marital status, and AA race 1 Follows a chronic course in most patients Insomnia is a risk factor for depression 2, metabolic syndrome 3, HTN 4, and CAD 5 1 Ohayon MM Sleep Med Rev 2002, 2 Baglioni C J Affect Disord 2011, 3 Troxel WM Sleep 2010, 4 Vgontzas AN Sleep 2009, 5 Laugsand LE Circulation 2011.
Individuals with insomnia focus cognitively or ruminate on insomnia and develop learned sleep preventing assoc. Maladaptive behaviors (prolonged time in bed, daytime napping, increased alcohol use) help to perpetuate Cortical arousal results from conditioning and promotes abnormal sensory and info processing and memory formation AIE pathway Attention, Intention, Effort 2 Basic idea is that normal sleep is largely automatic and involuntary and can be inhibited by selectively directing attention to it Explicit intention to sleep compromises the automaticity Increased effort results in maladaptive behaviors 1 Riemann D Sleep Med Rev 2010, 2 Espie CA Sleep Med Rev 2006
Neurocognitive Model of Insomnia 1 Riemann D Sleep Med Rev 2010
Insomnia: The Hyperarousal Model Elevated metabolic rate, cortisol, & ACTH during sleep period 1 Higher heart rates in insomnia patients and reduced parasympathetic tone in HR variability 1 Increased high freq EEG activity during NREM sleep 2 Increased activity on neuroimaging during sleep 2 1 Bonnet MH Sleep Med Rev 2010, 2 Riemann D Sleep Med Rev 2010,
Careful clinical history Sleep diaries, actigraphy Sleep study testing only if coexisting sleep disorder is suspected 3-P model 2 Predisposing factors Ms G : h/o childhood abuse, fam h/o insomnia Precipitating factors Ms G : when she started work 30 yr ago as a police officer on the street Perpetuating factors Ms G : hypervigilance, PTSD/OCD, increased time in bed 1 Buysse DJ JAMA 2013, 2 Spielman AJ Psych Clin North Am 19
Behavioral therapy Pharmacologic therapy
Maladaptive thoughts, beliefs and behaviors are often perpetutating factors in chronic insomnia. These are the targets of therapy for CBT. Use of sleep diaries to help inform baseline patterns Requires patient investment in changing patterns of behavior Use of voluntary waking behaviors to influence sleep Indicated for both primary and comorbid insomnia
Benzodiazepine receptor agonist drugs (BzRA) Benzodiazepines Non-benzodiazepines (zolpidem, zaleplon, eszopiclone) Sedating antidepressants Trazodone, doxepin, mirtazapine Melatonin receptor agonists Ramelteon, melatonin Gabapentin & pregabalin Antihistamines Antipsychotics
Facilitates Sleepiness Facilitates Arousal Adenosine X GABA X Galanin X Glycine X Melatonin X Acetylcholine X Dopamine X Glutamate X Histamine X Norepinephrine X Orexin 1 and 2 X Serotonin X GABA = γ-aminobutyric acid Gulyani S Chest 2012
Common OTC Sleep Aids Mechanism of Action FDA Indication (Insomnia) Nytol H1 receptor antagonist Yes Common Side Effects Daytime drowsiness/grogginess, daytime impairment, dizziness, dyskinesia, xerostomia, urinary retention Half-life 4-8 h Sominex H1 receptor antagonist Yes Same as Nytol 4-8 h Sleepinal H1 receptor antagonist Yes Same as Nytol 4-8 h Unisom H1 and H2 receptor antagonist Yes Daytime grogginess effect, daytime impairment 6-8 h Melatonin MT 1 and MT 2 receptor agonist No Daytime grogginess effect, daytime impairment, confusion 30-50 min Tryptophan Modulation of serotonin No Combination drugs Diphenhydramine H1 and H2 receptor antagonist No Drowsiness, headaches, dizziness Daytime drowsiness, daytime impairment 1-3 h N/A b Tylenol PM H1 receptor antagonist No Same as Nytol N/A b Anacin PM H1 receptor antagonist No Same as Nytol N/A b Nyquil Herbal aids Valerian, kava, chamomile H1 and H2 receptor antagonist No Daytime grogginess N/A b Unknown No Hepatotoxicity N/A b Adapted from Gulyani S Chest 2012
