Insomnia Research: 2002-2006
     
Am J Geriatr Psychiatry. 2006 Sep;14(9):803-807.
Paroxetine Treatment of Primary Insomnia in Older Adults.
Reynolds CF 3rd, Buysse DJ, Miller MD, Pollock BG, Hall M, Mazumdar S.
Advanced Center for Interventions and Services Research for Late-Life Mood Disorders (ACISR/LLMD) and the John A. Hartford Center of Excellence in Geriatric Psychiatry, Western Psychiatric Institute and Clinic, Pittsburgh, PA (CFR, DJB, MDM, MH); Division of Geriatric Psychiatry, University of Toronto, Faculty of Medicine, The Rotman Research Institute, Baycrest Centre for Geriatric Care, Toronto, Ontario, Canada (BGP); and Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA (SM).

Objective: The goal of this study was to test the efficacy of paroxetine for primary insomnia in older adults. Methods: Adults over age 55 with primary insomnia were randomly assigned to six weeks of double-blind treatment with paroxetine (N = 14) or placebo (N = 13). Outcome measures included persistence or resolution of insomnia; weekly diary measures of sleep quality, daytime alertness, and mood; and pre-/postpolysomnographic measures of sleep latency, wake time after sleep onset, and sleep efficiency. Results: Although weekly diary-based measures showed improved subjective sleep quality, daytime alertness, and mood with paroxetine, the authors observed no effect on sleep efficiency or categorical response rates. Conclusion: Paroxetine appears to be ineffective for treating primary insomnia in old age.

-----

Expert Opin Pharmacother. 2006 Sep;7(13):1731-8.
Emerging pharmacotherapeutic agents for insomnia: a hypnotic panacea?
Navab P, Guilleminault C.
Stanford Sleep Disorders Clinic, 401 Quarry Road, Suite 3301, Stanford, California, 94305, USA.

The burden of insomnia has had a significant effect not only on the socioeconomic matrix, but also the medical terrain, as signified by the increased morbidity and mortality of its associated psychiatric and organic sequelae. To this end, a plethora of pharmacotherapeutic agents have been recently introduced that address the vital need to combat insomnia and prevent the perpetuation in its chronic form. The previously and currently dispensed barbiturates and benzodiazepines, respectively, have paved the way for newer agents that are purported to be just as effective, or even more so, with a favourable profile in all domains of sleep. In assessing both published clinical studies and unpublished reports conducted on these emerging agents, this article profiles the most contemporary, therapeutic options in lieu of older hypnotics, over-the-counter medications and supplements. Furthermore, this paper aims to indicate both the future course of hypnotics and the developments currently in progress.

-----

Curr Treat Options Neurol. 2006 Sep;8(5):376-86.
Sleep dysfunction in women and its management.
Lee KA.
Department of Family Health Care Nursing, School of Nursing, University of California, San Francisco, San Francisco, CA 94143, USA. kathryn.lee@nursing.ucsf.edu.

Women generally have more complaints about sleep, compared with men of the same age. At various stages of reproduction, the reasons for these complaints become rather obvious--menstrual cramps and discomfort, pregnancy and postpartum factors, and menopausal hot flashes can fragment sleep. In addition, there are lifestyle factors, such as going to bed late and getting up early in order to attend to various family responsibilities, restricting the time allowed for sleep. Factors outside a woman's control, such as caregiving for sick family members during the night, can also result in disrupted sleep patterns, with little opportunity to make up for the lost sleep on weekends or days off. This article discusses the types of insomnia commonly experienced by women during key reproductive stages of life and proposes gender-specific assessment and management strategies. Pharmacologic management of sleep problems is useful for brief episodes of insomnia, but not usually desirable during pregnancy and lactation, or for management of chronic insomnia. For most women, regardless of reproductive stage, nonpharmacologic strategies that involve behavioral therapies, or short-term focused use of hypnotics at key time points, are more effective for quality of life than is long-term use of pharmacologic interventions.

-----

Curr Treat Options Neurol. 2006 Sep;8(5):367-75.
Treatment of sleep dysfunction and psychiatric disorders.
Becker PM.
Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, 5477 Glen Lakes Drive, #100, Dallas, TX 75234, USA. pbecker@sleepmed.com.

Patients with neurologic disorders commonly experience sleep dysfunction and psychiatric disorders. The most common sleep dysfunction is insomnia, which is a primary symptom in 30% to 90% of psychiatric disorders. Insomnia and fatigue are prominent symptoms of anxiety disorders and major depression, including patients who are treated but have residual symptoms. Anxiety and depressive disorders account for 40% to 50% of all cases of chronic insomnia. It is also recognized that primary insomnia and other primary sleep disorders produce symptoms that are similar to those reported by patients with psychiatric disorders. A clinician must judge whether sleep deprivation causes mood disturbance or whether depressive or anxiety disorder represents the primary reason for sleep dysfunction. When insomnia is comorbid with mild to moderate depression, therapy should begin with bedtime dosing of sedating antidepressants such as mirtazapine, nefazodone, or tricyclic antidepressants, which are preferred because of their sedative effects, although side effects may limit their usefulness. Intervention for chronic insomnia is similar in nonpsychiatric and psychiatric patients. Behavioral therapies, particularly cognitive behavioral therapy, and lifestyle changes show significant long-term efficacy as treatments for chronic insomnia. Sedative hypnotic agents are the most studied agents to treat insomnia, particularly those that are active through the benzodiazepine receptor-GABA complex, such as benzodiazepines, eszopiclone, zaleplon, and zolpidem. The new melatonin-receptor agonist ramelteon has not yet been studied in psychiatric patients. Prescription of adjunctive trazodone 50 to 150 mg is a common clinical practice to treat comorbid insomnia during antidepressant therapy, but published data are surprisingly limited when considered against the frequent usage of trazodone. Although there has been insufficient research on the use of atypical antipsychotic agents in severe insomnia, psychiatrists use quetiapine, olanzapine, or other agents to lessen agitation that disrupts sleep onset or maintenance. When insomnia or hypersomnia continues even as mood, anxiety, or thought disorders improve with standard therapy, the physician should consider the potential presence of underlying sleep disorders.

-----

BMC Pediatr. 2006 Aug 16;6:23.
Hypnosis for treatment of insomnia in school-age children: a retrospective chart review.
Anbar RD, Slothower MP.
Department of Pediatrics, University Hospital, State University of New York Upstate Medical University, Syracuse, NY, USA. anbarr@upstate.edu
Free full text at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16914044

BACKGROUND: The purposes of this study are to document psychosocial stressors and medical conditions associated with development of insomnia in school-age children and to report use of hypnosis for this condition. METHODS: A retrospective chart review was performed for 84 children and adolescents with insomnia, excluding those with central or obstructive sleep apnea. All patients were offered and accepted instruction in self-hypnosis for treatment of insomnia, and for other symptoms if it was felt that these were amenable to therapy with hypnosis. Seventy-five patients returned for follow-up after the first hypnosis session. Their mean age was 12 years (range, 7-17). When insomnia did not resolve after the first instruction session, patients were offered the opportunity to use hypnosis to gain insight into the cause. RESULTS: Younger children were more likely to report that the insomnia was related to fears. Two or fewer hypnosis sessions were provided to 68% of the patients. Of the 70 patients reporting a delay in sleep onset of more than 30 minutes, 90% reported a reduction in sleep onset time following hypnosis. Of the 21 patients reporting nighttime awakenings more than once a week, 52% reported resolution of the awakenings and 38% reported improvement. Somatic complaints amenable to hypnosis were reported by 41%, including chest pain, dyspnea, functional abdominal pain, habit cough, headaches, and vocal cord dysfunction. Among these patients, 87% reported improvement or resolution of the somatic complaints following hypnosis. CONCLUSION: Use of hypnosis appears to facilitate efficient therapy for insomnia in school-age children.

-----

CNS Spectr. 2006 Aug;11(8 Suppl 8):1-13.
New approaches in managing chronic insomnia.
Neubauer DN.
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Despite a high prevalence in the United States, insomnia remains underdiagnosed and undertreated. Extensive research has identified several factors that contribute to the inadequate treatment of insomnia, including the failure of patients to report insomnia to physicians, limited physician training, and physician misconceptions about the risks associated with hypnotic medications. To achieve optimal patient outcomes, physicians differentiate acute from chronic insomnia and distinguish primary insomnia from sleep disorders that occur with comorbid conditions, most notably psychiatric illnesses such as circadian rhythm disturbances. In addition, they utilize sleep hygiene measures, behavioral therapy, and/or pharmacologic medications to improve sleep problems in patients with insomnia. Newer nonbenzodiazepine receptor agonists are effective with fewer side effects than older benzodiazepine agonists; however, in 2005 a National Institutes of Health panel on chronic insomnia management indicated that clinical trials are needed to establish the long-term benefits of the newer drugs. Since 2005, data from clinical trials lasting 6 months to 1 year have been published for hypnotics including eszopiclone, zaleplon, and zolpidem extended-release. As the result of potentially altered dosing and monitoring, elderly patients require special consideration.

