Treatment of Insomnia Miodrag Radulovacki M D Ph D Department of Pharmacology UIC Function of Sleep Restoration Sleep serves to reverse and or restore biochemical and or physiological processes degraded during prior wakefulness Energy and recovery conservation 10 reduction of metabolic rate below basal level Memory consolidation Thermoregulation Homeostasis Page The Sleep Cycle Alternating states and stages of sleep that occur over an 8 hour time period NREM Non Rapid Eye Movement Stages 1 4 75 of the night REM Rapid Eye Movement Dreams occur 25 of the night During the Sleep Cycle Brain waves represent different stages of sleep NREM Stages of Sleep REM Sleep Page Sleep needs vary over the life cycle During the Sleep Cycle cont Body temperature lowers Hormone levels rise and fall Page Conditions of Insomnia Insomnia Primary Insomnia Insomnia that is not a result of another condition hyper arousal disorder Secondary Insomnia Insomnia resulting from Psychiatric depression anxiety Medical conditions pain CV neurological or GI illnesses Substance abuse Behavior Another primary sleep disorder RLS PLMS Apnea Narcolepsy Circadian rhythm disorders Insomnia Prevalence Over 30 of American adults experience occasional insomnia 10 on a chronic basis Those most at risk Women Older adults Pts w psychiatric disorders Pts w medical disorders pain syndromes asthma CV 2nd 3rd shift workers Page Types of Insomnia Page Reduced Total Sleep Time Impacts Health Next day Functioning Increased number 4 5 fold of serious accidents or injuries2 200 000 MVA each year caused by drowsiness US DOT Impaired alertness memory Impaired psychomotor performance Increased healthcare utilization3 and absenteeism 1 2 Mahowald et al Sleep Medicine 2000 1 179 Balter et al J Clin Psychiatry 1992 53 Suppl 34 3Simon et al Am J Psychiatry 1997 154 1417 Treatment of Insomnia Pharmacological OTCs Over The Counter Diphenhydramine Doxylamine L Tryptophan Melatonin Alcohol Plant based herbals Valerian Chamomile Hops Lemon Balm Lavender Ylang Ylang Melissa Passion Flower Kava Kava Barbiturates Chloral Hydrate Antidepressants GABA A Receptor Allosteric Modulators Benzodiazepines Non Benzodiazepines Melatonin Receptor Agonists Silenor doxepin Page Page Page Effects of 100 mg of secobarbital on sleep in an insomniac Page Trazodone Not FDA approved for hypnotic use Produces sedating effects via antagonistic effects at H1 5 HT2 receptors Low doses 50 100mg often used as adjunct to SSRI treatment Men must be counseled about priapism persistent and painful erections Severe postural hypotension can occur due to antagonism of alpha 1 receptors Long T1 2 may lead to daytime sedation Recent concerns about administration with strong inhibitors of CYP3A4 i e itra ketoconazole Sleep Promoting CNS Neurotransmitters GABA inhibitory amino acid Role Initiation and maintenance of sleep spindles and SWS Melatonin hormone of darkness Secreted from pineal gland during darkness High levels secreted prior to sleep Page Select Benzodiazepines Drug Estazolam Prosom Usual adult oral dose mg 1 2 Tp hrs 2 T1 2 hrs 8 28 Protein binding Urinary excretion unchanged 93 5 Flurazepam 15 30 Dalmane 0 5 1 2 3 1 7 6 13 6 47 100 1 97 1 Quazepam Doral 7 5 15 2 1 2 41 47 100 1 95 Trace Temazepam 15 30 Restoril 1 2 1 6 3 5 18 4 9 15 96 0 2 Triazolam Halcion 1 2 1 5 5 5 78 89 2 1N desalkylflurazepam 0 1250 5 active metabolite Not all BZDs have been approved by the FDA for insomnia Facts and Comparisons eFacts Benzodiazepines BZDs suppress SWS and REM sleep as well as prolong REM latency Stage 2 sleep is prolonged with an increase in spindle density sleep latency is shortened TST is increased Flurazepam has long elimination half life of up to 100 hours Shortest acting is triazolam with half life of 1 5 5 hours Acute withdrawal is associated with decreased TST as well as REM SWS rebound Page Elimination of diazepam in 33 and 77 years old males Page GABAA Receptor Complex Page Non Benzodiazepines GABA A Receptor Allosteric Modulators Drug class Half Dose Life mg hr Indications Side Effects Contraindications and Drug Interactions Eszopiclone Lunesta Tx of insomnia Unpleasant taste dry mouth drowsiness dizziness Drugs that inhibit CYP3A4 etoh olanzapine 5 7 1 3 cyclopyrrolone Zolpidem Ambien Ambien CR 3 5 10 6 2512 5 CR Short term Tx of insomnia Tx of insomnia CR Drowsiness dizziness occasionally amnesia Possibly drugs that inhibit CYP3A4 etoh 1 5 20 Short term Tx of insomnia SL Drowsiness Possibly drugs that inhibit CYP3A4 etoh imipramine thioridazine imidazopyridine Zaleplon Sonata pyrazolopyrimidine Adapted from Silber M NEJM 353 8 806 Page Non benzodiazepines cont Zolpidem Ambien Zaleplon Sonata Approved for short term use 7 10 days Reassess in 2 3 weeks Decrease sleep latency and increase TST zolpidem PK T 2 5 hrs for 10 mg Zolpidem inactive metabolites CYP3A4 main route of metabolism minor renal elimination T 1 hr for 10 mg Zaleplon elderly dose 5 mg Efficacy Zolpidem longest nightly use 5 weeks 8 12 weeks intermittent use Zaleplon 30 days nightly use Can be taken late at night without next day effects Non benzodiazepines cont Safety Minimal changes in sleep architecture Minimal next day effects No improvement in middle insomnia sleep maintenance Adverse Events Zolpidem common ADR s drowsiness headache dizziness Amnesia more common at doses 10mg No significant rebound insomnia 5 week study Reports of abuse in those with hx of substance abuse Rare reports of hallucinations at recommended doses Page Non benzodiazepines cont Ambien CR zolpidem tartrate extended release tablets Approved Sept 6 2005 indicated for the treatment of insomnia sleep onset maintenance Zolpidem CR consists of a coated two layer tablet One layer releases drug immediately Another layer that allows slower release of additional drug Available in 6 25 mg and 12 5 mg strengths The clinical trials were both 3 weeks in duration assessment of SL and maintenance were performed after 2 weeks of treatment Ambien CR press release Sept 6 2005 Ambien CR package insert Non benzodiazepines cont Eszopiclone Lunesta non benzodiazepine cyclopyrrolone Indications Sleep onset and sleep maintenance insomnia Approved for long term use Eszopiclone S Zopiclone contains pharmacologic activity of racemate Available Racemic R S zopiclone Imovane Zimovan Zimovane Currently mg since 1987 marketed in over 85 countries at doses of 5 10 Page Non benzodiazepines cont Eszopiclone Efficacy Longest study was 2 6 month double blind
View Full Document
Unlocking...