FDA Approved Drugs for Insomnia Trade Name Generic Name Mechanism of Action Dose, mg Common Side Effects Half-life, h ProSom Estazolam GABA A modulator 1-2 Dalmane Flurazepam GABA A modulator 15-30 Halcion Triazolam GABA A modulator 0.25-0.5 Restoril Temazepam GABA A modulator 7.5-30 Doral Quazepam GABA A modulator 7.5-30 Daytime grogginess effect, dry mouth, weakness, coordination issues, dizziness GI upset, irritability drug dependence, ataxia, dizziness, headache Amnestic events, euphoria, GI upset, headache, dizziness, tingling of skin, coordination issues Daytime grogginess effect, GI upset, dizziness, hypotension, blurred vision GI upset, hallucinations, slurred speech, dizziness, headache 10-24 2 a 1.5-5 8 39 Sonata Lunesta Ambien Rozerem Zaleplon Eszopiclone Zolpidem Ramelteon GABA A α1βγ2 modulator GABA A α1-3βγ2 modulator GABA A α1βγ2 modulator Melatonin (MT 1 and MT 2 receptor agonist) 5-20 2-3 1.75-12.5 b Silenor Doxepin H1 receptor antagonist 3-6 8 Dizziness, loss of appetite, eye pain, coordination issues, numbness, headache Disorders of taste, respiratory effects, dizziness, headache, GI upset, coordination issues Headache, dizziness, amnestic events, confusion, slurred speech Fatigue, dizziness, nausea, GI upset, fertility issues 1-3 Urinary retention, respiratory effects, dizziness 15 Adapted from Gulyani S Chest 2012 1 6 2-3
Non-FDA-Approved Antidepressant Meds Used as Sleep Aids Class Generic Trade Name Dose, mg Side Effects Half-life, h Tricyclic antidepressants Trazodone Desyrel 100-150 Nervousness, fatigue, diarrhea 7 Amitriptyline Elavil 75 Weight gain, xerostomia 15 Nortriptyline Pamelor 25 Dysrhythmia, cardiotoxicity 15-39 H1 receptor antagonist Mirtazapine Remeron 15 Weight gain, increase of appetite, liver toxicity 26-37 SNRI, 5-HT2 antagonist Nefazodone Serzone 100 Headaches, dizziness, confusion 2-4 D2 and 5-HT2 receptor antagonist Quetiapine Seroquel 100-300 Agitation, dizziness, extrapyramidal effects 6 5-HT =5-hydroxytryptamine (serotonin); D2 =dopamine; SNRI =serotonin-norepinephrine reuptake inhibitor. Adapted from Gulyani S Chest 2
The five subunits of a GABA A receptor. In addition to a Cl channel pore and two GABA active binding sites, a BZD allosteric binding site exists at the interface of the γ2 subunit and one of four isoforms of the α subunit (α1, α2, α3, and α5). BZDs have nonselective binding affinity for the BZD site regardless of the α-subunit isoform, whereas newer BZD receptor agonist insomnia medications have more selective affinity to the BZD binding sites that contain specific α-subunit isoforms as depicted in the key. This selectivity allows for not only greater control of clinical effects but also association with specific side effect profiles (Table 4). BZD = benzodiazepine; Cl = chloride ion; GABA = γ-aminobutyric acid.
Effects Mediated by GABA A Receptor α Subunits Clinically Relevant Effects Side Effects Subunit Sedation Anxiolytic Muscle Relaxant Anticonvulsive Antidepressant Amnesia Dependence α1 X X X X α2 X X X α3 X α5 X Zolpidem (Ambien): α1 Zaleplon (Sonata): α1 Eszopiclone (Lunesta) : α2 & α3
Edited from Table 3 in Buysse DJ JAMA 2013 Class/Drug Benzodiazepine TMax (hours) Elimination Half Life (hours) Usual Hypnotic Dose (mg) Triazolam 1 2 2 6 0.125 0.25 Yes Temazepam 1 2 8 22 15 30 Yes Estazolam 1.5 2 10 24 1 2 Yes Approved for Insomnia Comments Early reports of adverse effects were likely dose-related Metabolized mainly by conjugation (no CYP-related drug interactions) Triazolo ring structure similar totriazolam Quazepam 2 3 48 120 7.5 15 Yes Active metabolite accumulates with repeated dosing Flurazepam 1.5 4.5 48 120 15 30 Yes Active metabolite accumulates with repeated dosing Alprazolam 0.6 1.4 6 20 No Lorazepam 0.7 1 10 20 1 4 No Often noted for significant withdrawal Metabolized by conjugation (no CYP-related drug interactions) Clonazepam 1 2.5 20 40 0.5 3 No Often used for other sleep disorders including RLS, parasomnias