-----

Dialogues Clin Neurosci. 2006;8(2):217-26.
Depression and sleep: pathophysiology and treatment.
Thase ME.
University of Pittsburgh Medical Center, PA, USA. thaseme@upmc.edu

This review examines the relationship between sleep and depression. Most depressive disorders are characterized by subjective sleep disturbances, and the regulation of sleep is intricately linked to the same mechanisms that are implicated in the pathophysiology of depression. After briefly reviewing the physiology and topography of normal sleep, the disturbances revealed in studies of sleep in depression using polysomnographic recordings and neuroimaging assessments are discussed. Next, treatment implications of the disturbances are reviewed at both clinical and neurobiologic levels. Most antidepressant medications suppress rapid eye movement (REM) sleep, although this effect is neither necessary nor sufficient for clinical efficacy. Effects on patients' difficulties initiating and maintaining sleep are more specific to particular types of antidepressants. Ideally, an effective antidepressant will result in normalization of disturbed sleep in concert with resolution of the depressive syndrome, although few interventions actually restore decreased slow-wave sleep. Antidepressants that block central histamine 1 and serotonin 2 tend to have stronger effects on sleep maintenance, but are also prone to elicit complaints of daytime sedation. Adjunctive treatment with sedative hypnotic medications--primarily potent, shorter-acting benzodiazepine and gamma-aminobutyric acid (GABA A)-selective compounds such as zolpidem--are often used to treat associated insomnia more rapidly. Cognitive behavioral therapy and other nonpharmacologic strategies are also helpful.

-----

J Psychiatr Pract. 2006 Jul;12(4):229-43.
Searching for new options for treating insomnia: are melatonin and ramelteon beneficial?
Bellon A.
Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, 6555 Travis, Houston, TX 77030, USA. alfredobellon@yahoo.com

Insomnia is one of the most common complaints faced in clinical practice. The limited pharmacological options available make the treatment of this complaint a challenge. All of the available benzodiazepines and non-benzodiazepine hypnotics have the potential to induce addiction, cause withdrawal symptoms, or trigger rebound insomnia. Further, the evidence supporting the utility of commonly prescribed options such as antidepressants and antipsychotics is limited. Melatonin is a hormone that has been associated with soporific effects. Based on this premise, a melatonin receptor agonist was created. Ramelteon was approved by the Food and Drug Administration in 2005 and is the only medication indicated for the long-term treatment of insomnia. A critical review with a clinical perspective of randomized, placebo-controlled clinical trials was conducted to determine the efficacy of melatonin and ramelteon for the treatment of insomnia. Based on this review, it appears that more placebo-controlled trials are indicated before valid judgments concerning the efficacy of both melatonin and ramelteon can be made. In the meantime, there is some support for the use of melatonin for the treatment of insomnia, and findings concerning ramelteon also appear promising. Nevertheless, clinicians who prescribe melatonin or ramelteon should be cautious and carefully monitor both potential benefits and adverse effects, since data on melatonin are based on studies with multiple limitations and only three controlled trials have been done with ramelteon.

-----

Behav Sleep Med. 2006;4(3):135-51.
Cognitive behavioral treatment in clinically referred chronic insomniacs: group versus individual treatment.
Verbeek IH, Konings GM, Aldenkamp AP, Declerck AC, Klip EC.
Center for Sleep and Wake Disorders Kempenhaeghe, Heeze, The Netherlands.

In this study, we compared the effect of group and cognitive behavioral treatment (CBT) in clinically referred patients with chronic insomnia. The participants were 32 individually treated primary insomniacs and 74 individuals with either primary or secondary insomnia treated in a group (5-7 patients per group). The primary outcome measures were subjective sleep, quality of life (QOL), and psychological well-being. CBT produced significant changes in sleep onset latency, total sleep time, sleep efficiency, and wake after sleep onset. For total sleep time and sleep efficiency, the improvements were maintained at follow-up as well. In the questionnaires, significant improvements from treatment were seen for the Sickness Impact Profile, Sleep Evaluation Form, and Dysfunctional Beliefs and Attitudes About Sleep. All these improvements remained significant at follow-up. We conclude that CBT for insomnia is effective for both individual and group treatment. Improvements were seen in subjective sleep parameters, QOL, attitudes about sleep, and sleep evaluation in general, both posttreatment and at follow-up.

-----

Pharmacol Ther. 2006 Jul 27; [Epub ahead of print]
Treating insomnia: Current and investigational pharmacological approaches.
Ebert B, Wafford KA, Deacon S.
Department of Electrophysiology, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Copenhagen, Denmark.

Chronic insomnia affects a significant proportion of young adult and elderly populations. Treatment strategies should alleviate nighttime symptoms, the feeling of nonrestorative sleep, and impaired daytime function. Current pharmacological approaches focus primarily on GABA, the major inhibitory neurotransmitter in the central nervous system. Benzodiazepine receptor agonists (BzRA) have been a mainstay of pharmacotherapy; the classical benzodiazepines and non-benzodiazepines share a similar mode of action and allosterically enhance inhibitory chloride currents through the GABA(A) receptor, a ligand-gated protein comprising 5 subunits pseudosymmetrically arranged around a core anion channel. Variations in GABA(A) receptor subunit composition confer unique pharmacological, biophysical, and electrophysiological properties on each receptor subtype. Classical benzodiazepines bind non-selectively to GABA(A) receptors containing a gamma2 subunit, whereas non-benzodiazepine hypnotics bind with higher relative affinity to alpha1-containing receptors. The non-benzodiazepine compounds generally represent an improvement over benzodiazepines as a result of improved binding selectivity and pharmacokinetic profiles. However, the enduring potential for amnestic effects, next day residual sedation, and abuse and physical dependence, particularly at higher doses, underscores the need for new treatment strategies. Novel pharmacotherapies in development act on systems believed to be specifically involved in the regulation of the sleep-wake cycle. The recently approved melatonin receptor agonist, ramelteon, targets circadian mechanisms. Gaboxadol, an investigational treatment and a selective extrasynaptic GABA(A) receptor agonist (SEGA), targets GABA(A) receptors containing a delta subunit, which are located outside the synaptic junctions of thalamic and cortical neurons thought to play an important regulatory role in the onset, maintenance, and depth of the sleep process.

-----

Biol Psychiatry. 2006 Mar 30; [Epub ahead of print]
Eszopiclone Co-Administered With Fluoxetine in Patients With Insomnia Coexisting With Major Depressive Disorder.
Fava M, McCall WV, Krystal A, Wessel T, Rubens R, Caron J, Amato D, Roth T.
>From Depression Clinical and Research Program, Massachusetts General HospitalBoston.

BACKGROUND: Insomnia and major depressive disorder (MDD) can coexist. This study evaluated the effect of adding eszopiclone to fluoxetine. METHODS: Patients who met DSM-IV criteria for both MDD and insomnia (n = 545) received morning fluoxetine and were randomized to nightly eszopiclone 3 mg (ESZ+FLX) or placebo (PBO+FLX) for 8 weeks. Subjective sleep and daytime function were assessed weekly. Depression was assessed with the 17-item Hamilton Rating Scale for Depression (HAM-D-17) and the Clinical Global Impression Improvement (CGI-I) and Severity items (CGI-S). RESULTS: Patients in the ESZ+FLX group had significantly decreased sleep latency, wake time after sleep onset (WASO), increased total sleep time (TST), sleep quality, and depth of sleep at all double-blind time points (all p < .05). Eszopiclone co-therapy also resulted in: significantly greater changes in HAM-D-17 scores at Week 4 (p = .01) with progressive improvement at Week 8 (p = .002); significantly improved CGI-I and CGI-S scores at all time points beyond Week 1 (p < .05); and significantly more responders (59% vs. 48%; p = .009) and remitters (42% vs. 33%; p = .03) at Week 8. Treatment was well tolerated, with similar adverse event and dropout rates. CONCLUSIONS: In this study, eszopiclone/fluoxetine co-therapy was relatively well tolerated and associated with rapid, substantial, and sustained sleep improvement, a faster onset of antidepressant response on the basis of CGI, and a greater magnitude of the antidepressant effect.

