Pharmacological Help for a Good Night s s Sleep Thomas Owens, MD
Objectives 1. Define insomnia and characterize the symptoms and array of causes. 2. Describe traditional and new pharmacologic approaches to the management of insomnia. 3. Evaluate the comparative efficacy, pharmacokinetics and contraindications of agents used in the treatment of insomnia. 4. List strategies for pharmacists to educate and counsel patients with insomnia.
What is Insomnia? Difficulty falling asleep, maintaining sleep, or not feeling rested DSM-IV Psychophysiologic Insomnia Very common 1 to 10% population Up to 25% of elderly Idiopathic Insomnia Dipiro, 2002
Epidemiology of Insomnia Insomnia Studies U.S. Study: one third, 17% serious NIH Study: 10.2% Significantly higher: females, unemployed, elderly, separated/widowed, lower SES Psychiatric disorders: 40% of individuals Only 5% seek medical assistance 10 to 20% use non-prescription drugs Dipiro, 2002
Clinical Features of Insomnia Negative Conditioning Usually a stressful event occurs Arouse anxiety or concern May sleep better on couch or in hotel Sleep labs may give false negative Home Polysomnography Moore & Jefferson, 2004
Stages of Insomnia Short Sleepers Sleep very little with no complaints Sleep State Misperception Normal sleep with complaints of insomnia Initial Insomnia Trouble falling asleep Middle Insomnia Awakens for no reason, may take hour or more to fall back asleep Moore & Jefferson, 2004
Diagnostic Evaluation Physical and mental status exams Laboratory tests Blood count with differential Liver function Thyroid function Medication and substance abuse histories Cause may be multi-dimensional Dipiro, 2002
Common Causes of Insomnia Situational Interpersonal Conflicts Medical Psychiatric Pharmacologically Induced Work or financial stress Major life events, Jet lag, shift work Cardiovascular, Respiratory, Arthritis, other chronic pain, Endocrine disorders, Gastrointestinal, Neurological, Pregnancy, Circadian rhythm sleep disorder Mood disorders, Anxiety disorders, Schizophrenia, Substance abuse Anticonvulsants, Central adrenergic blockers, Diuretics, Selective serotonin reuptake inhibitors, Steroids, Stimulants, Drug withdrawal Dipiro, 2002
Assessment of Insomnia Sleep Diary Duration, frequency, symptoms, sleep habits, treatment history Black Box 25 hr cycles Push back bedtime 1 hr every night Dipiro, 2002
Counseling Patients: Non-Pharmacologic Therapy Stimulus control, progressive muscle relaxation, good sleep intentions Sleep restriction, biofeedback, multi-faceted cognitive behavior therapy Patients should avoid: alcohol, stimulants, nicotine Dipiro, 2002
Case Study: Coal Miners Work/Sleep Cycle 24 hr Mines 8hr shifts Swing shifts in reverse Results on their sleep?
Counseling Patients: Non-Pharmacologic Approaches to Better Sleep Moore & Jefferson, 2004
Counseling Patients: Pharmacologic Therapy for Better Sleep Older: Barbiturates (drugs ending in barbital ) Alcohols / Choral Hydrate Mickey Finn Where does that term come from? There are many tales -- a man from 19th century Chicago. Finn was the keeper of Chicago's Lone Star Saloon. He was alleged to have drugged and robbed his customers. Moore & Jefferson, 2004
Counseling Patients: Pharmacologic Therapy Anti-depressants amitriptyline, doxepin and trazodone Antihistamines may be complicated by anti-cholinergic side effects Nonprescription sleep aids commonly contain antihistamines and analgesics Moore & Jefferson, 2004
Counseling Patients: OTC Pharmacologic Therapy Melatonin Hormone released by pineal gland at night Over-the-counter sleep aid Valerian 2-3 grams one to several times a day Side effects similar to those of sedatives avoid in pregnancy Moore & Jefferson, 2004
Gamma-Aminobutyric Acid: GABA Benzodiazepine hypnotics enhancing the postsynaptic effectiveness BZ-1 subtype zolpidem and zaleplon benzodiazepines BZ-2 subtype benzodiazepines Princeton, 2007
Benzodiazepine Hypnotics relieve insomnia by reducing the latency to sleep onset and number of awakenings and by increasing the total sleep time Princeton, 2007
Sleep Cycle REM
Benzodiazepines onset and duration of activity are the most important characteristics to be considered when choosing an agent onset of action depends on the rate of absorption flurazepam triazolam estazolam temazepam quazepam N-Desalkylflurazepam (N-DAF) Moore & Jefferson, 2004
