Addressing Pharmacologic Issues in. DSM-5 Sleep-Wake. Insomnia. Disorders. DSM-5 Insomnia Disorder. Insomnia. Disorder

Transcription

1 Addressing Pharmacologic Issues in David N. Neubauer, MD Associate Professor of Psychiatry and Behavioral Sciences Johns Hopkins School of Medicine Baltimore, Maryland Restless Legs Syndrome Substance/ Medication- Induced Parasomnias DSM-5 -Wake s Circadian Rhythm s Hypersomnia Breathing- Related s Narcolepsy DSM-5 Restless Legs Syndrome Substance/ Medication- Induced Parasomnias Circadian Rhythm s Hypersomnia Breathing- Related s Narcolepsy Key criteria Dissatisfaction with sleep quality or quantity in relation to difficulty initiating or maintaining sleep or early morning awakening There must be clinically significant distress or impairment The sleep difficulty must be at least 3 nights per week persisting for at least 3 months The sleep problem must be in the context of adequate opportunity for sleep The sleep problem is not better explained or attributed to another sleep disorder, mental disorder or medical condition, or the effects of a substance American Psychiatric Association. Diagnostic and Statistical Manual of Mental s. Fifth DSM-5 (cont d) May specify coexistence with: Another sleep disorder Medical condition Mental disorder (including substance use disorders) May specify: Episodic < 3 months > 1 month Persistent 3 months Recurrent 2 episodes within 1 year DSM-5 (cont d) Daytime impairments associated with nighttime sleep problems Fatigue (sleepiness?) Cognitive performance impairment Attention Concentration Memory Mood disturbance Irritability Lability American Psychiatric Association. Diagnostic and Statistical Manual of Mental s. Fifth American Psychiatric Association. Diagnostic and Statistical Manual of Mental s. Fifth

2 DSM-5 (cont d) Persistent insomnia functional consequences Increased future risk of Major depressive disorder Hypertension Myocardial infarction Decreased productivity and higher absenteeism Greater economic burden Decreased quality of life Restless Legs Syndrome Substance/ Medication- Induced DSM-5 -Wake s Hypersomnia Narcolepsy Parasomnias Breathing- Related s American Psychiatric Association. Diagnostic and Statistical Manual of Mental s. Fifth Circadian Rhythm s DSM-5 Description Manic/Hypomanic Episodes Decreased need for sleep Major Depressive Episode or hypersomnia Premenstrual Dysphoric Hypersomnia or insomnia Melancholic Features Early-morning awakening Generalized Anxiety disturbance Posttraumatic Stress Recurrent distressing dreams; sleep disturbance Acute Stress disturbance Alcohol Withdrawal Caffeine Intoxication Cannabis Withdrawal difficulty insomnia, disturbing dreams Opioid Withdrawal Sedative, Hypnotic, Anxiolytic Withdrawal Stimulant Withdrawal or hypersomnia Tobacco Withdrawal DSM-5 s Commonly Associated with Disturbed Mood s Anxiety s Trauma- and Stressor-related s Schizophrenia Spectrum and Other Psychotic s Substance-related and Addictive s Neurocognitive s American Psychiatric Association. Diagnostic and Statistical Manual of Mental s. Fifth : Natural Course Prevalence Approximately 30% of general population 6% to 10% of population has associated symptoms of daytime functional impairment Up to 50% prevalence in clinical practices Natural evolution of insomnia General population sample in California Baseline 3249 individuals; follow-up at 3 years 1957 individuals symptoms (3 nights/week for 1 month) Baseline: 42.1% of population Persistent at 3-year follow-up: 72.2% of those with baseline insomnia New insomnia at 3-year follow-up: 15.5% without baseline insomnia National Institutes of Health ;28(9): Ohayon MM. Med Clin. 2009;4(1): Risk Factors for Comorbid mental and physical disorders Temperamental factors Anxiety/worry-prone personality or cognitive style Increased arousal predisposition Tendency to repress emotions Environmental Noise Light Uncomfortable temperature High altitude American Psychiatric Association. Diagnostic and Statistical Manual of Mental s. Fifth