Edited from Table 3 in Buysse DJ JAMA 2013 Class/Drugs Non-Benzodiazepine TMax (hours) Elimination Half Life (hours) Usual Hypnotic Dose (mg) Approved for Insomnia Comments Zaleplon 1 (0.5 2) 1 (0.8 1.3) 5 20 Yes Shortest-acting BzRA Eszopiclone 1.5 (0.5 2) 6 (5 8) 1 3 Yes ~30% may have unpleasant taste or side-effects Zolpidem Oral tablet 1.6 (0.5 1.5) 2.5 (1.4 4.5) 5 10 Yes Most widely-prescribed hypnotic Zolpidem: Extended Release (Ambien CR ) 1.5 (1.5 2.0) 2.8 (1.6 4.5) 6.25 12.5 Yes Higher concentrations 3-8 hours post dose than traditional zolpidem Zolpidem: Sublingual (Intermezzo ) 0.6 (0.6 1.3) 2.5 (1.4 3.6) 1.75 3.5 Yes Buffer permits increased buccal absorp, lower dose Zolpidem: Sublingual (Edluar ) 1.4 (0.5 3.0) 2.7 ( 1.5 6.7) 10 Yes Mainly absorbed via GI tract Zolpidem: Oral Spray (Zolpimist ) 0.9 2.8 (1.7 8.4) 10 Yes Bioequivalent to tablets in terms of C max, T max, t 1/2
Class/Drug T Max (hours) Sedating antidepressant drugs Half Life (hours) Mechanism 2 Usual Hypnotic Dose (mg) FDA Approved Indication Comments, Side Effects Doxepin 3.5 (1.5 4) 15 (10 30) Low dose: H1 antagonist Higher doses: 5HT 2, α 1, M 1, antagonist; NE, 5HT reuptake inhibitor 3 6 (Silenor ) 10 100 (generic) Insomnia Depression Anxiety 3-6 mg dose approved for insomnia; Side effects at higher doses: orthostatic hypotension, anticholinergic, cardiac conduction delay Amitriptyline 2 5 30 (5 45) 5HT 2, α 1, M 1 antagonist; NE, 5HT reuptake inhibitor 10 100 Depression Side effects at higher doses: orthostatic hypotension, anticholinergic, cardiac conduction delay Trazodone 1 2 9 (7 15) 5HT 2, α 1, H 1 antagonist; 5HT reuptake inhibitor 25 150 Depression Side effects: dizziness, risk of priapism Mirtazapine 2 (1 3) 30 (20 40) Edited from Table 4 in Buysse DJ JAMA 2013 5HT 2-3, α 1-2, H 1, M 1 antagonist; 5HT reuptake inhibitor 7.5 30 Depression Increased appetite, weight gain, anticholinergic
Slide borrowed from Suzie Bertisch,
Slide borrowed from Suzie Bertisch, MD Buscemi N, et al JGIM. 2007 Sep 22(9):133-50
Edited from Table 4 in Buysse DJ JAMA 2013 Class/Drug T Max (hours) Half Life (hours) Mechanism 2 Usual Hypnotic Dose (mg) FDA Approved Indication Comments, Side Effects Melatonin agonist drugs Melatonin 0.3 1 0.6 1 MT 1, MT 2 agonist 0.5 3 No FDA approval FDA defined as a dietary supplement Ramelteon 0.75 (0.5 1.5) 1 2.6 MT 1, MT 2 agonist 8 Insomnia Main effect on sleep latency Anticonvulsant drugs Gabapentin 1.6 3 5 9 Uncertain. GABA analog, but does not have activity at GABA receptors. Possible alpha 2 - delta receptor ligand 100 900 Post herpetic neuralgia; epilepsy Renal excretion,non-linear pharmacokinetics (reduced bioavailability at higher doses); dizziness, ataxia, fatigue Pregabalin 1.5 6.3 alpha 2 -delta receptor ligand. GABA analog, but does not have activity at GABA receptors. 50 300 Diabetic peripheral neuropathy; Post herpetic neuralgia; Adjunct for partial seizures; Fibromyalgia Renal excretion; dizziness, headache, weight gain, dry mouth
Edited from Table 4 in Buysse DJ JAMA 2013 Class/Drug T Max (hours) Half Life (hours) Mechanism 2 Usual Hypnotic Dose (mg) FDA Approved Indication Comments, Side Effects Sedating antipsychotic drugs Olanzapine 4 6 20 54 5HT 2, D 1-4, α 1, H 1, M 1-5 antagonist 2.5 20 Schizophrenia Bipolar Disorder Hypotension weight gain, akathisia, dizziness Quetiapine 1 2 6 5HT 1-2, D 1-2, α 1-2, H 1 antagonist 25 50 Schizophrenia Bipolar Disorder Dry mouth, constipation, weight gain, asthenia, headache Antihistamine drugs Diphenhydramine 1 4 4 8 H 1, M 1 antagonist 25 50 Allergic reactions, motion sickness, Parkinsonism Anticholinergic Doxylamine 2 3 10 H 1, M 1 antagonist 25 mg Allergies, hypersensitivity, insomnia Anticholinergic; Dystonic reaction
