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  • During sleep, we experience two alternating types or states of sleep over an 8-hour time period: NREM sleep and REM sleep. The cycle repeats itself every 90 minutes. This slide shows you our sleep architecture.   NREM or Non-Rapid Eye Movement includes 4 stages of sleep. As we shut our eyes for sleep, we first enter light sleep or Stage 1 , the link between being awake and falling asleep.   Stage 2 marks the actual onset of sleep when you become disengaged from the environment, breathing and heart rate are regular and body temperature continues to go down. We spend about ½ of our sleep cycle in the first two stages.   Stage 3 and 4 are the deepest states of sleep when we experience the most restorative sleep, so essential to functioning. Muscles are completely relaxed, blood pressure drops and breathing is slower. During these deep stages of sleep, blood supply to the muscles is increased, energy is restored, tissue growth and repair occur and important hormones are released for growth and development.   REM or Rapid-Eye Movement sleep occurs increasingly over the later part of the night and is also necessary for providing energy to our brains and body. During REM sleep, our brains are active and dreaming occurs. As we enter REM sleep, our bodies actually become immobile, muscles shut down, and again, we are relaxed. Breathing and heart rate may become irregular. During this stage of active brain activity, the eyes dart back and forth under the eyelids - giving REM sleep its name. Because getting enough REM sleep may contribute to memory consolidation, it is especially important following a learning experience. REM sleep typically comprises about ¼ of our night.  
  • During a sleep study, electrodes are attached to the head to measure our brain waves at different stages of sleep. This study is called an electroencephelogram or EEG. It measures the brain’s activity by observing brain waves that appear in amplitude, or height, and frequency.   During Stage 1, we see theta, or short, frequent waves, which get higher as we progress through the sleep cycle. During Stage 2, an EEG will reveal more theta waves with a mix of high wave bursts of energy, which are called sleep spindles. As sleep becomes deeper at Stage 3 and 4 and we become more difficult to arouse, more delta or high amplitude, slow-wave sleep appears.
  • Changes in body temperature occur in accordance with the circadian clock and the sleep cycle. At night, before bedtime, the body’s temperature drops, making sleeping in a cool room conducive to sleep. Sleep accelerates this drop and temperature changes can actually disrupt sleep.   It is also important to allow enough time between exercise and bedtime to allow the body to cool down. The body cools down after taking a warm bath, which in itself can be relaxing and help ease the transition into sleep.   During the sleep cycle, especially during the first part of the night when in deep sleep, critical hormones that are important to body functions and your health are released. These include:   Growth hormone, which is released during the deep stages of sleep in the earlier part of the night. It is essential for growth and development, particularly for young children, but also plays a role in muscle development and tissue repair. Sleeping long enough to allow secretion of growth hormone is important.   Cortisol is normally released when we are stressed. It is also released during sleep and increases over the night to promote alertness when it is time to wake up. Corisol levels peak around 6:00 am and dips to their lowest around bedtime.   In response to light and dark signals entering the brain, the pineal gland—located in the base of the brain—produces melatonin . As night approaches and it becomes darker, melatonin is released and may help to induce sleep. Animals also produce melatonin. In humans, its production tends to drop during puberty and is much lower in older people than children.   Getting a full night’s sleep provides enough time for all of these functions to occur and contribute to optimal health and performance. Thus, spending 1/3 of your life in sleep provides you with what you need to function during the other 2/3’s of your waking life.   Materials Melatonin: The Facts brochure Helping Yourself to a Good Night’s Sleep brochure
  • Over the life cycle, our sleep needs and the amount of hours required to sustain a quality lifestyle vary as we develop and age.   Infants or newborn babies (up to 2 months) need 10.5-18 hours over a 24-hour cycle. Sleep is definitely a priority for new babies and they need a lot of sleep to grow and develop. Although sleep patterns will change, establishing a a regular schedule at this time and putting babies to bed early in the evening helps them get all the sleep they need.   From 2-18 months, the average baby requires 13-15 hours of sleep. From 2-6 months, most sleep will occur at night; from 9-12 months, a baby will be taking 2 naps a day and by 18 months, only 1 nap. Naps are independent ofnighttime sleep and just as important.   Around 18 months and during the toddler or pre-school age, children need around 11-14 hours of sleep. When children reach the age of 5 they need 10 hours at night. Most children give up a nap by the age of 5.   Recent research indicates that adolescents need about as much sleep as when they were younger, a minimum of 8 ½ hours to an average of 9 ¼ hours. Although teens are often involved in more activities that deprive them of sleep and experience a lot of daytime sleepiness, sleep is just as important to their development.   Adults perform best with 7-9 hours although most adults get betwee 4 and 10 hours of sleep. Allow yourself to sleep naturally and without waking to an alarm clock, then observe how you function during the day. You need enough sleep to perform optimally during the day.   Contrary to a common myth, older adults need just as much sleep as younger adults; however, they often have more medical or sleep problems, they often do not sleep as efficiently due to pain, discomfort or disruptions and may not experience as much deep sleep as they age. Reference Mindell J, Owens J. A clinical guide to pediatric sleep. Philadelphia, PA: Lippincott Williams & Wilkins, 2003.   Materials Pediatric Sleep Guidelines Sleep Diary brochure Children & Sleep sleep sheet Adolescent Sleep Needs and Patterns report Children’s Sleep Diary Sleep & Aging brochure