3 Risk Factors for (cont d) Advancing age Genetic Female gender: (Females > Males 1.44:1) Familial predisposition for disrupted sleep First-degree relatives Twins: monozygotic > dizygotic Treatment Modalities Promote healthy sleep habits Education about sleep and mental health Optimize treatment of comorbid conditions Psychotherapeutic techniques Behavioral strategies Cognitive-Behavioral Therapy for (CBTi) Light/dark exposure Schedule manipulations Pharmacotherapeutic: Substances Medications American Psychiatric Association. Diagnostic and Statistical Manual of Mental s. Fifth Schutte-Rodin S, et al. J Clin Med. 2008;4(5): NHANES National Use of Prescription Medications for NHANES ,328 noninstitutionalized community-dwelling US adults MCUFI Benzodiazepine receptor agonists Barbiturates Doxepin Quetiapine Ramelteon Trazodone Use in the preceding month Assessed concurrent non-mcufi sedating medications MCUFI = medications commonly used for insomnia; NHANES = National Health and Nutrition Examination Survey. Bertisch SM, et al ;37(2): NHANES Medications Findings 3% of adults used a MCUFI in the preceding month Use increased to Most common Zolpidem Trazodone Concurrent use with MCUFI is high 55% of MCUFI users also taking at least 1 other sedating medicine 10% of MCUFI users taking 3 sedating medications MCUFI with opioids: 24.6% MCUFI with non-mcufi benzodiazepines: 19.5% Highest MCUFI use by age category: 80 years! Bertisch SM, et al ;37(2): What People Take for FDA-Approved Medications Prescription Required? Yes No Formal Indication? No Yes Dietary Supplements Assorted Sedating Medications Off-label Over-the-Counter Aids FDA-Approved Medications Benzodiazepine receptor agonists Benzodiazepines 5 compounds Non-benzodiazepines 3 compounds, various formulations Selective melatonin receptor agonist 1 compound Selective histamine receptor antagonist 1 compound Orexin/hypocretin receptor antagonist 1 compound

4 Generic Name Brand Name Available Doses (mg) Elimination Half-Life (hr) BENZODIAZEPINE RECEPTOR AGONISTS Benzodiazepine Immediate Release Estazolam ProSom 1, Flurazepam Dalmane 15, / active metabolite Quazepam Doral 7.5, 15 39/73 active metabolite Temazepam Restoril 7.5, 15, 22.5, Triazolam Halcion 0.125, Non-benzodiazepine Immediate Release Eszopiclone Lunesta 1, 2, 3 6/ 9 in elderly Zaleplon Sonata 5, 10 1 Zolpidem Ambien 5, in males Non-benzodiazepine Extended Release Zolpidem ER Ambien CR 6.25, Non-benzodiazepine Alternate Delivery Zolpidem oral spray Zolpimist 5, Zolpidem sublingual Edluar 5, 10 ~2.5 Zolpidem sublingual Intermezzo 1.75, 3.5 ~2.5 Brand names are included in this table for participant clarification purposes only. No product promotion should be inferred. Generic Name Brand Name Available Doses (mg) Elimination Half-Life (hr) SELECTIVE MELATONIN RECEPTOR AGONIST Ramelteon Rozerem SELECTIVE HISTAMINE RECEPTOR ANTAGONIST Doxepin (low dose) Silenor 3, DUAL OREXIN RECEPTOR ANTAGONIST Suvorexant Belsomra 5, 10, 15, Brand names are included in this table for participant clarification purposes only. No product promotion should be inferred. Benzodiazepine Receptor Agonists Benzodiazepines Pharmacodynamics Positive allosteric modulators of GABA responses at the GABA A receptor complex Multiple GABA A receptor α subunit subtypes Targeted action in the hypothalamic sleep nuclei Global CNS effects Pharmacokinetics Relatively rapidly absorbed Very wide range of elimination half-lives: Hours to days Expect prolonged half-life in older adults Most efficacious for sleep onset and maintenance Potential for residual daytime sedation CNS = central nervous system. Walsh JK, et al. In: Kryger MH, et al (Eds). Principles and Practice of Medicine. Fifth Edition. St. Louis, MO: Elsevier Saunders; 2011: Benzodiazepine Receptor Agonists Possible Adverse Effects Residual effects Cognitive impairment Somnolence Headache Dizziness Nausea Diarrhea Anterograde amnesia Somnambulism and confused behaviors Rebound insomnia Walsh JK, et al. In: Kryger MH, et al (Eds). Principles and Practice of Medicine. Fifth Edition. St. Louis, MO: Elsevier Saunders; 2011: Zolpidem: 2013 FDA Update Drug Safety Communication Recommends lower doses for women due to slower metabolism and possible excessive blood levels the following morning Initial dose for women should be 5 mg (IR) or 6.25 mg (ER) Consider these lower doses for men as well since they often provide sufficient efficacy Exception: Dissolvable MOTN formulation (1.75, 3.5 mg) already recommends lower dose for women Eszopiclone: 2014 FDA Update Drug Safety Communication Recommends lower initial dose for men and women to be 1 mg at bedtime the previously recommended dose of 3 mg can cause impairment to driving skills, memory, and coordination that can last more than 11 hours after receiving an evening dose Dosage may be increased to 2 or 3 mg at bedtime with caution IR = immediate release; ER = extended release; MOTN = middle-of-the-night. US Food and Drug Administration. May 14, Accessed June 12, US Food and Drug Administration. May 15, Accessed June 12, 2017.

