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Pharmacological Treatment 179 Table 1 Benzodiazepines Approved in the United States for the Treatment of <strong>Insomnia</strong> Peak plasma Active Drug T 1/2 half life level metabolites Type Quazepam 39 hours 2 hours Yes Long half-life Estazolam 10–15 hours 0.5–2 hours No Medium half-life Flurazepam 48–120 hours 2 hours Yes Long half-life Temazepam 8–15 hours 30–60 min No Medium half-life Triazolam 1.5–5.5 hours 15–30 min No Short half-life ing. They have potent hypnotic, muscle relaxant, anticonvulsant, and anti-anxiety properties. Benzodiazepines act nonselectively at two central receptor sites, named omega(1) and omega(2), which are located in different areas of the central nervous system. The sedative action of benzodiazepines is related to omega(1) receptors, whereas omega(2) receptors are responsible for their effects on memory and cognitive functioning (34). According to their pharmacokinetic profile, benzodiazepines can be classified into three groups: short half-life (24 hours). Table 1 lists those benzodiazepines approved for the treatment of insomnia. Benzodiazepines are proven to be efficacious in the treatment of insomnia. In 2000, in Canada, Holbrook et al. (35) published a meta-analysis of benzodiazepine trials in primary insomnia. They identified 89 randomized controlled trials but excluded 44 from the meta-analysis for various reasons. The remaining 45 randomized controlled trials represented 2672 patients. Twenty-seven studies compared a benzodiazepine with a placebo, 13 compared a benzodiazepine with an alternate active treatment, and 5 studies involved a combination of both. The duration of the studies ranged from 1 day to 6 weeks. There was a statistically significant difference of SL and sleep duration both subjectively and objectively between a benzodiazepine and placebo. The question of whether tolerance to any sleep-promoting effect of benzodiazepines occurs could not be answered because all of the trials eligible for the meta-analyses were of short duration. Although more adverse effects were experienced by patients taking a benzodiazepine for the treatment of insomnia, dropout rates in the benzodiazepine and placebo groups were similar (35). Most benzodiazepine adverse reactions are viewed as extensions of the therapeutic effect beyond the desired time. Mendelson et al. looked at the reported rate of adverse effects in a 1000-bed hospital over a period of 3 years and discovered that the median frequency of reported adverse reactions was 0.01%, or 1 in 10,000 doses. The vast majority of reactions was considered mild, and without sequelae. All adverse reactions occurred in patients over 55 years old except for four patients under age 50 who received lorazepam (36). Temazepam, the most commonly used benzodiazepine as a hypnotic, has been shown to be safe even in the elderly (37).
180 Attarian The use of benzodiazepines has been generally restricted in the treatment of insomnia because of concerns of addiction, dependence, and tolerance. The risk of habituation and abuse, however, is lower than previously thought in patients who are properly diagnosed and use these medications for medicinal purposes (38). In a double-blind fashion, Roehrs et al. gave 18 subjects with insomnia 1 week of triazolam and 1 week of placebo. The number of triazolam capsules taken nightly was stable and the number of placebo capsules variable. It was concluded that insomniacs showed no short-term escalation of triazolam dose, but did choose an increased and variable number of placebos, a pattern that was interpreted as being insomnia relief-seeking behavior (39). Schenck and Mahowald followed 170 patients for 12 years who were receiving nightly benzodiazepines for the treatment of a variety of sleep disorders including injurious sleepwalking and sleep terrors (n = 69); rapid eye movement sleep behavior disorder (n = 52); chronic, severe insomnia (n = 25); and RLS/periodic limb movement disorder (n = 24). Only 2% had relapses of alcohol or chemical abuse requiring hospitalization and another 2% at times misused their medications (40). In conclusion, benzodiazepines are effective and safe in treating primary insomnia. There some strong data to suggest that in the absence of prior history of alcohol or substance abuse, when used judiciously, that the risk of tolerance, abuse, dependence and addiction is low. More studies are needed to fully answer that question, however. Imidazopyridines The newer non-benzodiazepine agents (see Table 2) zopiclone, zolpidem, and zaleplon, have a hypnotic action comparable with that of benzodiazepines, but they display specific pharmacokinetic and pharmacodynamic properties. They are structurally unrelated to benzodiazepines and belong to a new chemical class, the imidazopyridines. These three agents all share a short plasma half-life and limited duration of action. Additionally, these agents are selective compounds that interact preferentially with omega(1) receptors (sedative effect), whereas benzodiazepines also interact with omega(2) receptors (adverse effects on cognitive performance and memory). Zaleplon is characterized by an ultrashort half-life, zolpidem and zopiclone have longer half-lives. These properties, together with the low risk of residual effect, may explain the limited negative influences of these agents on daytime performance. Cognitive functions are better preserved by non-benzodiazepine agents than by benzodiazepines (34). When present, cognitive deficits almost always coincide with the peak plasma concentration, especially in the first hours after drug administration, whereas cognitive testing administered 7–8 hours later (i.e., in the morning) generally shows no impairment (34). Zolpidem is an effective and safe hypnotic with minimal adverse effects and no dependence, withdrawal, tolerance, or rebound insomnia over long-term use. Zolpidem’s elimination half-life is 2.2 hours, and peak plasma levels are reached in 90 minutes. The dose needs to be adjusted in the setting of hepatic impairment but
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Clinical Handbook of Insomnia Edite
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C URRENT CLINICAL NEUROLOGY Daniel
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© 2004 Humana Press Inc. 999 River
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Series Editor’s Introduction The
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x Foreword nervous system hypersomn
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Contents Series Editor’s Introduc
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Contributors HRAYR P. ATTARIAN, MD
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2 Attarian et al.