  • There are clear differences in sleep patterns and characteristics throughout our lives. Until the age of 6 weeks, the sleep of newborns occurs around the clock; each period lasting 30 minutes to 3 hours. Between 2-4 months, a regular sleep pattern develops.   Infants are generally more active in their sleep than adults. This activity occurs during REM sleep and takes up about 50% of the infants sleep time. They start the night in REM sleep when they are generally not quiet and may smile, whimper, squeak, or move their arms or legs during sleep. The other half of the time is quiet when they are in non-REM sleep. In NREM, they lie still and have regular breathing. At 6 months of age, they develop 4 stages of NREM. Cycles of NREM and REM last about 60 minutes each. The best time to establish good sleep habits and help children sleep through the night is 6 weeks-3 months   Although newborns experience several periods of sleep and need naps, by 3-6 months, longer periods of sleep occur at night. By the end of the first year, babies are taking 1-2 naps per day. It is best for them to nap in the same place and there should be no less than 4 hours between afternoon nap and bedtime.   The American Academy of Pediatrics recommends that babies should be placed on their backs while sleeping to decrease the risk of sudden infant death syndrome (SIDS). They also caution parents against using water beds, sofas, soft mattresses or soft materials as infant sleep surfaces.   Most toddlers sleep through the night. By 3-4 years of age, or as toddlers, the sleep of children starts to resemble that of adults. Overall, they go into the deeper stages of sleep earlier and they still have several periods of sleep as compared to adults who have one consolidated period of sleep.   At this age, children often go from a crib to a bed. It is important that they have learned to go to sleep on their own at bedtime so they are better able to all asleep on their own if they wake in the middle of the night. This is a good time to establish a regular bedtime routine.   When children learn healthy sleep habits and establish a positive association with sleep, they are less likely to experience difficulties sleeping and may have less behavioral problems. Many children, between the ages of 5-12, begin to have a number of sleep problems. A regular, relaxing sleep routine before bed that does not include TV watching or other alerting activities will help promote good sleep practices and may prevent nightmares, difficulty falling asleep and getting enough sleep as well as other sleep problems. Sleep is absolutely fundamental for school-age children, particularly as it contributes to their growth and development.   During adolescence , there is a shift to a delayed bed and wake time. Teens are often not naturally sleepy until around 11:00 pm or later, yet they often have to wake early to meet school starting times or other responsibilities. As they become more independent and experience peer pressure, a hectic schedule may leave them sleep deprived.   Older Persons experience changes in their sleep patterns and tend to sleep less efficiently. Although they may be in bed 8 hours, they may actually be sleeping only 80% of the time and may experience less deep sleep. There may be more disturbances to sleep such as medical conditions, sleep disorders, medications, pain or discomfort, and greater sensitivity to the environment. Older adults are more sensitive to external conditions including bedding, noise, light and temperature.   Materials Children and Sleep sleep sheet Sleep & Aging brochure
  • DSM-IV is only way of defining
  • There are many causes of insomnia and doctors first look for these underlying issues and conditions when treating this problem. How long someone experiences insomnia will indicate if it is acute or short-term , lasting for 1-2 weeks or chronic , experienced for a month or longer.   Most acute insomnia can be attributed to a recent change or loss (e.g. death, divorce, job), which may be very stressful. Feeling stressed, anxious, depressed or when you are consumed with thinking about something can make it difficult to sleep.   When insomnia is chronic, it is essential to get a medical diagnosis and treatment. Addressing the cause of the insomnia is the first line of action. Often, this will resolve the problem. In the course of acute insomnia, some people may become anxious about sleep and adopt poor sleep habits that lead to long-term insomnia. Seeking assistance from a professional with expertise in behavioral therapy can be very helpful.   In some cases, the underlying cause cannot be identified and the insomnia continues indefinitely. This situation may require referral to a sleep specialist and an overnight sleep study for a more in-depth assessment and comprehensive treatment.