5 Melatonin Receptor Agonist Ramelteon Pharmacodynamics Melatonin MT 1 and MT 2 receptor agonist Targeted action in the hypothalamic SCN Reduces evening circadian driven arousal Reinforces circadian periodicity Enhances sleep onset Pharmacokinetics Relatively rapidly absorbed Relatively short elimination half-life: 1 to 2.6 hours Indication for sleep onset Limited potential for residual daytime sedation Homeostatic and Circadian Regulation Homeostatic Circadian 9 AM 3 PM 9 PM 3 AM 9 AM Wake SCN = suprachiasmatic nucleus. Kato K, et al. Neuropharmacology. 2005;48(2): Ramelteon Adverse effects Somnolence Dizziness Fatigue Prescribing guidelines Take approximately 30 minutes before bedtime Avoid hazardous activities after dose Avoid with hepatic impairment (moderate to severe) Avoid with fluvoxamine Question What is the only antidepressant that you can prescribe in a cream formulation? Low-Dose Doxepin Approved by the FDA (2010) Ultra-low dose (3 mg, 6 mg) Very high histamine H 1 selectivity Beneficial for sleep maintenance Indicated for the treatment of insomnia characterized by difficulties with sleep maintenance No abuse liability Low-Dose Doxepin Warnings do not use with: MAOI in past 2 weeks Untreated narrow angle glaucoma Severe urinary retention Adverse reactions Somnolence/sedation Nausea Upper respiratory tract infections MAOI = monoamine oxidase inhibitor.