-----

Sleep. 2006 Mar 1;29(3):335-41.
Effect of tiagabine on sleep in elderly subjects with primary insomnia: a randomized, double-blind, placebo-controlled study.
Roth T, Wright KP Jr, Walsh J.
Sleep Disorders and Research Center, Henry Ford Hospital, 2799 West Grand Boulevard, CFP-3, Detroit, MI 48202, USA. troth1@hfhs.org

SUBJECT OBJECTIVE: This study further evaluated the effects of tiagabine on sleep in elderly subjects with primary insomnia. METHODS: Elderly subjects (aged 65-85 years) meeting DSM-IV-TR criteria for primary insomnia were randomly assigned to receive tiagabine 2, 4, 6, or 8 mg or placebo on 2 consecutive nights. Efficacy was assessed using standard polysomnography and a postsleep questionnaire. Additional assessments included the Assessment of Daily Functioning, Digit Symbol Substitution Test (for residual effects), and visual analog scale (for sleepiness/alertness). RESULTS: A total of 207 subjects were randomly assigned to study medication (tiagabine: 2 mg, n = 43; 4 mg, n = 38; 6 mg, n = 45; 8 mg, n = 43; placebo, n = 38). Tiagabine did not significantly effect wake after sleep onset, latency to persistent sleep, or total sleep time compared with placebo (P > .05). Significant increases in Stage 3+4 sleep (i.e., slow-wave sleep) were found for tiagabine 4, 6, and 8 mg versus placebo, with a corresponding significant decrease in Stage 1 sleep (P < .05). At 6 and 8 mg, tiagabine also significantly reduced the number of awakenings and increased the ratio of Stage 3+4/(Stage 1 +wake after sleep onset). In general, there were no significant effects on subjects' ratings of sleep or daily functioning with tiagabine 2, 4, and 6 mg versus placebo. These 3 doses had tolerability profiles comparable with that of placebo and were not associated with significant residual effects or reduced alertness. The 8-mg dose, however, significantly decreased subjective total sleep time and refreshing quality of sleep, as well as daily functioning. This dose was associated with troublesome adverse events, significant residual effects, and reduced alertness. CONCLUSIONS: In elderly subjects with primary insomnia, tiagabine did not have a significant effect on wake after sleep onset, latency to persistent sleep, total sleep time, or the subjective rating of sleep. Tiagabine 4, 6, and 8 mg significantly increased slow-wave sleep, with a corresponding significant decrease in Stage 1 sleep. Tiagabine was generally well tolerated, with doses of less than 6 mg having tolerability profiles generally similar to that of placebo. The 8-mg dose, however, was associated with troublesome adverse events, residual effects, and reduced alertness.

-----

Sleep Breath. 2006 Mar;10(1):16-28.
Nasal dilator strip therapy for chronic sleep-maintenance insomnia and symptoms of sleep-disordered breathing: a randomized controlled trial.
Krakow B, Melendrez D, Sisley B, Warner TD, Krakow J, Leahigh L, Lee S.
Sleep and Human Health Institute, Suite 380, 6739 Academy NE, Albuquerque, NM, 87109, USA.

To test the impact of nasal dilator strips (NDSs) on insomnia severity, sleep-disordered breathing (SDB) symptoms, sleep quality, and quality of life. Randomized, controlled trial of 4 weeks' duration. Community sample of nonobese, adults with a primary sleep complaint of chronic sleep-maintenance insomnia and mild to moderate SDB symptoms (treatment, n=42; control, n=38). Primary outcomes were four validated scales: Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index (PSQI), Functional Outcomes of Sleep Questionnaire (FOSQ), and Quality of Life Enjoyment and Satisfaction Questionnaire (QLESQ). Secondary outcomes were sleep indices, nonrestorative sleep ratings, and SDB symptoms, assessed retrospectively and prospectively. Both groups received nonspecific education about sleep disorders. Treatment group also received a brief SDB education and nasal strip instructions. At 4 weeks' follow-up, the treatment group demonstrated significant (p=.0001), large improvements in ISI and PSQI (mean Cohen's d=1.18) and significant (p<.02), medium-sized improvements in FOSQ and QLESQ (mean d=0.51) compared to small, nonsignificant changes in control group (Cohen's d range=0.36-0.09). Treatment group change scores among all four primary variables were significantly correlated (mean r=0.50, p=0.01). Secondary prospective and retrospective outcomes showed medium to large improvements in treatment compared to controls for sleep indices (mean d=0.52 vs 0.28), nonrestorative sleep ratings (mean d=0.69 vs 0.11), and sleep breathing symptoms (mean d=0.47 vs 0.09). Significance was obtained for prospective sleep indices (p=0.01), retrospective, and prospective nonrestorative sleep ratings (p=0.003, <0.05), and retrospective sleep breathing symptoms (p=0.03). SDB education and NDSs demonstrated therapeutic efficacy in a select sample of insomnia patients with SDB symptoms. Replication of results requires placebo controls and objectively confirmed SDB cases.

-----

Ann Clin Psychiatry. 2006 Jan-Mar;18(1):49-56.
Sleep maintenance insomnia: strengths and weaknesses of current pharmacologic therapies.
Rosenberg RP.
Northside Hospital Sleep Medicine Institute, Atlanta, GA, USA. rosenberg@mindspring.com

BACKGROUND: Although insomnia is highly prevalent, sleep disturbances often go unrecognized and untreated. When insomnia is recognized, considerable emphasis has been placed on improving sleep onset; however, there is growing evidence that improving sleep maintenance is an equally important treatment goal. METHODS: A MEDLINE literature search was performed using the search parameters "insomnia," "zolpidem," "zaleplon," "flurazepam," "estazolam," "quazepam," "triazolam," and "temazepam," as these agents are FDA-approved for the treatment of insomnia. Per reviewer comments, the search criteria was later expanded to include lorazepam. A literature search using the terms "trazodone" and "insomnia" was also performed, as this is the second-most commonly prescribed agent for treating insomnia. Sleep efficacy endpoints from randomized, placebo-controlled clinical trials in adult populations and key review articles published between 1975 and 2004 were included in this review. As only one randomized placebo-controlled trial evaluated trazodone use in primary insomnia, the trazodone search was expanded to include all clinical trials that evaluated trazodone use in insomnia. Relevant texts and other articles that evaluated side effect profiles of these agents were also included, one of which was published in January of 2005. In all publications, impact of treatment on sleep maintenance parameters (wake time after sleep onset, number of awakenings) and measures of next-day functioning were evaluated, in addition to sleep onset parameters (sleep latency, time to sleep onset/induction) and sleep duration data (total sleep time). RESULTS: Many of the currently available agents used to treat insomnia, including the antidepressant trazodone, the non-benzodiazepine hypnotics zolpidem and zaleplon, and some of the benzodiazepines, have not consistently demonstrated effectiveness in promoting sleep maintenance. Furthermore, the benzodiazepines with established sleep maintenance efficacy are associated with next-day sedation, the risk of tolerance and dependence, or both. CONCLUSIONS: New agents that offer relief of sleep maintenance insomnia without residual next day impairment while improving next day function are needed. Several compounds currently under development may offer clinicians a more effective and safer treatment for this common disorder.

-----

Expert Opin Pharmacother. 2006 Feb;7(3):345-56.
Eszopiclone for the treatment of insomnia.
Scharf M.
Tri-State Sleep Disorders Center, Cincinnati, OH 45246, USA. sleepsat1@aol.com

Eszopiclone, a single-isomer, non-benzodiazepine hypnotic agent, is approved for use in the US for the treatment of insomnia for patients who have difficulty falling asleep (sleep latency) as well as for those who have difficulty staying asleep (sleep maintenance). Efficacy in sleep maintenance has not been consistently demonstrated with previous hypnotics, and long-term efficacy and safety data are lacking for these agents. In clinical trials, eszopiclone 3 mg significantly improved objective and subjective sleep measures in transient and chronic insomnia in adults. Nightly treatment with eszopiclone 1 mg effectively induced sleep in elderly patients and the 2-mg dose effectively induced and maintained sleep. The ability of eszopiclone 2 mg to significantly improve next-day functioning and daytime alertness (as demonstrated by a reduction in the number and duration of naps) in the elderly is an important finding in clinical trials, and is unique to the class of hypnotic agents for the treatment of insomnia. Eszopiclone was well tolerated in clinical trials < or = 12 months duration, with no clinically significant evidence of pharmacological tolerance, rebound insomnia or dependence. The most frequently reported adverse event was unpleasant taste. Eszopiclone is the only non-benzodiazepine sedative-hypnotic (in the Schedule IV class under the Controlled Substances Act) to be evaluated as a long-term treatment for chronic insomnia.