  • RR: I would point out that there is virtually no data with these drugs in primary insomnia. May wish to review doxepin study in addition to Walsh Trazodone
  • Talking Points Similar to other nonbenzodiazepine hypnotics (Ambien=Zolpidem and Sonata=Zaleplon), LUNESTA (eszopiclone) is believed to exert its hypnotic effects through its interaction with pentameric GABA-A receptor complexes. GABA is the major inhibitory neurotransmitter of the mammalian Central Nervous System ( 40% of Central Nervous System neurons are estimated to be gabaergic) and is thought to play the pivotal role within the sleep inducing and maintenance systems. GABA-A receptors are heterogeneous, i.e. comprised of different subtypes, largely based on the alpha unit (  -1,  -2,…  - -6) Different subtypes are located in different anatomical locations of the Central Nervous System and are involved in different unique neurophysiologic functions. Currently available nonbenzodiazepines are alpha-1 super-selective. They produce sedation, but may also produce amnesia in some patients because alpha-1 subtype receptors are so widely distributed throughout the brain and are not specific to the Central Nervous System sleep/wake systems. LUNESTA (eszopiclone) is believed to have unique, balanced activity at a-1 and a-3 GABA-A receptor subtypes. Alpha-3 subtypes are associated with brainstem arousal nuclei and are considered instrumental in mediating the inhibitory “off-signal” from the hypothalamic sleep control center projection neurons. This highly specific off-signal is the key event allowing for sleep onset and maintenance to proceed. The alpha-3 activity may allow LUNESTA (eszopiclone) to mediate sleep without amnesia by facilitating control of the hypothalamic sleep “on-switch.” The clinical significance of this pre-clinical data continues to be investigated.
  • Zolpidem (Ambien CR ®) Coated two-layer tablet – one immediate release layer, one extended release layer The CR is not restricted to short term use
  • US NDA received an “Approvable” letter from FDA 2-27-04 Talking Points Eszopiclone is a new treatment option in the United States, but its parent, racemic zopiclone, has been marketed around the world ex-U.S. since 1987, and is the most prescribed hypnotic outside the USA. 432 clinical studies were conducted for the registration of racemic zopiclone around the world Racemic (R,S)-zopiclone contains a 50-50 equal mixture of (R) and (S) -isomers Eszopiclone is the (S) -isomer and possesses nearly all of the pharmacologic activity of the racemate. Eszopiclone is a new hypnotic agent that is indicated for the treatment of transient and chronic insomnia. Sepracor received an “Approval” letter from FDA on December 15, 2004. The goal of the eszopiclone clinical program was to develop doses that would achieve rapid sleep onset while attaining sleep maintenance with no next-day residual effects in most patients. Eszopiclone comes in three strengths – 1 mg, 2 mg, and 3 mg.
  • US NDA received an “Approvable” letter from FDA 2-27-04 Talking Points Eszopiclone is a new treatment option in the United States, but its parent, racemic zopiclone, has been marketed around the world ex-U.S. since 1987, and is the most prescribed hypnotic outside the USA. 432 clinical studies were conducted for the registration of racemic zopiclone around the world Racemic (R,S)-zopiclone contains a 50-50 equal mixture of (R) and (S) -isomers Eszopiclone is the (S) -isomer and possesses nearly all of the pharmacologic activity of the racemate. Eszopiclone is a new hypnotic agent that is indicated for the treatment of transient and chronic insomnia. Sepracor received an “Approval” letter from FDA on December 15, 2004. The goal of the eszopiclone clinical program was to develop doses that would achieve rapid sleep onset while attaining sleep maintenance with no next-day residual effects in most patients. Eszopiclone comes in three strengths – 1 mg, 2 mg, and 3 mg.