6 Orexin/Hypocretin Receptor Antagonist Suvorexant Pharmacodynamics Dual orexin receptor (OX 1 and OX 2 ) antagonist Hypothalamic neurons with peptides orexin-a and orexin-b project to cortex and wake-promoting nuclei to reinforce and stabilize wakefulness Suvorexant promotes sleep by decreasing orexinassociated CNS arousal Pharmacokinetics Relatively rapidly absorbed Elimination half-life: About 12 hours Indication for sleep onset and maintenance Dose-dependent potential for residual daytime sedation Winrow CJ, et al. J Neurogenet. 2011;25(1-2): Neubauer D. Current Psychiatry. 2015;14(1): Suvorexant Recommended use: 10 mg taken only once Within 30 minutes of going to bed At least 7 hours remaining before the planned time of awakening Dose may be increased to a maximum of 20 mg 5 mg is recommended for people taking a moderate CYP3A4 inhibitor Time to effect may be delayed with food Medication Unspecified Early Onset Maintenance Awakening Estazolam Flurazepam Quazepam Temazepam Triazolam Eszopiclone Zaleplon Zolpidem Zolpidem ER Zolpidem spray Zolpidem sublingual Zolpidem sublingual-mont Ramelteon Low-dose doxepin Suvorexant Medication DEA Class PC Most Common Side Effects Estazolam IV X Somnolence, hypokinesia, dizziness, abnormal coordination Flurazepam IV X Dizziness, drowsiness, lightheadedness, loss of coordination, staggering, falling Quazepam IV X Drowsiness, headache Temazepam IV X Drowsiness, dizziness, lightheadedness, difficulty with coordination Triazolam IV X Drowsiness, headache, dizziness, pins & needles, coordination difficulty, lightheadedness Eszopiclone IV C Unpleasant taste, headache, somnolence, rash, respiratory and viral infections, dizziness, dry mouth, anxiety, hallucinations Zaleplon IV C Drowsiness, lightheadedness, dizziness, pins & needles, difficulty with coordination Zolpidem IV C Drowsiness, dizziness, diarrhea, drugged feeling Zolpidem ER IV C Headache, next-day somnolence, dizziness Zolpidem spray IV C Drowsiness, dizziness, diarrhea, drugged feeling Zolpidem sublingual IV C Drowsiness, dizziness, diarrhea, drugged feeling Zolpidem sublingual-mont IV C Headache, nausea, fatigue Ramelteon --- C Somnolence, dizziness, fatigue, nausea, exacerbated insomnia Low-dose doxepin --- C Somnolence/sedation, nausea, upper respiratory tract infection Suvorexant IV C Somnolence PC = pregnancy category. What People Take for Off-Label Prescriptions for Prescription Required? Yes No Formal Indication? No Dietary Supplements Assorted Sedating Medications Off-label Yes Over-the-Counter Aids FDA-Approved Medications Antidepressants Antipsychotics Anxiolytics Antihistamines Anticonvulsants/mood stabilizers Antihypertensives Anesthetics Issues Efficacy for insomnia Safety in insomnia patients Prescribing guidelines Knowledge of sleep effects Is there comorbidity with an indicated condition?

7 Trazodone What People Take for Pharmacodynamics 5-HT 1A partial agonist 5-HT 2A/C antagonist Serotonin reuptake inhibitor α 1 receptor antagonist (strong) H 1 receptor antagonist (mild) Pharmacokinetics Peak plasma: 1 2 hours Half-life: Biphasic 3 6 hours 5 9 hours Adverse effects Dizziness Sedation Hypotension Arrhythmias Priapism Serotonin syndrome Metabolite: mcpp Prescription Required? Yes No Formal Indication? No Dietary Supplements Assorted Sedating Medications Off-label Yes Over-the-Counter Aids FDA-Approved Medications Mendelson WB. J Clin Psychiatry. 2005;66(4): Over-the-Counter Aids All are regulated by the FDA All are antihistamines Diphenhydramine (most products) Peak concentration: 2 3 hours Elimination half-life: 8.5 ± 3.2 hours (short in children; longer in elderly) Doxylamine Peak concentration: 2 4 hours Elimination half-life: hours (longer in elderly) Pharmacodynamics Histamine H 1 receptor antagonist Muscarinic acetylcholine receptor antagonist Tolerance to sedating effects may develop with daily use Adverse effects: Sedation, anticholinergic symptoms Antihistamines: Potential Adverse Effects Next day residual sedation common Anticholinergic effects Confusion and delirium Urinary retention Dry mouth Blurred vision Narrow angle glaucoma exacerbation Greater risk: Elderly individuals Patients concomitantly taking other anticholingeric medications (eg, antidepressants, antipsychotics) Gerretsen P, et al. Expert Opin Drug Saf. 2011;10(5): Prescription Required? What People Take for Yes No Formal Indication? No Dietary Supplements Assorted Sedating Medications Off-label Yes Over-the-Counter Aids FDA-Approved Medications Dietary Supplements: Melatonin Hormone produced by the pineal gland with timing controlled by the circadian system Melatonin blood level: Low throughout daytime Gradually rises in the evening as bedtime approaches Relatively high during the nighttime sleep period Declines at the end of the normal sleep period in the morning May free run in totally blind individuals or in people not exposed to the photoperiod or 24-hour routines Minimal efficacy for insomnia when taken at typical bedtime Strong evidence for selected circadian rhythm disorders Buscemi N, et al. J Gen Intern Med. 2005;20(12):