-----

Health Psychol. 2006 Jan;25(1):15-9.
Who is a candidate for cognitive-behavioral therapy for insomnia?
Smith MT, Perlis ML.
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Behavioral Medicine Research Laboratory and Clinic, Baltimore, MD 21287-7101, USA. msmith62@jhmi.edu

Chronic insomnia impacts 1 in 10 adults and is linked to accidents, decreased quality of life, diminished work productivity, and increased long-term risk for medical and psychiatric diseases such as diabetes and depression. Recent National Institutes of Health consensus statements and the American Academy of Sleep Medicine's Practice Parameters recommend that cognitive-behavioral therapy for insomnia (CBT-I) be considered the 1st line treatment for chronic primary insomnia. Growing research also supports the extension of CBT-I for patients with persistent insomnia occurring within the context of medical and psychiatric comorbidity. In the emerging field of behavioral sleep medicine, there has yet to be a consensus point of view about who is an appropriate candidate for CBT-I and how this determination is made. This report briefly summarizes these issues, including a discussion of potential contraindications, and provides a schematic decision-to-treat algorithm. Copyright 2006 APA, all rights reserved.

-----

Health Psychol. 2006 Jan;25(1):3-14.
Comparative meta-analysis of behavioral interventions for insomnia and their efficacy in middle-aged adults and in older adults 55+ years of age.
Irwin MR, Cole JC, Nicassio PM.
Cousins Center for Psychoneuroimmunology, University of California, Los Angeles (UCLA) Neuropsychiatric Institute, Los Angeles, CA 90095-7057, USA. mirwin1@ucla.edu

Meta-analyses support the effectiveness of behavioral interventions for the treatment of insomnia, although few have systematically evaluated the relative efficacy of different treatment modalities or the relation of old age to sleep outcomes. In this meta-analysis of randomized controlled trials (k = 23), moderate to large effects of behavioral treatments on subjective sleep outcomes were found. Evaluation of the moderating effects of behavioral intervention type (i.e., cognitive-behavioral treatment, relaxation, behavioral only) revealed similar effects for the 3 treatment modalities. Both middle-aged adults and persons older than 55 years of age showed similar robust improvements in sleep quality, sleep latency, and wakening after sleep onset. A research agenda is recommended to examine the mechanisms of action of behavioral treatments on sleep with increased attention to the high prevalence of insomnia in older individuals. Copyright 2006 APA, all rights reserved.

-----

Am J Health Syst Pharm. 2006 Jan 1;63(1):41-8.
Eszopiclone.
Halas CJ.
Adult Critical Care, Penn State Milton S. Hershey Medical Center, Pharmacy, M.C. H079, 500 University Drive, Hershey, PA 17033, USA. chalas@psu.edu

PURPOSE: The pharmacology, pharmacokinetics, indications, clinical efficacy, adverse effects, drug interactions, dosing, and administration of eszopiclone are discussed. SUMMARY: The pharmacology of eszopiclone is not well understood. Eszopiclone is the S-isomer of racemic zopiclone. The relative bioavailability of oral racemic zopiclone is about 80%. Eszopiclone is rapidly absorbed after oral administration, with peak serum concentrations ranging from 1 to 1.3 hours. The efficacy of eszopiclone has been evaluated in healthy adults, including elderly patients, for the treatment of transient and chronic insomnia. Compared with placebo, eszopiclone has been shown to considerably reduce sleep induction and improve sleep maintenance, duration, quality, and depth, as well as next-day functioning. The most common adverse effects reported are unpleasant taste, headache, and dry mouth. Dosing should be individualized, and the lowest effective dose should be used to minimize the risk of adverse events. The recommended starting dosage for nonelderly patients is 2 mg immediately before bedtime, with adjustment to 3 mg if clinically indicated. Dosage adjustment is necessary in patients with severe hepatic disease and in those receiving concomitant potent cytochrome P-450 isoenzyme 3A4 inhibitors. No dosage adjustment is required for patients with renal dysfunction. The cost of eszopiclone is 3.70 dollars per tablet for all dosage strengths (1-, 2-, and 3-mg tablets). CONCLUSION: Its favorable adverse-effect profile and approved labeling for the treatment of chronic insomnia makes eszopiclone a viable alternative for insomnia treatment. Published data are limited, however, and more clinical trials, including comparator studies, are needed to further evaluate the use of this drug.

-----

Sleep Med. 2006 Jan;7(1):17-24. Epub 2005 Nov 23.
An efficacy, safety, and dose-response study of Ramelteon in patients with chronic primary insomnia.
Erman M, Seiden D, Zammit G, Sainati S, Zhang J.
Pacific Sleep Medicine Services, 10052 Mesa Ridge Court, Suite 100, San Diego, CA 92121, USA.

BACKGROUND AND PURPOSE: To evaluate the efficacy, safety, and dose response of Ramelteon, a novel highly selective MT(1)/MT(2) receptor agonist, in patients with chronic primary insomnia. PATIENTS AND METHODS: A randomized, multicenter, double-blind, placebo-controlled, five-period crossover study design was performed. A total of 107 patients, aged 18-64 years, were randomized into a dosing sequence that included 4, 8, 16, and 32mg of ramelteon and placebo. Patients received all five treatments, with a 5- to 12-day washout period between treatments, and served as their own controls. Medication was administered 30min before habitual bedtime and polysomnographic monitoring. Next-day residual effects were assessed with two visual analog scales (mood and feeling), digit symbol substitution test (DSST), word-list memory tests (immediate recall and delayed recall), and a post-sleep questionnaire that ascertained patients' alertness and ability to concentrate. RESULTS: All tested doses of ramelteon resulted in statistically significant reductions in latency to persistent sleep (LPS) and increases in total sleep time (TST). No next-day residual effects were apparent at any dose, as compared with placebo. There were no differences in the number or type of adverse events between any active treatment and placebo group. The most commonly reported adverse events were headache, somnolence, and sore throat. CONCLUSIONS: Ramelteon demonstrated a statistically significant reduction in LPS and a statistically significant increase in TST, with no apparent next-day residual effects, in patients with chronic primary insomnia.

-----

J Consult Clin Psychol. 2005 Dec;73(6):1164-74
A placebo-controlled test of cognitive-behavioral therapy for comorbid insomnia in older adults.
Rybarczyk B, Stepanski E, Fogg L, Lopez M, Barry P, Davis A.
Department of Behavioral SciencesRush University Medical Center, Chicago, IL, US. brybarcz@rush.edu.

The present study tested cognitive-behavioral therapy (CBT) for insomnia in older adults with osteoarthritis, coronary artery disease, or pulmonary disease. Ninety-two participants (mean age = 69 years) were randomly assigned to classroom CBT or stress management and wellness (SMW) training, which served as a placebo condition. Compared with SMW, CBT participants had larger improvements on 8 out of 10 self-report measures of sleep. The type of chronic disease had no impact on these outcomes. The hypothesis that CBT would improve daytime functioning more than SMW was only supported by a global rating measure. These results add to findings that challenge the dichotomy between primary and secondary insomnia and suggest that psychological factors are likely involved in insomnias that are presumed to be secondary to medical conditions. ((c) 2006 APA, all rights reserved).

-----

Arthritis Rheum. 2005 Dec 15;53(6):911-9.
Pain as a mediator of sleep problems in arthritis and other chronic conditions.
Power JD, Perruccio AV, Badley EM.
University of Toronto, and Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada. dpower@uhnres.utoronto.ca

OBJECTIVE: To examine the associations between arthritis and insomnia symptoms and unrefreshing sleep, as well as the role of pain as a mediator of these relationships. METHODS: Analyses were conducted on the cross-sectional, nationally representative, weighted sample of adults > or =18 years of age (n = 118,336) in the 2000/2001 Canadian Community Health Survey. Four logistic regression models were estimated for each sleep problem (model 1: arthritis only; model 2: model 1 + sociodemographic characteristics, lifestyle factors, and other chronic conditions; model 3: model 2 + mental health [stress, depression]; and model 4: model 3 + pain). Mediation by pain was quantified by the percentage change in the effect of arthritis on a particular sleep problem by comparing models 3 and 4. RESULTS: The prevalence of insomnia symptoms and unrefreshing sleep in persons with arthritis was 24.8% and 11.9%, respectively. These estimates are twice as high as those for persons without arthritis. In multivariate regression analyses, the addition of pain decreased the effect of arthritis by 53% (insomnia symptoms) and 64% (unrefreshing sleep). The effect of arthritis was still statistically significant in these models, suggesting that pain is a partial mediator of these relationships. CONCLUSION: Insomnia symptoms and unrefreshing sleep affect a considerable proportion of individuals with arthritis. Pain mediates a substantial amount of the relationship between arthritis and sleep problems. Better pain management could significantly improve sleep in individuals with arthritis.