Clonidine Used frequently in children with insomnia and ADHD or ASD 1 Prazosin Effective for treatment of nightmares in patients with PTSD 2 Gabapentin Some efficacy in treatment of hot flashes 3 1 Barrett JR Journal Child Adolescent Psychopharm 2013, 2 Hudson SM Prim Care Companion CNS Disord 2012 3 Saadait N Glob J Health Sci 2013
Orexin antagonist, recently FDA approved Suvorexant blocks OX1 and OX2 receptors Orexins promote wake and suppress REM sleep Orexin neurons are absent in narcoleptics with cataplexy
LPS WASO Dosing: non-elderly 20 or 40 mg elderly15 or 30 mg. n>250 in each group. Herring, et al, 2014
Efficacy Results from Herring et al. Kunal V. Ann Pharmacother 2015
Adverse Drug Events Associated With Suvorexant Kunal V. Ann Pharmacother 2015
Start at 10 mg qhs, increase to 20 mg if needed Concerns: Safety & efficacy similar in elderly, but consider lower dose Metabolized by CYP3A; do not use in pt with hepatic failure May cause hypnagogic hallucinations or sleep paralysis Do not use in pt with narcolepsy May worsen depression No obvious worsening of OSA or COPD Abuse & dependence: Among polydrug users, drug liking similar to zolpidem (both at high doses) No evidence of physical dependence Doses up to 240 mg cause just sleepiness
DBPCT found that eszopiclone 3mg improved sleep quality and duration without prolonging resp events or worsening hypoxemia 1 RCT showed eszopiclone group had greater CPAP adherence (1.3hr more of CPAP use per night). Another study showed use of eszopiclone during CPAP titration improved short term CPAP adherence. 2,3,4 Trazodone at doses up to 100mg increases arousal threshold in response to hypercapnia and allows patients to tolerate higher CO2 levels 5 RDBPCT showed shorter SOL with ramelteon in older individuals starting on APAP therapy without affecting APAP adherence or daytime function 6 1 Eckert DJ Clin Sci 2011, 2 Lettieri CJ Ann Intern Med 2009, 3 Bradshaw DA Chest 2006, 4 Lettieri CH Chest 2009, 5 Heinzer RC Eur Respir J 2008, 6 Gooneratne NS J Clin
Insomnia is one of the diagnostic features of depression. Data suggests that insomnia often predates depression. Insomnia is a risk factor for depression, anxiety, substance abuse and suicide 1 In study of adolescents, 69% of insomnia cases preceded comorbid depression and anxiety disorder preceded insomnia 73% of the time 2,3 Longterm outcomes sig improve when insomnia is managed concurrently 4 Adding trazodone (50-100mg) to SSRI has been shown to improve insomnia with comorbid depression 5 Eszopiclone and fluoxetine assoc with greater sleep improvements and depression scores than SSRI alone 6 1 Taylor DJ Behav Sleep Med 2003, 2 Mindell JA Pediatrics 2006, 3 Johnson EO Pediatrics 2006, 4 Riemann D Drugs 2009, 5 Nierenberg AA Am J Psychiatry 1994, 6 Fava M Biol
Discussed how her hypervigilance affects her sleep and makes it hard for her to relax Discussed how her childhood history and work stress have contributed to her hypervigilance Had her d/c sonata and lunesta 1mg Wrote her for lunesta 3mg qhs Sleep restriction: Instructed her to take at 1am and get into bed at 2am and to rise by 7am One week later we added clonidine 0.1mg Instructed to continue with regular PAP therapy
3 weeks later Ms G returned for followup: Sleeping much better with lunesta 3mg and clonidine 0.1mg Found comfort and reassurance in the acknowledgment of her hypervigilance, of the safety she finds with sleeping with her 4 dogs and for permission to go to bed later Felt more relaxed and accepting of her situation Got a book light to use with reading prior to bed and now gets sleepy after about 45 min Feels more refreshed during the day
Thank you!