  • Powerpoint slides

    1. 1. Miodrag Radulovacki M.D., Ph.D. Department of Pharmacology UIC Treatment of Insomnia
    2. 2. Presentation Objectives: <ul><li>Briefly review function of sleep and neurotransmitters associated with promotion of sleep </li></ul><ul><li>Review current and newly approved therapies for the treatment of insomnia – including mechanisms of action and pharmacology </li></ul><ul><li>Discuss agents in clinical development for the potential treatment of insomnia and their mechanisms of action </li></ul>
    3. 3. Function of Sleep <ul><li>“ If sleep does not serve an absolutely vital function, then </li></ul><ul><li>It is the biggest mistake the evolutionary process ever made.” </li></ul><ul><li>A. Rechtschaffen </li></ul>
    4. 4. Function of Sleep <ul><li>Restoration and recovery </li></ul><ul><ul><li>Sleep serves to reverse and/or restore biochemical and / or physiological processes degraded during prior wakefulness </li></ul></ul><ul><li>Energy conservation </li></ul><ul><ul><li>10% reduction of metabolic rate below basal level </li></ul></ul><ul><li>Memory consolidation </li></ul><ul><li>Thermoregulation </li></ul><ul><li>Homeostasis </li></ul>
    5. 5. The Sleep Cycle <ul><li>Alternating states and stages of sleep that occur over an 8-hour time period: </li></ul><ul><ul><li>NREM: Non-Rapid Eye Movement; Stages 1-4; 75% of the night </li></ul></ul><ul><ul><li>REM: Rapid Eye Movement; Dreams occur; 25% of the night </li></ul></ul>
    6. 6. During the Sleep Cycle <ul><li>Brain waves represent different stages of sleep. </li></ul>NREM Stages of Sleep REM Sleep
    7. 7. During the Sleep Cycle (cont.) <ul><li>Body temperature lowers </li></ul><ul><li>Hormone levels rise and fall </li></ul>
    8. 8. Sleep needs vary over the life cycle. Newborns/Infants 0 - 2 months: 2 - 12 months: 10.5-18 hours 14-15 hours Toddlers/Children 12 mo - 18 mo: 18 mo - 3 years: 3 - 5 years: 5 - 12 years: 13-15 hours 12-14 hours 11-13 hours 10-11 hours Adolescents On Average: 9.25 hours Adults/Older Persons On Average: 7-9 hours
    9. 9. Sleep patterns and characteristics change over the life cycle. Newborns/Infants More active in sleep; 50% REM; several periods of sleep; need naps Toddlers Sleep begins to resemble adult patterns Children Experience more deep sleep Adolescents Shift to later sleep-wake cycle; experience daytime sleepiness Adults Need regular sleep schedule to obtain sufficient, quality sleep Older Adults More likely to have medical problems; sleep disrupters & disorders; sleep less efficiently
    10. 10. Sleep Promoting CNS Neurotransmitters <ul><li>GABA (inhibitory amino acid) </li></ul><ul><ul><li>Ventral Lateral Pre-Optic Nucleus (VLPO) within anterior hypothalamus -- “command & control center” for sleep </li></ul></ul><ul><ul><ul><li>Inhibitory connections to thalamus, descending projections inhibit cell bodies and dendrites of serotonin, norepinephrine, histamine, acetylcholine-producing inter-neurons </li></ul></ul></ul><ul><ul><ul><li>Role: Initiation and maintenance of sleep spindles and SWS </li></ul></ul></ul><ul><li>Melatonin (hormone of darkness) </li></ul><ul><ul><li>Secreted from pineal gland during darkness/ indirectly feedbacks to SCN </li></ul></ul><ul><ul><li>High levels secreted prior to sleep </li></ul></ul><ul><ul><li>Levels low during wakefulness </li></ul></ul>
    11. 12. Conditions of Insomnia: Insomnia Primary Insomnia Secondary Insomnia Insomnia that is not a result of another condition -hyper-arousal disorder <ul><li>Insomnia resulting from: </li></ul><ul><li>Psychiatric: depression, anxiety </li></ul><ul><li>Medical conditions: pain, CV, neurological or GI illnesses </li></ul><ul><li>Substance abuse </li></ul><ul><li>Behavior </li></ul><ul><li>Another primary sleep disorder </li></ul><ul><ul><li>RLS/PLMS </li></ul></ul><ul><ul><li>Apnea </li></ul></ul><ul><ul><li>Narcolepsy </li></ul></ul><ul><ul><li>Circadian rhythm disorders </li></ul></ul>