Counseling Patients on Adverse Effects: Hypnotic Effect Tolerance to BZ hypnotic effect develops sooner with triazolam flurazepam, quazepam, temazepam maintained for 1 month of continuous nightly use Estazolam maintains the duration and quality of sleep at the maximum dosage (2 mg nightly) for up to 12 weeks Long-term use (>6 months) of BZs associated with a low risk of abuse, side effects, and tolerance triazolam flurazepam quazepam estazolam Moore & Jefferson, 2004
Counseling Patients on Adverse Effects: Side Effects Anterograde amnesia occurs more frequently with triazolam than with temazepam lowest effective dosage should be used United Kingdom suspended sales of triazolam in October 1991 high incidence of CNS adverse effects possible memory problems, daytime anxiety and rebound insomnia Moore & Jefferson, 2004
Counseling Patients on Adverse Effects: Side Effects Rebound insomnia occurs more frequently after high doses of triazolam Short and intermediate elimination half life drugs are associated with fewer performance deficits may increase daytime anxiety in elderly patients association between falls and hip fractures and the use of long-elimination-half life BZs Moore & Jefferson, 2004
New BZ-1 1 Agonists Zolpidem Zaleplon imidazolpyridines chemically unrelated to BZs or barbiturates indicated for the short term treatment of insomnia Moore & Jefferson, 2004
Educating Patients: Treatment Guidelines Hypnotic therapy transient or short term insomnia Strategies for stimulus control and good sleep hygiene Chronic Insomnia intermittent pharmacotherapy Educate patients frequency of drug use expected duration of therapy to prevent development of dependence Dipiro, 2002
Educating Patients: BZ Hypnotics Difficulty initiating sleep and those who require daytime alertness Short-acting BZ hypnotics zolpidem or zaleplon Difficulty maintaining sleep or early morning awakening Intermittent elimination half life agents Long elimination half life BZs (anxiety mgt) Dipiro, 2002
BZ Hypnotic Prescriptions Should not be prescribed for individuals with sleep apnea, a history of substance abuse, or during pregnancy Avoid alcohol Provide patients with printed information and verbal counseling on precautions Overdoses with these drugs are managed supportively Abrupt withdrawal of BZ s after chronic use can present as seizures Dipiro, 2002
GABA Benzodiazepine Receptor Agonist Hypnotics HALF-LIFE (HRS) ABSORPTION TYPICAL DOSAGE Zaleplon (Sonata) 1 1.2 Fast 5 10 mg Zolpidem (Ambien) 1.5 4 Fast 2.5 10 mg Zolpidem (Ambien CR) 1.5-4 Fast 12.5 mg Triazolam (Halcion) 2 5 Fast 0.125 0.25 mg Zopiclone 5 6 Fast 3.75 7.5 mg Temazepam (Restoril) 8 12 Moderate 7.5 30 mg Estazolam (Prosom) 12 20 Moderate 1 2 mg Oxazepam (Serax) 5 15 Moderate 10 25 mg Alprazolam (Xanax) 12 20 Fast 0.25 1.0 mg Lorazepam (Ativan) 10 22 Moderate 0.5 2 mg Clonazepam (Klonipin) 22 38 Slow 0.5 2 mg Quazepam (Doral) 50 200 Fast 7.5 15 mg Flurazepam (Dalmane) 50 200 Fast 15 30 mg Ramelteon (Rozerem) 1-2.6 Fast 8 mg Eszopiclone (Lunesta) 6 Fast 2-3 mg
What drugs are most helpful for sleep onset or initial insomnia? zolpidem effective, rapidly absorbed, cleared quickly from the system zaleplon same rapid onset of action and rapid clearing and may have less risk of impairing coordination or cognition triazolam equivalent in efficacy and side effects (except rebound insomnia) temazepam slowly absorbed, least expensive of the four Dipiro, 2002
What drugs are most helpful for nocturnal and early morning awakening? temazepam first choice for nocturnal and early morning awakenings flurazepam, quazepam, chlorazepate effective for nocturnal and early morning awakenings but may have daytime hangover, memory loss, or incoordination zaleplon 3 to 4 hours after ingestion, patients are nearly free of impaired cognition or coordination Dipiro, 2002
Case Study: Patient having trouble with sleep 52 year old white male difficulty falling asleep for 2 months relates this to a recent job change more pressure on him at work, without adequate rewards uses coffee in the morning stays up watching the news on TV otherwise healthy serial checkups routine labs and workups have been normal not depressed
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