-----

J Clin Psychiatry. 2005;66 Suppl 9:24-30.
Sleep and aging: prevalence of disturbed sleep and treatment considerations in older adults.
Ancoli-Israel S.
>From the Department of Psychiatry, University of California, San Diego, and Veterans Affairs San Diego Healthcare System.

Although sleep patterns change with age, it is the change in the ability to sleep that precipitates sleep complaints in older adults. Waking not rested, waking too early, trouble falling asleep, daytime napping, nocturnal waking, and difficulty initiating or maintaining sleep are among the chief sleep complaints of older adults. The consequences of poor sleep include difficulty sustaining attention, slowed response time, difficulty with memory, and decreased performance. Both medical and psychiatric conditions as well as the medications used to treat them lead to sleep complaints in older adults. Circadian rhythm disturbances and primary sleep disorders may also result in sleep complaints. Appropriate treatment may be dictated by severity of symptoms and concurrent medications. Efficacious pharmacologic interventions are the nonbenzodiazepine hypnotics zolpidem, zaleplon, and eszop-iclone. Two new agents, ramelteon, which was recently approved by the U.S. Food and Drug Administration for use in adults with insomnia, and immediate release and modified release indiplon, which is currently under investigation, have been effective in clinical trials. Cognitive-behavioral therapy alone and in combination with medication have been effective in improving sleep in older adults. Sleep disturbance is not a natural consequence of aging, but rather a treatable condition.

------

J Clin Psychiatry. 2005;66 Suppl 9:18-23.
Therapeutic options in the treatment of insomnia.
Erman MK.
>From the Department of Psychiatry, University of California, San Diego, School of Medicine.

Pharmacologic and nonpharmacologic therapies both have roles in the treatment of insomnia. The benzodiazepines, when first introduced, were a major improvement over earlier treatments for insomnia in terms of their safety and efficacy. Since then, the nonbenzodiazepine benzodiazepine receptor agonists have been developed, which have provided advantages over the older medications and are currently first-line medication treatment for insomnia. Although antidepressants, antipsychotics, and anticonvulsants are often prescribed for the treatment of insomnia, they are not approved by the U.S. Food and Drug Administration for this indication and have side effects that are sometimes severe. New types of medications that have different modes of action from the benzodiazepine receptor agonists are now being developed, and one, a selective melatonin receptor agonist, has recently been approved for treatment of insomnia. Nonpharmacologic therapies can also help patients learn how to fall asleep faster and improve sleep quality. It is important for physicians to teach patients good sleep hygiene as part of their treatment. Cognitive-behavioral therapy is effective in the treatment of insomnia, alone and in combination with pharmacotherapy, but finding a qualified provider can be difficult and the patient must be willing to take the time to learn the therapies and wait for them to show effect.

-----

Sleep. 2005 Nov 1;28(11):1465-71.
Valerian-hops combination and diphenhydramine for treating insomnia: a randomized placebo-controlled clinical trial.
Morin CM, Koetter U, Bastien C, Ware JC, Wooten V.
Universite Laval, Ecole de Psychologie, Sainte-Foy, Quebec, Canada. cmorin@psy.ulaval.ca

CONTEXT: Insomnia is a prevalent health complaint associated with daytime impairments, reduced quality of life, and increased health-care costs. Although it is often self-treated with herbal and dietary supplements or with over-the-counter sleep aids, there is still little evidence on the efficacy and safety of those products. OBJECTIVE: To evaluate the efficacy and safety of a valerian-hops combination and diphenhydramine for the treatment of mild insomnia. DESIGN AND SETTING: Multicenter, randomized, placebo-controlled, parallel-group study conducted in 9 sleep disorders centers throughout the United States. PATIENTS: A total of 184 adults (110 women, 74 men; mean age of 44.3 years) with mild insomnia. INTERVENTIONS: (1) Two nightly tablets of standardized extracts of a valerian (187-mg native extracts; 5-8:1, methanol 45% m/m) and hops (41.9-mg native extracts; 7-10:1, methanol 45% m/m) combination for 28 days (n = 59), (2) placebo for 28 days (n = 65), or (3) 2 tablets of diphenhydramine (25 mg) for 14 days followed by placebo for 14 days (n = 60). OUTCOME MEASURES: Sleep parameters measured by daily diaries and polysomnography, clinical outcome ratings from patients and physicians, and quality of life measures. RESULTS: Modest improvements of subjective sleep parameters were obtained with both the valerian-hops combination and diphenhydramine, but few group comparisons with placebo reached statistical significance. Valerian produced slightly greater, though nonsignificant, reductions of sleep latency relative to placebo and diphenhydramine at the end of 14 days of treatment and greater reductions than placebo at the end of 28 days of treatment. Diphenhydramine produced significantly greater increases in sleep efficiency and a trend for increased total sleep time relative to placebo during the first 14 days of treatment. There was no significant group difference on any of the sleep continuity variables measured by polysomnography. In addition, there was no alteration of sleep stages 3-4 and rapid eye movement sleep with any of the treatments. Patients in the valerian and diphenhydramine groups rated their insomnia severity lower relative to placebo at the end of 14 days of treatment. Quality of life (Physical component) was significantly more improved in the valerian-hops group relative to the placebo group at the end of 28 days. There were no significant residual effects and no serious adverse events with either valerian or diphenhydramine and no rebound insomnia following their discontinuation. CONCLUSIONS: The findings show a modest hypnotic effect for a valerian-hops combination and diphenhydramine relative to placebo. Sleep improvements with a valerian-hops combination are associated with improved quality of life. Both treatments appear safe and did not produce rebound insomnia upon discontinuation during this study. Overall, these findings indicate that a valerian-hops combination and diphenhydramine might be useful adjuncts in the treatment of mild insomnia.

-----

CNS Drugs. 2005;19(12):1057-65; discussion 1066-7.
Ramelteon.
McGechan A, Wellington K.
Adis International Limited, Auckland, New Zealand. demail@adis.co.nz

Ramelteon, approved in the US for the treatment of insomnia characterised by difficulty with sleep onset, is a highly selective agonist for the melatonin MT1/MT2 receptors, which are believed to mediate the circadian rhythm in mammals. Ramelteon has negligible affinity for the MT3 binding sites and other receptors in the brain, including the opiate, dopamine, benzodiazepine and serotonin receptors, which may explain the lack of significant adverse events and lack of abuse or dependence potential observed with ramelteon. In three clinical trials in patients with chronic insomnia, ramelteon 8mg was effective in reducing sleep latency, without being associated with any significant or clinically relevant residual effects. It also generally increased total sleep time and, where assessed, sleep efficiency. In a first-night-effect model of transient insomnia, ramelteon 8mg was significantly more effective than placebo at reducing sleep latency and increasing total sleep time. Ramelteon was generally well tolerated; the most commonly reported adverse events occurring in more ramelteon than placebo recipients were somnolence (5% vs 3%), fatigue (4% vs 2%) and dizziness (5% vs 3%). Adverse events were mostly mild or moderate in nature. Ramelteon has been shown to have no potential for abuse or dependence.

-----

Arch Intern Med. 2005 Nov 28;165(21):2527-35.
Behavioral insomnia therapy for fibromyalgia patients: a randomized clinical trial.
Edinger JD, Wohlgemuth WK, Krystal AD, Rice JR.
Psychology Service, Veterans Affairs Medical Center, Durham, NC 27705, USA. jack.edinger@duke.edu

BACKGROUND: Insomnia is common and debilitating to fibromyalgia (FM) patients. Cognitive-behavioral therapy (CBT) is effective for many types of patients with insomnia, but has yet to be tested with FM patients. This study compared CBT with an alternate behavioral therapy and usual care for improving sleep and other FM symptoms. METHODS: This randomized clinical trial enrolled 47 FM patients with chronic insomnia complaints. The study compared CBT, sleep hygiene (SH) instructions, and usual FM care alone. Outcome measures were subjective (sleep logs) and objective (actigraphy) total sleep time, sleep efficiency, total wake time, sleep latency, wake time after sleep onset, and questionnaire measures of global insomnia symptoms, pain, mood, and quality of life. RESULTS: Forty-two patients completed baseline and continued into treatment. Sleep logs showed CBT-treated patients achieved nearly a 50% reduction in their nocturnal wake time by study completion, whereas SH therapy- and usual care-treated patients achieved only 20% and 3.5% reductions on this measure, respectively. In addition, 8 (57%) of 14 CBT recipients met strict subjective sleep improvement criteria by the end of treatment compared with 2 (17%) of 12 SH therapy recipients and 0% of the usual care group. Comparable findings were noted for similar actigraphic improvement criteria. The SH therapy patients showed favorable outcomes on measures of pain and mental well-being. This finding was most notable in an SH therapy subgroup that self-elected to implement selected CBT strategies. CONCLUSIONS: Cognitive-behavioral therapy represents a promising intervention for sleep disturbance in FM patients. Larger clinical trials of this intervention with FM patients seem warranted.