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4 Attarian et al. until the 1970s t
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6 Attarian et al. Table 2 Diagnosti
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8 Attarian et al. Duration of Illne
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10 Attarian et al. REFERENCES 1. Ma
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12 Attarian Another study in Austri
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14 Attarian even less well studied.
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16 Attarian communities. A structur
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18 Attarian 5. Sutton, D. A., Moldo
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20 Attarian 53. Kageyama, T., Kabut
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22 Attarian
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24 Bonnet and Arand Table 1 Reporte
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26 Bonnet and Arand On the day spen
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28 Bonnet and Arand SUMMARY These m
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30 Bonnet and Arand chronic caffein
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32 Bonnet and Arand response that a
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34 Bonnet and Arand The Development
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36 Bonnet and Arand ACKNOWLEDGMENT
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38 Bonnet and Arand 45. Bonnet, M.
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40 Attarian Table 1 Types of Insomn
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42 Attarian 15 to 40 seconds. PLMs
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44 Fig. 1. Example of a 1-week slee
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46 Fig. 3. One-week printout of an
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48 Attarian Fig. 4. Algorithm. (Use
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50 Attarian 27. Polo-Kantola, P., E
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52 Garcia
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54 Garcia association is known as s
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56 Fig. 1. A sleep log used in chil
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58 Garcia the reality that the tend
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60 Fig. 2. Actigraph recording in a
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62 Garcia neurodevelopmental disabi
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64 Garcia 35. Czeisler, C., kronaue
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66 Garcia
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68 Attarian showed similar degrees
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70 Attarian agitation and hence the
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72 Attarian Affective disorder is s
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74 Attarian and Drug Administration
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76 Fig. 2. Sleep log after treatmen
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78 Attarian 18. Bonnet, M. H. and A
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80 Attarian 65. Perlis, M., Aloia,
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82 Attarian was confirmed by resear
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84 Attarian times worrying about th
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86 Attarian insomnia or for other s
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88 Attarian
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90 Duntley tion systems found that
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92 Duntley Case 1 A 36-year-old fem
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94 Fig. 2. The objective amount of
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96 Duntley PROGNOSIS AND COMPLICATI
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98 Duntley
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100 Attarian EPIDEMIOLOGY There are
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102 Attarian CLINICAL MANIFESTATION
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104 Attarian DIAGNOSTIC WORKUP The
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106 Attarian 13. Hauri, P. J. (1998
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108 Plotkin
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110 Plotkin quality of sleep. Ultim
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112 Plotkin of the therapeutic effi
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114 Plotkin months or years. The ef
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116 Plotkin associated somatic disc
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118 Plotkin Table 1 Causes of Secon
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120 Plotkin Table 1 (continued) Lew
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122 Plotkin REFERENCES 1. Foley, D.
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124 Plotkin 48. Marchetti, F., Rome
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126 Plotkin
Page 145 and 146: 128 Karaz Table 1 DSM-IV Diagnoses
Page 147 and 148: 130 Karaz poor. Focusing only on th
Page 149 and 150: 132 Karaz He felt hopeless that his
Page 151 and 152: 134 Karaz Table 4 Diagnostic Criter
Page 153 and 154: 136 Karaz complained of feeling anx
Page 155 and 156: 138 Karaz other physicians avoided
Page 157 and 158: 140 Karaz 17. Attarian, H. P. (2000
Page 159 and 160: 142 Duntley disorders has been conf
Page 161 and 162: 144 Duntley itance. A recent study
Page 163 and 164: 146 Duntley The patient’s primary
Page 165 and 166: 148 Duntley return to sleep. He tos
Page 167 and 168: 150 Duntley Treatment of RLS should
Page 169 and 170: 152 Duntley 34. Cartwright, R. (197
Page 171 and 172: 154 Perlis et al.
Page 173 and 174: 156 Perlis et al. Fig. 1. A schemat
Page 175 and 176: 158 Perlis et al. ditioned arousal
Page 177 and 178: 160 Perlis et al. subjected to empi
Page 179 and 180: 162 Perlis et al. effect), (3) may
Page 181 and 182: 164 Perlis et al. Cognitive Therapy
Page 183 and 184: 166 Perlis et al. Table 2 Cognitive
Page 185 and 186: 168 Perlis et al. Perhaps more impo
Page 187 and 188: 170 Perlis et al. 28. Carskadon, M.
Page 189 and 190: 172 Perlis et al.
Page 191 and 192: 174 Attarian Secondary Insomnias Re
Page 193 and 194: 176 Attarian 50 years of age who sl
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Page 199 and 200: 182 Attarian to placebo. Zaleplon a
Page 201 and 202: 184 Attarian 3. Wyatt, R. J., Engel
Page 203 and 204: 186 Attarian residual sedation foll
Page 205 and 206: 188 Index Clonidine, 183 CNS arousa
Page 207 and 208: 190 Index Proton pump inhibitors, 1
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