8 Valerian Kava-Kava Passion flower Skullcap Lavender Hops Glycine Magnesium GABA Dietary Supplements: Everything Else Leach MJ, et al. Med Rev. 2014;24:1-12. Hyoscyamus Stramonium L-Theanine Griffonia Wild jujube seeds Lemon balm Chamomile L-Tryptophan L-Glutamine Wuling There was no statistically significant difference between any herbal medicine and placebo, or any herbal medicine and active control, for any of the thirteen measures of clinical efficacy. Dietary Supplement Concerns None are regulated by the FDA Safety issues Purity Concentration Toxicity Seeff LB, et al. Gastroenterology. 2015;148(3):517.e3-532.e3. Clinical Guidelines American Academy of Medicine AASM Chronic Clinical Guideline Consensus Recommendations Short-term hypnotic treatment should be supplemented with behavioral and cognitive therapies when possible OTC antihistamine as well as herbal and nutritional substances are not recommended in the treatment of chronic insomnia due to the relative lack of efficacy and safety data Older approved drugs for insomnia including barbiturates, barbiturate-type drugs, and chloral hydrate are not recommended for the treatment of insomnia 2008 AASM Chronic Clinical Guideline Consensus Recommendations The choice of a specific pharmacologic agent within a class should be directed by: Symptom pattern Treatment goals Past treatment response Patient preference Cost Availability of other treatments Comorbid conditions Contraindications Concurrent medication interactions Side effects Schutte-Rodin S, et al. J Clin Med. 2008;4(5): Schutte-Rodin S, et al. J Clin Med. 2008;4(5):

9 Grading of Recommendations Assessment, Development and Evaluation (GRADE) From evidence to recommendations transparent and sensible Working group began in 2000 gradeworkinggroup.org Sateia MJ, et al. J Clin Med. 2017;13(2): GRADE PICO Questions Chronic : PICO P: Patients, population I : Intervention C: Comparison O: Outcome In adult patients diagnosed with primary chronic insomnia, how does [intervention] improve [outcomes], compared to placebo? Sateia MJ, et al. J Clin Med. 2017;13(2): Sateia MJ, et al. J Clin Med. 2017;13(2): Clinical Significance Threshold Sateia MJ, et al. J Clin Med. 2017;13(2): Sateia MJ, et al. J Clin Med. 2017;13(2):

10 AASM: Clinical Practice Guideline Chronic Pharmacotherapy All specific recommendations are WEAK, whether FOR or NOT FOR This should not be construed to mean that no sleeppromoting medications are clearly efficacious or indicated in the treatment of chronic insomnia. The strength (or weakness) of these recommendations speaks as much, or more, to the limitations of the data as it does to the relative benefits and risks of the treatments per se. Sateia MJ, et al. J Clin Med. 2017;13(2): Sateia MJ, et al. J Clin Med. 2017;13(2): Take-Away Points Sateia MJ, et al. J Clin Med. 2017;13(2): A wide diversity of medications are now available for the treatment of chronic insomnia Customize pharmacologic treatment for individual patients Consider both pharmacodynamic and pharmacokinetic properties in selecting medications for insomnia patients Employ medications strategically, but aim to minimize exposure whenever possible Always use medications as part of a broader insomnia treatment plan Chronic insomnia is not due to a deficiency of medications, so prescribe wisely