1. INSOMNIA Pharmacotherapy 3 for PharmD students Fall semester 2013

2. References 1- J.Dipiro, R.Talbert, et al. (2011), Pharmacotherapy, a pathophysiologic approach, 8th edition: Sleep Disorders.ch 81. 2- M. Koda Kimble, et al.. (2013), Applied Therapeutics, Sleep Disorders, 10th edition, 3- NICE guideline: Zaleplon, zolpidem and zopiclone for the short-term management of insomnia. April 2007. 4-Pharmacist Letters. Comparison of Insomnia Treatments. May 2012.

3. Introduction  Insomnia is a very common disorder that can present in a number of different ways. Patients may have difficulty falling asleep (sleep latency), difficulty staying asleep (sleep maintenance), or may not feel rested by a night’s sleep (sleep quality). This disorder can be transient (lasts days to weeks) or chronic (defined as occurring nightly for greater than 30 days and often greater than six months).  It is estimated that one third of Americans experience insomnia nightly. The first-line treatments for chronic insomnia tend to focus on nonpharmacologic interventions, and then include pharmacologic treatments if necessary.  In general, the benzodiazepines have more side-effects and have a higher potential for dependence, tolerance, and rebound insomnia.  The newer nonbenzodiazepines have a better side effect profile. In general, pharmacologic agents should be started at the low end of the dose range and increased as necessary based on effect.

4. Definitions Insomnia: when it takes >30 minutes to fall asleep, when individuals awaken throughout night & cannot immediately return to sleep, when individuals experience early-morning awakening, or when total sleep time is decreased to ≤ 6 hours. Insomnia is the most common sleep complaint, but the resulting daytime sleepiness, fatigue, or hypersonmia may become troubling after-effects. 3 general types: transient (lasting a few days), short-term (lasting ≤ 3 weeks), or chronic (persisting for >3 weeks).

5. STAGES OF SLEEP Deep sleep is most abundant in infants & children. At age 65, it accounts for only 10% of sleep REM (paradoxic) sleep has aspects of both deep & light sleep Body & brain-stem functions are in deep-sleep state as muscle & sympathetic tone drop. In contrast, neurochemical processes & higher cortical brain function appear active. Dreaming occurs in REM sleep, & when a person is awakened from REM, alertness returns quickly. In depressive disorders, ↓ REM latency (i.e., time from sleep onset to appearance of REM) is a classic finding.

7. Neurochemistry of Sleep Noradrenergic, histaminergic, acetylcholine, glutamate, substance P, thyrotropin-releasing factor & corticotropin-releasing factor promote wakefulness. Serotonin-containing neurons of brainstem dampen sensory input & inhibit motor activity, promoting emergence of slow-wave sleep. Opiate peptides (e.g., enkephalin, endorphin) & GABA, an inhibitory neurotransmitter, also promote sleep

8. Drug-Induced Effects on Neurochemicals  GABA facilitating hypnotics e.g. BDZ induce sleep & ↓ arousals between stages, providing more continuous stage 2 sleep.  BDZ also ↓ stage 4 slow-wave sleep & suppress REM → REM rebound upon abrupt discontinuation.  Antihistamines promote sleep by blocking histamine- containing neurons involved in maintaining wakefulness.  Excitatory effects of caffeine & other methylxanthines are attributed to their antagonism of adenosine receptors.

9. Drug-Induced Effects on Neurochemicals  Drug-induced NA & 5-HT modulation ↓ REM sleep.  ↑ in DA neurotransmission can ↑ wakefulness but has no direct effect on REM sleep.  ↑ cholinergic neurotransmission triggers REM sleep.  Cortisol ↓REM sleep in young & old with unpredictable effects on slow-wave sleep & increased wakefulness in the old

10. Complaints or findings Difficulty initiating sleep (sleep latency). Frequent nocturnal awakenings. Early morning awakening. Subjective feeling of insufficient sleep. Daytime fatigue or sleepiness. Inability to concentrate. Irritability-poor quality of sleep. Anxiety, Depression, Forgetfulness Psychosomatic symptoms as pain.

12. Hypnotic Use Behavioral interventions are the preferred treatment for insomnia. Hypnotic medications are recommended when behavioral interventions fail or cannot be implemented. Prescribing trends have shifted away from older BDZ hypnotics toward sedating antidepressants, namely trazodone, sedating antipsychotics such as quetiapine, and newer “Z-hypnotics” (zaleplon, zolpidem, eszopiclone)

14. Pharmacologic Treatment When insomnia is severe & persistent, nondrug therapeutic interventions may not be sufficient. Either BDZ hypnotics or newer, BDZ omega-I selective hypnotics are 1st-line therapies. Some patients need pharmacologic treatment for insomnia but do not seek treatment from their health care provider. Alcohol & OTC sleep aids containing antihistamines are widely used to self-medicate insomnia, although results are less than ideal.

15. Nonprescription Sleep Aids Most nonprescription sleep aids contain antihistamines such as diphenhydramine (Benadryl) or doxylamine. Antihistamines can cause drowsiness Some patients do not feel well rested the next day after taking antihistamine, & daytime residual effects are experienced by ~50% of patients (“hangover effect”) Tolerance may develop to sedative effects of antihistamines after 1-2 weeks of continued use.