    12. 13. <ul><li>Over 30% of American adults experience occasional insomnia; 10% on a chronic basis </li></ul><ul><li>Those most at risk: </li></ul><ul><ul><li>Women </li></ul></ul><ul><ul><li>Older adults </li></ul></ul><ul><ul><li>Pts w/ psychiatric disorders </li></ul></ul><ul><ul><li>Pts w/ medical disorders </li></ul></ul><ul><ul><li>(pain syndromes, asthma, CV </li></ul></ul><ul><ul><li>2 nd / 3 rd shift workers </li></ul></ul>Insomnia Prevalence
    13. 14. Causes and Types of Insomnia Cause Type Duration Change: acute illness; jet lag, emotional stress Stress: loss of loved one or job Acute Transient: few nights a week Short Term: 1 – 2 weeks Variety of physical, medical, psychiatric or environmental conditions Chronic > 1 month (at least 3 nights a week) Not associated with underlying or known cause. Primary > 1 month Chronic stress, hyperarousal, or behavioral conditioning may contribute. Chronic
    14. 15. Reduced Total Sleep Time Impacts Health & Next-day Functioning <ul><ul><li>Increased number (4.5-fold) of serious accidents or injuries 2 </li></ul></ul><ul><ul><ul><li>200,000 MVA each year caused by drowsiness (US DOT) </li></ul></ul></ul><ul><ul><li>Impaired alertness & memory </li></ul></ul><ul><ul><li>Impaired psychomotor performance </li></ul></ul><ul><ul><li>Increased healthcare utilization 3 and absenteeism </li></ul></ul>1 Mahowald et al. Sleep Medicine . 2000; 1: 179. 2 Balter et al. J Clin Psychiatry . 1992; 53 Suppl: 34 3 Simon et al, Am J Psychiatry. 1997; 154: 1417
    15. 16. <ul><li>Behavioral Interventions – CBT (Cognitive Behaviral Therapy) </li></ul><ul><li>Pharmacological </li></ul><ul><ul><li>OTCs (Over-The-Counter) </li></ul></ul><ul><ul><ul><li>Diphenhydramine </li></ul></ul></ul><ul><ul><ul><li>Doxylamine </li></ul></ul></ul><ul><ul><ul><li>L-Tryptophan </li></ul></ul></ul><ul><ul><ul><li>Melatonin </li></ul></ul></ul><ul><ul><ul><li>Alcohol </li></ul></ul></ul><ul><ul><ul><li>Plant based herbals – Valerian, Chamomile, Hops, Lemon Balm, Lavender, Ylang Ylang, Melissa, Passion Flower, Kava Kava </li></ul></ul></ul><ul><ul><li>Barbiturates </li></ul></ul><ul><ul><li>Chloral Hydrate </li></ul></ul><ul><ul><li>Antidepressants </li></ul></ul><ul><ul><li>GABA-A Receptor Allosteric Modulators </li></ul></ul><ul><ul><ul><li>Benzodiazepines </li></ul></ul></ul><ul><ul><ul><li>Non-Benzodiazepines </li></ul></ul></ul><ul><ul><li>Melatonin Receptor Agonists </li></ul></ul>Treatment of Insomnia
    16. 22. Antidepressants <ul><li>Tricyclic Antidepressants (TCAs) </li></ul><ul><li>SSRIs/SNRIs </li></ul><ul><li>Trazodone </li></ul>
    17. 23. TCAs (Not FDA approved for hypnotic use) <ul><li>Tertiary amines (amitriptyline, doxepin,imipramine..) greater sedation than secondary amines (desipramine, nortriptyline, protriptyline) </li></ul><ul><li>TCAs decrease REM sleep & prolong REM latency </li></ul><ul><li>May increase TST but may worsen periodic limb movements (PLMs)/ specific agents may prolong SWS </li></ul><ul><li>MOA: Block 5-HT and NE reuptake/ anticholinergic and antihistaminic activity </li></ul><ul><li>Weak alpha-1 blockade results in orthostatic hypotension </li></ul><ul><li>TCAs have poor sleep onset activity </li></ul><ul><li>Acute withdrawal can cause REM rebound </li></ul>
    18. 24. SSRIs/SNRIs (Not FDA approved for hypnotic use) <ul><li>Antidepressant drugs can both improve and disturb sleep, as well as have effects on waking function. </li></ul><ul><li>Evaluation of the effects of these drugs on sleep and wakefulness is complicated by the fact that many individuals with depression typically have: </li></ul><ul><ul><li>disturbed sleep </li></ul></ul><ul><ul><li>daytime fatigue </li></ul></ul><ul><ul><li>sleepiness </li></ul></ul><ul><ul><li>somatic complaints </li></ul></ul><ul><ul><li>decreased cognitive and psychomotor functioning </li></ul></ul><ul><li>PSG (polysomnogram) and subjective patient reports of sleep do not always correlate </li></ul>Schweitzer P. Principles and Practice of Sleep Medicine , 3 rd Edition, 441.