-----

Behav Res Ther. 2005 Dec;43(12):1611-30.
Sequential combinations of drug and cognitive behavioral therapy for chronic insomnia: An exploratory study.
Vallieres A, Morin CM, Guay B.
Ecole de psychologie, Universite Laval, Pavillon FAS, Quebec, Canada G1K 7P4; Centre de recherche Universite Laval-Robert Giffard, Quebec, Canada G1J 2G3.

This study explores the efficacy of sequential treatments involving medication and cognitive behavioral treatment (CBT) for primary insomnia. Seventeen participants took part in a multiple baseline design and were assigned to: (a) medication for 5 weeks, followed by combined medication plus CBT for 5 weeks; (b) combined treatment for 5 weeks, followed by CBT alone; or (c) CBT alone. Each treatment sequence produced significant sleep improvements, but at different points in time. For the first sequence, most of the sleep improvement was obtained after the introduction of CBT, while for the other sequence and CBT alone, improvement appeared during the first weeks. These results suggest that sleep improvement seems affected by the way treatments are combined. Also, a sequence beginning with a combined treatment followed by CBT alone seems to produce the best outcome. Additional research should be conducted with larger samples to determine the most effective sequence.

-----

Sleep Med. 2005 Oct 13; [Epub ahead of print]
An evaluation of the efficacy and safety of eszopiclone over 12 months in patients with chronic primary insomnia.
Roth T, Walsh JK, Krystal A, Wessel T, Roehrs TA.
Henry Ford Hospital Sleep Center, 2799 West Grand Blvd, CFP-3, Detroit, MI 48202, USA.

BACKGROUND AND PURPOSE: A double-blind placebo-controlled study of eszopiclone found significant, sustained improvement in sleep and daytime function. The 6-month open-label extension phase is described herein. PATIENTS AND METHODS: Adults (21-64) with primary insomnia who reported sleep duration <6.5h/night or sleep latency >30min/night were included. Patient-reported endpoints included sleep and daytime function. Safety and compliance were assessed at monthly clinic visits. The final double-blind month was used as the baseline for efficacy analyses of the open-label period. RESULTS: Patients who were initially randomized to double-blind placebo and then switched to open-label eszopiclone (n=111) significantly reported the following: (1) decreased sleep latency, wake time after sleep onset, and number of awakenings; (2) increased total sleep time and sleep quality; and (3) improved ratings of daytime ability to function, alertness and sense of physical well-being compared to baseline (P</=0.0001 all monthly endpoints). There was no evidence of tolerance on any measure in either group. These subjects (n=360) sustained the double-blind treatment gains for all sleep and daytime parameters, with further significant improvement in a number of measures. Eszopiclone was well tolerated in both groups; unpleasant taste was the only undesirable effect reported by >5% of patients. CONCLUSIONS: The significant improvements in sleep and daytime function were evident in those switched from double-blind placebo to 6 months of open-label eszopiclone therapy and were sustained during the 6 months of open-label treatment for those receiving prior double-blind eszopiclone. During 12 months of nightly treatment, eszopiclone 3mg was well tolerated; tolerance was not observed.

-----

Ann Pharmacother. 2005 Oct;39(10):1659-65. Epub 2005 Aug 30.
Eszopiclone for insomnia.
Melton ST, Wood JM, Kirkwood CK.
1 Patient Assistance Program, C-Health, P.C., Lebanon, VA.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy data, and adverse effects of eszopiclone in the treatment of transient and chronic insomnia in adult and geriatric patients. DATA SOURCES: A MEDLINE literature search (1966-May 2005) was conducted to retrieve articles and abstracts involving eszopiclone. The manufacturer of the drug provided a general summary of clinical data and abstracts of unpublished Phase III clinical trials. STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were reviewed, and information deemed relevant was included for this review. DATA SYNTHESIS: Food and Drug Administration approval of eszopiclone was based on 6 double-blind, placebo-controlled trials. Five trials published in abstract or study form were reviewed. The sixth trial was not available for evaluation. An open-label continuation trial was also reviewed. All studies showed statistically significant improvements in sleep parameters in adult and elderly patients treated for insomnia with eszopiclone. CONCLUSIONS: The results of the 5 available double-blind, placebo-controlled studies (and 1 open-label, 6-month extension) showed that eszopiclone was safe and effective in the treatment of transient and chronic insomnia in adult and geriatric patients. Tolerance with long-term exposure (6 mo) and rebound insomnia were not observed. The results of the 6-month, open-label extension trial demonstrated that improvements in sleep parameters were sustained. Future studies comparing eszopiclone with other non benzodiazepine sedative-hypnotics (eg, zolpidem, zaleplon) are needed with cost data to clearly define the role of eszopiclone in the pharmacotherapy of chronic insomnia.

-----

J Support Oncol. 2005 Sep-Oct;3(5):349-59.
Pathogenesis and management of cancer-related insomnia.
Graci G.
Northwestern University, Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois 60611, USA. GGraci@nmff.org

Insomnia is the most common sleep disorder reported by cancer patients. Oncologists have noticed that alterations in sleep patterns are endemic among their patients, yet sleep problems are rarely assessed in a typical patient evaluation. Other concerns, such as morbidity and mortality, appear to take precedence. The cause of chronic sleep difficulties is multifaceted and up until recently, little attention has been given to the potential factors associated with the pathogenesis of cancer-related insomnia.The unique contributions of psychologic, medical, treatment side effects, environmental, behavioral, and pharmaceutical pathways on cancer-related insomnia cannot be ignored.This paper explores an overview of the incidence and severity of sleep disturbance in cancer patients, a review of the mechanisms of sleep, and the potential factors associated with the pathogenesis of cancer-related insomnia. Nurses, physicians, and other healthcare providers are in a unique position to greatly improve the quality of sleep in cancer patients. Cancer patients face many challenges; sleep problems do not have to be one of the necessary consequences associated with the cancer experience.

-----

Arch Women Ment Health. 2005 Sep 30; [Epub ahead of print]
Insomnia in women: an overlooked epidemic?
Soares CN.
Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, Canada.

Insomnia is a common and significant healthcare problem, and affects a large percentage of women seen by general practitioners, obstetrician-gynecologists and mental health professionals. Specific risk factors for insomnia may be gender-related, including higher prevalence rates of depression and anxiety among women, environmental and social factors, as well as reproductive-related factors (e.g., peri-menstrual difficulties and menopause-related symptoms).Sleep problems interfere significantly with daytime functioning and overall well-being, and may lead to serious clinical consequences. Treatment options include benzodiazepines, non-benzodiazepines, nonprescription sleep aids, and non-pharmacologic interventions such as sleep hygiene measures.This article reviews the existing literature on the prevalence, clinical characteristics of insomnia in women, and highlights some of the treatment options available. Healthcare providers should be aware of the variety of pharmacologic and non-pharmacologic options for treatment of insomnia and, in particular, be able to weigh their efficacy against the risks of side effects and next-day sedation.