17. Antidepressants Are alternatives for patients with nonrestorative sleep who should not receive BDZs, especially those who have depression, pain, or risk of substance abuse. Sedating antidepressants such as amitriptyline, doxepin, & nortriptyline are effective for inducing sleep continuity, but daytime sedation & side effects can be significant. Some of new generation antidepressants such as mirtazapine & nefazodone are also sedating. Trazodone is popular for treatment of insomnia in patients prone to substance abuse, as dependence is not a problem. Trazodone is frequently used in patients with SSRI- & bupropion-induced insomnia

19. Melatonin Naturally occurring hormone secreted by pineal gland of brain which is connected to retina via nerve pathway that runs through hypothalamus, body’s circadian clock. Byproduct of serotonin metabolism. Released only during nocturnal phase of circadian cycle & only in relative darkness. Has been studied as treatment for circadian rhythm sleep disorders (e.g., jet lag, shift work sleep disorder,) & insomnia

20. Melatonin…cont’d Safety & effectiveness has not been clearly established & purity of melatonin is not regulated by FDA. ADRs: sleepiness, headache & nausea although usually well tolerated. Reports of depression, liver disease, vasoconstrictive, immunologic & contraceptive effects. Ramelteon is melatonin receptor agonist that has recently been approved for treatment of sleep onset insomnia. Ramelteon is selective for MT1 & MT2 melatonin receptors

21. Valerian Herbal sleep remedy. Mechanism of action is unknown, but may involve inhibition of enzyme that breaks down γ -aminobutyric acid (GABA). May be used also as dried herbal valerian root herbal products are not regulated by FDA for quality or consistency. Should be avoided in pregnancy. Songha® Night :Combination of Valerian & Melissa (Lemon Balm) extracts.

22. BDZs Relieve insomnia by reducing sleep latency & increasing total sleep time. Increase stage 2 sleep while decreasing REM, stage 3, & stage 4 sleep Should not be prescribed for individuals with sleep apnea, history of substance abuse, or during pregnancy. Patients should be instructed to avoid alcohol & other CNS depressants.

25. Short-Acting BDZ: Triazolam Is appropriate for occasional difficulty in falling asleep. Induces sleep rapidly: reaches peak plasma concentrations in 30 minutes & has ultrashort elimination half-life of 2-5 hours → minimal likelihood of causing residual daytime sedation May be used safely on as-needed basis Rebound insomnia is likely It is safe & effective for nongeriatric patients if used for ≤ 1 week

26. Intermediate BDZs Estazolam & temazepam Greater potential for producing daytime sedation & performance impairment Temazepam is less lipophilic → slower onset of effect Long acting BDZs Flurazepam, Quazepam Longer-acting BDZs have side-effects that persist to next day. Greater potential for producing daytime sedation & performance impairment.

27. BDZs Elimination With exception of temazepam, which is eliminated by conjugation, all hypnotic BDZs are metabolized by hepatic microsomal oxidation, then glucuronide conjugation. Oxidation may be inhibited in patients with impaired liver function, advanced age, or concurrent use of drugs that inhibit oxidation.

28. BDZs Side Effects Side effects are dose dependent : Day time sedation & performance impairment Tolerance:Triazolam (after 2 weeks) Anterograde amnesia :Triazolam. To reduce it, use the lowest effective dose & taper it before D/C. Rebound insomnia : occur with high dose of Triazolam even if intermittently taken. CNS effects : confusion, bizarre behavior, agitation, & hallucination.

29. Avoiding tolerance & dependence Lowest possible dose Intermittent administration Shortest duration possible HW: Use of BDZs in the elderly

30. Non-BDZ GABA A Agonists Zolpidem, zaleplon & eszopiclone selectively bind to GABA A receptors & effectively induce sleepiness

34. Zolpidem (Ambien) chemically unrelated to BDZs or BARBs, duration of action is 6-8 hours. ↓ sleep latency & nocturnal awakenings & increasing total sleep time. does not appear to have significant effects on next-day psychomotor performance safety & efficacy is similar to that of BDZ. treatment optimally should not exceed 4 weeks to minimize tolerance & dependence. is less disruptive of sleep stages than BDZs

35. Zaleplon (Sonata) rapid onset of action, half-life ~ 1 hour, is effective for ↓ time to sleep onset but not for for ↑ total sleep has no effect on next-day psychomotor performance & can be best used as sleep aid for middle-of-the night awakenings the most common ADRs: dizziness, HA, & somnolence.

37. NICE guidelines When hypnotic drug therapy is considered appropriate, it is recommended for short periods of time only. lack of evidence to distinguish between zaleplon, zolpidem, zopiclone or shorter acting BDZ hypnotics → drug with the lowest purchase cost should be prescribed. switching from one of these hypnotics to another should only occur if patient experiences ADEs considered to be directly related to specific agent. patients who have not responded to one of these hypnotic drugs should not be prescribed any of the others.

38. HW: 1.Eszopiclone 2.Sequence of hypnotic drug trials? (from Clinical Guideline for the Evaluation and Management of Chronic Insomnia in Adults. J.Clin. Sleep Med. 2008; 4(5):458-504.

39. EVALUATION OF THERAPEUTIC OUTCOMES Patients with short-term or chronic insomnia should be evaluated after 1 week of therapy to assess for drug efficacy, adverse effects, & adherence to nonpharmacologic recommendations. Patients should be instructed to keep sleep diary. For patients with chronic insomnia, possible medical, psychiatric, & pharmacologic causes should be identified & managed. Patients with insomnia should receive education about possible medication side effects & their management.

40. EVALUATION OF THERAPEUTIC OUTCOMES (cont’d) Prescriptions for BDZ receptor agonists should be accompanied by printed information & verbal counseling on precautions. Clinicians should educate patients about the concepts of tolerance, withdrawal, & rebound insomnia. Tolerance & dependence can be avoided by using hypnotics at the lowest possible dose, intermittently, & for the shortest duration possible. Withdrawal symptoms can be ↓ by tapering dosage gradually