    19. 25. Effects of Newer Antidepressants on Sleep and Waking Behavior <ul><li>Most SSRIs  wakefulness,  TST (no data on sertraline and no change in TST or W with citalopram) </li></ul><ul><li>Insomnia incidence in SSRI treated patients ranges from 5-16% </li></ul><ul><li>Daytime sedation incidence in SSRI treated patients ranges from 2-26% </li></ul><ul><li>Venlafaxine (5HT/NE reuptake inhibitor): similar to SSRIs, insomnia 8%, sedation 3-31% </li></ul><ul><li>Bupropion (DE/NE reuptake inhibitor): insomnia 5-19% </li></ul>
    20. 26. Trazodone (Not FDA approved for hypnotic use) <ul><li>Produces sedating effects via antagonistic effects at H1 & 5-HT2 receptors </li></ul><ul><li>Low doses (50-100mg) often used as adjunct to SSRI treatment </li></ul><ul><li>Men must be counseled about priapism (persistent and painful erections) </li></ul><ul><li>Severe postural hypotension can occur due to antagonism of alpha-1 receptors </li></ul><ul><li>Long T1/2 may lead to daytime sedation </li></ul><ul><li>Recent concerns about administration with strong inhibitors of CYP3A4 (i.e.. itra-, ketoconazole) </li></ul>
    21. 27. Select Benzodiazepines* 1 N-desalkylflurazepam, active metabolite *Not all BZDs have been approved by the FDA for insomnia Facts and Comparisons, eFacts Drug Usual adult oral dose (mg) Tp (hrs) T1/2 (hrs) Protein binding (%) Urinary excretion, unchanged (%) Estazolam (Prosom  ) 1-2 2 8-28 93 < 5 Flurazepam (Dalmane  ) 15-30 0.5-1 (7.6-13.6) 1 2-3 (47-100) 1 97 < 1 Quazepam (Doral  ) 7.5-15 2 (1-2) 41 (47-100) 1 > 95 Trace Temazepam (Restoril  ) 15-30 1.2-1.6 3.5-18.4 (9-15) 96 0.2 Triazolam (Halcion  ) 0.125-0.5 1-2 1.5-5.5 78-89 2
    22. 28. <ul><li>BZDs suppress SWS and REM sleep as well as prolong REM latency </li></ul><ul><li>Stage 2 sleep is prolonged with an increase in spindle density, sleep latency is shortened, TST is increased </li></ul><ul><li>Flurazepam has long elimination half-life of up to 100 hours </li></ul><ul><li>Shortest acting is triazolam with half-life of 1-5.5 hours </li></ul><ul><li>Acute withdrawal is associated with decreased TST as well as REM & SWS rebound </li></ul>Benzodiazepines
    23. 29. MOA of BZDs and Non-BZDs: The Role of GABA A Receptors <ul><li>The GABA A receptor is a pentameric complex </li></ul><ul><li>Currently, there have been 7 subunit families comprising at least 18 subunits in the CNS: </li></ul><ul><ul><li> 1-6 ,  1-3 ,  1-3 ,  ,  ,  ,  1-3 </li></ul></ul><ul><li>The major subtype combination (60% of all GABA-A receptors) consist of  1  2  2 </li></ul>Mohler H et al. J Pharmacology and Experimental Therapeutics, 300; 1:2-8.