-----

Nord J Psychiatry. 2005;59(3):217-21.
Effect of melatonin-rich night-time milk on sleep and activity in elderly institutionalized subjects.
Valtonen M, Niskanen L, Kangas AP, Koskinen T.
Institute of Applied Biotechnology, University of Kupio, Finland. maija.valtonen@uku.fi

Melatonin production decreases with advancing age, leading to insomnia and changes in circadian rhythmicity. Administration of melatonin in variable doses resulting in supraphysiological or physiological night-time blood levels of melatonin has been shown to improve sleep quality in the elderly. To study the effect of low doses of melatonin, which do not affect daytime blood melatonin concentrations, night-time milk containing 10-40 ng/l melatonin was used as a drink with meals. The effect of about 0.5 l night-time milk daily on sleep quality and circadian activity was studied in elderly institutionalized subjects in two long-term double-blind, placebo-controlled, crossover studies. Night-time milk was given for 8 weeks and normal day-time milk for 8 weeks with a 1-week washout period in between. In the first study, which was performed during spring with sleep quality evaluated subjectively by specially trained nurses, 70 demented patients showed only a seasonal effect on their sleep quality. In the second study performed around the winter solstice, 81 fairly healthy subjects living in rest-homes were divided into three groups, two for the crossover study as in the first investigation with a third group consuming only normal daytime milk as a control group to evaluate the effect of season. Caregivers graded the sleep quality and activity that was monitored separately for the morning before noon and for the evening after noon. In the second study, the effect of season was recognizable in the scores for sleep quality, which increased in all groups after the winter solstice. However, there were no changes in activity in the control group or in the group that consumed night-time milk during the first period of the crossover study, whereas both morning and evening activity increased significantly in the group that consumed night-time milk during the later period. Even ultra-low doses of melatonin may benefit the elderly by increasing their daytime activity.

-----

Altern Med Rev. 2005 Sep;10(3):222-229.
Folic Acid - Monograph.
[No authors listed]

Folic acid, also known generically as folate or folacin, is a member of the B-complex family of vitamins, and works in concert with vitamin B12. Folic acid functions primarily as a methyl-group donor involved in many important body processes, including DNA synthesis. Therapeutically, folic acid is instrumental in reducing homocysteine levels and the occurrence of neural tube defects. It may play a key role in preventing cervical dysplasia and protecting against neoplasia in ulcerative colitis. Folic acid also shows promise as part of a nutritional protocol to treat vitiligo, and may reduce inflammation of the gingiva. Furthermore, certain neurological, cognitive, and psychiatric presentations may be secondary to folate deficiency. Such presentations include peripheral neuropathy, myelopathy, restless legs syndrome, insomnia, dementia, forgetfulness, irritability, endogenous depression, organic psychosis, and schizophrenia-like syndromes.

-----

J Clin Oncol. 2005 Sep 1;23(25):6097-106.
Randomized study on the efficacy of cognitive-behavioral therapy for insomnia secondary to breast cancer, part II: Immunologic effects.
Savard J, Simard S, Ivers H, Morin CM.
Laval University Cancer Research Center, 11 Cote du Palais, Quebec, Quebec, Canada, G1R 2J6. josee.savard@psy.ulaval.ca

PURPOSE: Cross-sectional studies suggest that clinical insomnia is associated with immune downregulation. However, there is a definite need for experimental studies on this question. The goal of this randomized controlled study was to assess the effect of an 8-week cognitive-behavioral therapy (CBT) for chronic insomnia on immune functioning of breast cancer survivors. Previous analyses of this study showed that CBT was associated with improved sleep and quality of life, and reduced psychological distress. PATIENTS AND METHODS: Fifty-seven women with chronic insomnia secondary to breast cancer were randomly assigned to CBT (n = 27) or to a waiting-list control condition (WLC; n = 30). Peripheral-blood samples were taken at baseline and post-treatment (and postwaiting for WLC patients), as well as at 3-, 6-, and 12-month follow-up for immune measures, including enumeration of blood cell counts (ie, WBCs, monocytes, lymphocytes, CD3+, CD4+, CD8+, and CD16+/CD56+) and cytokine production (ie, interleukin-1-beta [IL-1beta] and interferon gamma [IFN-gamma]). RESULTS: Patients treated with CBT had higher secretion of IFN-gamma and lower increase of lymphocytes at post-treatment compared with control patients. Pooled data from both treated groups indicated significantly increased levels of IFN-gamma and IL-1beta from pre- to post-treatment. In addition, significant changes in WBCs, lymphocytes, and IFN-gamma were found at follow-up compared with post-treatment. CONCLUSION: This study provides some support to the hypothesis of a causal relationship between clinical insomnia and immune functioning. Future studies are needed to investigate the clinical impact of such immune alterations.

-----

J Altern Complement Med. 2005 Aug;11(4):631-7.
A Single-Blinded, Randomized Pilot Study Evaluating the Aroma of Lavandula augustifolia as a Treatment for Mild Insomnia.
Lewith GT, Godfrey AD, Prescott P.
University of Southampton, Southampton, United Kingdom., University of Southampton, Southampton, United Kingdom., Complementary Medicine Research Unit, Primary Medical Care, Aldemoor Health Centre, Southampton, United Kingdom.

Background: Insomnia is the most common of all sleep complaints and is under-researched. The current treatments of choice are conventional hypnotics agents, but these have potential for serious adverse reactions. Uncontrolled and anecdotal evidence suggests that lavender oil is an effective treatment for insomnia, but this has not been formally investigated. Objectives: The aims of this study were to evaluate the proposed trial methodology and the efficacy of Lavandula augustifolia (lavender) on insomnia. Interventions: Interventions consisted of Lavandula augustifolia (treatment) and sweet almond oil as placebo/control. The aroma was supplied via an Aromastream device (Tisserand Aromatherapy, Sussex, UK). Design: This was a pilot study with randomized, single-blind, cross-over design (baseline, two treatment periods, and a washout period, each of 1 week duration). Subjects and setting: Volunteers with defined insomnia treated on a domiciliary basis participated in the study. Outcome measures: Outcomes were assessed with the following: Pittsburgh Sleep Quality Index (PSQI) indicating insomnia (score > 5 at entry); Borkovec and Nau (B&N) Questionnaire evaluating treatment credibility; and Holistic Complementary and Alternative Medicine Questionnaire (HCAMQ) assessing attitudes to CAM and health beliefs. Results: Ten (10) volunteers (5 male and 5 female) were entered and completed the 4 week study. Lavender created an improvement of -2.5 points in PSQI (p = 0.07, 95% CI - 4.95 to - 0.4). Each intervention was equally credible and belief in CAM did not predict outcome. Women and younger volunteers with a milder insomnia improved more than others. No period or carry-over effect was observed. Conclusion: The methodology for this pilot study appeared to be appropriate. Outcomes favor lavender, and a larger trial is required to draw definitive conclusions.

-----

Int J Clin Pharmacol Ther. 2005 Aug;43(8):355-9.
A comparison of placebo and no-treatment during a hypnotic clinical trial.
Mccall WV, Perlis ML, Tu X, Groman AE, Krystal A, Walsh JK.
Department of Psychiatry and Behavioral Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1071, USA. vmccall@wfubmc.edu

OBJECTIVE: Sleep parameters commonly improve during placebo treatment in insomnia clinical trials. We examined whether the improvement seen with placebo was related to taking pills or other non-specific factors. METHOD: 95 insomniacs took either a placebo pill (pill+) or no pill (pill-) on nights of their choosing over 12 weeks. RESULTS: Pills were consumed on about half of the nights. Consistent improvement was seen with reduced reported sleep latency, wakefulness after sleep onset, number of awakenings, and total sleep time over the 12 weeks for both the pill+ and pill condition. A difference between pill+ and pill- was detected only for total sleep time, and this difference favored pill+. CONCLUSIONS: This study suggests that improvement seen during placebo treatment is more related to non-specific factors of participating in clinical trial than to pill taking behavior.

-----

Curr Treat Options Neurol. 2005 Sep;7(5):339-52.
Treatment of sleep disorders in elderly patients.
Harrington JJ, Avidan AY.
Department of Neurology, University of Michigan Health Systems, 8D-8702 University Hospital, Box 0117, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA. avidana@umich.edu.

Sleep disorders are common among the elderly and are associated with diminished quality of life, increased risk for development of psychiatric disorders, inappropriate use of sleep aids, and decreased daytime functioning. The most common and important sleep disorders in the elderly include insomnia, obstructive sleep apnea syndrome, restless legs syndrome, rapid eye movement sleep behavior disorder, and the advanced sleep phase syndrome. In this article, we summarize the current treatment strategies for each of these sleep-related disorders. Before contemplating specific treatments, the authors recommend that more conservative and nonpharmacologic therapies be attempted first because the elderly are more likely to have medication side effects or complications related to surgery. Many sleep problems can be treated by simple sleep hygiene modifications that can be implemented and adopted easily. For others, therapies that specifically consider older adults may be required. For each of the sleep disorders we provide an updated discussion of therapies beginning with diet and lifestyle, pharmacologic treatment, interventional procedures, surgery, assistive devices, physical and speech therapy, exercise, and emerging therapies with specific considerations for older adults.