    24. 30. MOA and GABA A Receptor Complex BZD binding GABA
    25. 31. Non-Benzodiazepines (GABA-A Receptor Allosteric Modulators) Adapted from Silber M, NEJM 353;8: 806. Drug & class Half Life (hr) Dose (mg) Indications Side Effects Contraindications and Drug Interactions Eszopiclone (Lunesta) cyclopyrrolone 5-7 1-3 Tx of insomnia Unpleasant taste, dry mouth, drowsiness, dizziness Drugs that inhibit CYP3A4, etoh, olanzapine Zolpidem (Ambien, Ambien CR) imidazopyridine 3 5-10; 6.25-12.5 (CR) Short term Tx of insomnia (Tx of insomnia – CR) Drowsiness,dizziness, occasionally amnesia Possibly drugs that inhibit CYP3A4, etoh Zaleplon (Sonata) pyrazolopyrimidine 1 5-20 Short term Tx of insomnia (SL) Drowsiness Possibly drugs that inhibit CYP3A4, etoh, imipramine, thioridazine
    26. 32. Non-benzodiazepines, cont. <ul><li>Zolpidem (Ambien ®) / Zaleplon (Sonata®) </li></ul><ul><ul><li>Approved for short term use (7-10 days) </li></ul></ul><ul><ul><li>Reassess in 2-3 weeks </li></ul></ul><ul><ul><li>Decrease sleep latency and increase TST (zolpidem) </li></ul></ul><ul><li>PK </li></ul><ul><ul><li>T ½ = 2.5 hrs for 10 mg Zolpidem; inactive metabolites </li></ul></ul><ul><ul><ul><li>CYP3A4 main route of metabolism; minor renal elimination </li></ul></ul></ul><ul><ul><li>T ½ = 1 hr for 10 mg Zaleplon; elderly dose = 5 mg </li></ul></ul><ul><li>Efficacy </li></ul><ul><ul><li>Zolpidem: longest nightly use 5 weeks/ 8-12 weeks intermittent use </li></ul></ul><ul><ul><li>Zaleplon: 30 days nightly use </li></ul></ul><ul><ul><ul><li>Can be taken late at night without next-day effects </li></ul></ul></ul>
    27. 33. <ul><li>Safety: Minimal changes in sleep architecture </li></ul><ul><ul><li>Minimal next-day effects </li></ul></ul><ul><ul><li>No improvement in middle insomnia (sleep maintenance). </li></ul></ul><ul><li>Adverse Events </li></ul><ul><ul><li>Zolpidem: common ADR’s: drowsiness, headache, dizziness </li></ul></ul><ul><ul><ul><li>Amnesia more common at doses > 10mg </li></ul></ul></ul><ul><ul><ul><li>No significant rebound insomnia (5 week study) </li></ul></ul></ul><ul><ul><ul><li>Reports of abuse in those with hx of substance abuse </li></ul></ul></ul><ul><ul><ul><li>Rare reports of hallucinations at recommended doses </li></ul></ul></ul>Non-benzodiazepines (cont)
    28. 34. <ul><li>Ambien CR  (zolpidem tartrate extended release tablets) - Approved Sept 6, 2005 – indicated for the treatment of insomnia (sleep onset/maintenance) </li></ul><ul><li>Zolpidem CR consists of a coated two-layer tablet: </li></ul><ul><ul><li>One layer releases drug immediately </li></ul></ul><ul><ul><li>Another layer that allows slower release of additional drug </li></ul></ul><ul><li>Available in 6.25 mg and 12.5 mg strengths </li></ul><ul><li>The clinical trials were both 3 weeks in duration (assessment of SL and maintenance were performed after 2 weeks of treatment) </li></ul>Ambien CR press release – Sept 6, 2005 Ambien CR package insert Non-benzodiazepines (cont)
    29. 35. <ul><li>Eszopiclone (Lunesta  ): non-benzodiazepine cyclopyrrolone </li></ul><ul><li>Indications: Sleep onset and sleep maintenance insomnia – Approved for long term use </li></ul><ul><li>Eszopiclone = (S)-Zopiclone, contains pharmacologic activity of racemate </li></ul><ul><ul><li>Available since 1987 </li></ul></ul><ul><ul><li>Racemic (R,S)-zopiclone (Imovane , Zimovan, Zimovane) </li></ul></ul><ul><ul><li>Currently marketed in over 85 countries at doses of 5-10 mg </li></ul></ul>Non-benzodiazepines (cont)
    30. 36. <ul><li>Eszopiclone: PK </li></ul><ul><ul><li>T ½ = 5-7 hrs for 3 mg eszopiclone; active metabolite, but to lesser degree than parent compound </li></ul></ul><ul><ul><ul><li>CYP3A4 main route of metabolism, 2E1 minor path </li></ul></ul></ul><ul><ul><li>Tmax = 1 hr for 3 mg; elderly dose = 1-2 mg </li></ul></ul><ul><li>Efficacy </li></ul><ul><ul><li>Longest study was 2-6 month double blind randomized studies of eszopiclone 3 mg vs. placebo with a 6 mo open label extension </li></ul></ul><ul><ul><ul><li>Decrease in sleep latency, increase in TST </li></ul></ul></ul><ul><ul><li>Minimal changes to sleep architecture </li></ul></ul><ul><li>Adverse Events & Safety </li></ul><ul><ul><li>Unpleasant taste, dry mouth, dizziness and drowsiness </li></ul></ul><ul><ul><li>No significant PSG rebound after 44 nights of therapy nor after 180 nights with 3 mg dose </li></ul></ul><ul><ul><li>Abuse study performed with s-isomer </li></ul></ul>Non-benzodiazepines (cont)
    31. 37. Ramelteon (Rozerem  ) <ul><li>Ramelteon was approved by the FDA in July 2005 for the treatment of insomnia characterized by difficulty with sleep onset </li></ul><ul><li>Ramelteon specifically targets the MT1 and MT2 receptors in the brain, believed to be critical in the regulation of the body's sleep-wake cycle </li></ul><ul><li>PK </li></ul><ul><ul><li>T ½ = 2-5 hours, dose is 8 mg 30 minutes before going to bed </li></ul></ul><ul><ul><li>Metabolized by CYP1A2, CYP2C and CYP3A4 minor paths </li></ul></ul><ul><ul><li>Should not be used in severe hepatic impairment or with fluvoxamine, and used with caution in patients with moderate hepatic impairment </li></ul></ul><ul><ul><li>Do not take with a high fat meal </li></ul></ul>Ramelteon package insert.
    32. 38. Ramelteon (Rozerem  ) <ul><li>Efficacy </li></ul><ul><ul><li>Significant decrease in LPS w/ treatment vs. placebo: </li></ul></ul><ul><ul><ul><li>Adult chronic insomnia 35 night trial </li></ul></ul></ul><ul><ul><ul><li>Elderly chronic insomnia 3 period crossover trial </li></ul></ul></ul><ul><ul><ul><li>Healthy adults first night effect model of transient insomnia </li></ul></ul></ul><ul><li>Adverse Events & Safety </li></ul><ul><ul><li>Drowsiness, dizziness, increased prolactin levels </li></ul></ul><ul><ul><ul><li>Patients should be advised to consult their healthcare provider if they experience 1 of the following: cessation of menses or galactorrhea in women, decreased libido, or problems with fertility. </li></ul></ul></ul><ul><ul><li>No abuse potential </li></ul></ul>Ramelteon package insert. Drug Facts and Comparisons, eFacts
    33. 41. Conclusions <ul><li>The function and mechanisms of sleep are complex </li></ul><ul><li>Insomnia may be a symptom of another illness, may co-exist with another illness or exist alone </li></ul><ul><li>Insomnia impacts psychiatric and medical illness and next-day functioning </li></ul><ul><li>Sleep hygiene should always be cornerstone of treatment </li></ul>
    34. 42. Conclusions <ul><li>Barbiturates & BZDs change sleep architecture; withdrawal can ppt rebound effects </li></ul><ul><li>Non-BZDS are safer, minimal next-day effects, but most are approved for short term use and best for sleep onset insomnia </li></ul><ul><li>The wide array of compounds in current development appear promising for the treatment of chronic insomnia </li></ul>
    35. 43. Information on sleep and sleep disorders <ul><li>American sleep disorders association </li></ul><ul><ul><li>( http://www.asda.org ) </li></ul></ul><ul><li>The national sleep foundation </li></ul><ul><ul><li>( http://sleepfoundation.org ) </li></ul></ul><ul><li>Sleep home pages </li></ul><ul><ul><li>( www.sleephomepages.org/ ) </li></ul></ul><ul><li>American academy of sleep medicine (AASM) </li></ul><ul><ul><li>( http://www.aasmnet.org ) </li></ul></ul><ul><li>Associated professional sleep societies (APSS) </li></ul><ul><ul><li>( http://www.apss.org ) </li></ul></ul>

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