-----

CNS Spectr. 2005 Aug;10(8 Suppl 9):1-13.
The role of modified-release formulations in hypnotic therapy for insomnia.
Erman MK, Young T, Patel SR, Neubauer DN.
Department of Psychiatry, University of California, San Diego, San Diego, CA, USA.

In addition to the psychological and medical health risks associated with lack of adequate sleep, effects of insomnia include impaired daytime functioning and decreased quality of life. Many patients experience delayed sleep onset, frequent awakenings, early waking, or nonrestorative sleep. Longitudinal data on insomnia indicate that the prevalence of persistent/chronic insomnia is high and appears to be characterized by multiple symptoms related to initiating or maintaining sleep. Physiologic studies indicate that short-term sleep restriction can cause physiologic problems that lead to long-term health consequences, such as high blood pressure, impaired glucose tolerance, and systemic inflammation. Epidemiologic studies have shown that sleep deprivation is independently associated with increased risk of cardiovascular disease, diabetes, obesity, and mortality. While the available agents are effective, those with a long half life may have carryover effects while short-acting agents may not provide enough sleep continuity. Pharmacologic therapies available for patients who suffer from insomnia include immediate-release nonbenzodiazepine hypnotics, which have a positive benefit/risk profile compared to the benzodiazepines. Modified-release (MR) formulations of these agents may offer the additional benefit of improving sleep continuity throughout the night without sacrificing the rapid elimination properties that minimize next-day residual effects. MR agents in development include zolpidem MR and indiplon MR.

-----

Prim Care Companion J Clin Psychiatry. 2005;7(3):106-113.
15 Years of Clinical Experience With Bupropion HCl: From Bupropion to Bupropion SR to Bupropion XL.
Fava M, Rush AJ, Thase ME, Clayton A, Stahl SM, Pradko JF, Johnston JA.
Department of Psychiatry, Harvard Medical School and Massachusetts General Hospital, Boston ; the Department of Psychiatry, University of Texas, Southwestern Medical Center, Dallas ; the Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, Pa. ; the Department of Psychiatric Medicine, University of Virginia, Charlottesville ; the Neuroscience Education Institute, University of California, San Diego ; Bay Pointe Depression Clinic, New Baltimore, Mich. ; and Innovaa Research, Chapel Hill, N.C.

Background: Bupropion has been available in the United States since 1989. Initially a thrice-daily immediate-release formulation, a twice-daily sustained-release formulation followed in 1996, and, in August 2003, a once-daily extended-release formulation was introduced. On the 15th anniversary of its introduction, we undertook a review of the background/history, mechanism of action, formulations, and clinical profile of bupropion.Data Sources: Major efficacy trials and other reports were obtained and reviewed from MEDLINE searches, review of abstracts from professional meetings, and the bupropion SR manufacturer's databases. Searches of English-language articles were conducted from June 2003 through August 2004. No time limit was specified in the searches, which were conducted using the search terms bupropion, bupropion SR, and bupropion XL.Data Synthesis: Bupropion inhibits the re-uptake of norepinephrine and dopamine neurotransmission without any significant direct effects on serotonin neurotransmission. Bupropion is an effective antidepressant with efficacy comparable to selective serotonin reuptake inhibitors and other antidepressants. It is well tolerated in short-and longer-term treatment. Headache, dry mouth, nausea, insomnia, constipation, and dizziness are the most common adverse events. Seizure and allergic reactions are medically important adverse events associated with bupropion and are reported rarely. Among all the newer antidepressants in the United States, bupropion appears to have among the lowest incidence of sexual dysfunction, weight gain, and somnolence. Although not U.S. Food and Drug Administration approved for these indications, bupropion has also been used as an adjunctive treatment to reverse antidepressant-induced sexual dysfunction and to augment anti-depressant efficacy in partial responders and non-responders to other agents.Conclusion: Bupropion has played and will continue to play an important role as a treatment for major depressive disorder in adults, as well as for other related disorders.

-----

Medicine (Baltimore). 2005 Jul;84(4):197-207.
An internet-based randomized, placebo-controlled trial of kava and valerian for anxiety and insomnia.
Jacobs BP, Bent S, Tice JA, Blackwell T, Cummings SR.
Department of Medicine, Osher Center for Integrative Medicine, University of California-San Francisco, California, USA. jacobsb@ocim.ucsf.edu

The herbal extracts kava and valerian are the leading dietary supplements used in the self-management of anxiety and insomnia, respectively. There is limited evidence to support their effectiveness for these common symptoms. The Internet has been used to a limited extent for research, but it is not known whether randomized controlled trials can be conducted entirely using Internet technology. We performed a randomized, double-blind, placebo-controlled trial using a novel Internet-based design to determine if kava is effective for reducing anxiety and if valerian is effective for improving sleep quality. E-mail recruitment letters and banner advertisements on websites were used to recruit a large pool of interested participants (1551) from 45 states over an 8-week period. Participants were first asked to read study information, complete an online informed consent process, and undergo electronic identity verification. In order to be eligible for the study, participants were required to have 1) anxiety as documented by scores of at least 0.5 standard deviations above the mean on the State-Trait Anxiety Inventory State subtest (STAI-State) on 2 separate occasions, and 2) insomnia, defined as a "problem getting to sleep or staying asleep over the past 2 weeks." We randomly assigned 391 eligible participants to 1 of the following 3 groups, and mailed 28 days' supply: kava with valerian placebo (n = 121), valerian with kava placebo (n = 135), or double placebo (n = 135). The primary outcome measures were changes from baseline in anxiety (STAI-State questionnaire) and insomnia (Insomnia Severity Index [ISI]) compared with placebo. Participants receiving placebo had a 14.4 point decrease in anxiety symptoms on the STAI-State score and an 8.3 point decrease in insomnia symptoms on the ISI. Those receiving kava had similar reductions in STAI-State score (2.7 point greater reduction in placebo compared with kava; 95% confidence interval [CI], -0.8 to +6.2). Those receiving valerian and placebo had similar improvements in sleep (0.4 point greater reduction in the placebo than the valerian group; 95% CI, -1.3 to +2.1). Results were similar when limited to the 83% of participants who adhered to study compounds for all 4 weeks. Neither kava nor valerian relieved anxiety or insomnia more than placebo. This trial demonstrates the feasibility of conducting randomized, blinded trials entirely via the Internet.

-----

J Psychopharmacol. 2005 Jul;19(4):414-21.
Medicinal plants for insomnia: a review of their pharmacology, efficacy and tolerability.
Wheatley D.
Consultant Psychiatrist, Harley St, London, UK. Wheatley@ukgateway.net

A number of medicinal plants are traditionally endowed with anxiolytic or sedative properties and, in the context of this revue, both indications are considered since the former may induce a mood conducive to the latter. For any sleep-inducing drug to be effective, a tranquil ambience needs to be established a priori. Thus, physical ailments (i.e. pain), factors interfering with sleep (i.e. noise), psychological conditions causing stress, psychiatric illnesses (i.e. depression) and other drugs that interfere with sleep (i.e. caffeine) need to be controlled, if possible. Kava-kava is a well-established hypnotic drug, with a rapid onset of effect, adequate duration of action and minimal morning after-effects. However, reports of serious hepatotoxicity with this preparation have led to it being banned in most countries worldwide. On the other hand, side-effects with valerian would appear to be bland indeed. However, it's slow onset of effect (2-3 weeks) renders it unsuitable for short-term use (i.e. 'jet-lag'), but it does have profound beneficial effects on sleep architecture (augments deep sleep) that may make it particularly suitable for long-term use and for the elderly. In a personal trial (not double-blind) in stress-induced insomnia, both kava and valerian improved sleep and the ill-effects of stress, and the combination of the two was even more effective for the control of insomnia. Aromatherapy (lavender, chamomile, Ylang-Ylang) would appear to improve sleep, but how practical a form of treatment this may be remains to be determined. The only other plant drug that may have some effect on sleep is melissa, but reports are too scanty to form any opinion about this. Based on animal experiments, passion flower (passiflora) may have a sedative action, but the sedative action of hops has not been investigated in any detail. In conclusion, there is a need for longer-term controlled studies with some of these compounds (particularly valerian). Aromatherapy constitutes a tantalising possibility. In the interpretation of this review, it should be borne in mind that the evidence on which it is based is often incomplete or missing, but that is all that is available. Consequently some conjecture on the part of the author is inevitable and should be appreciated as such.

-----

Clin Psychol Rev. 2005 Jul;25(5):629-44.
Adolescents, substance abuse, and the treatment of insomnia and daytime sleepiness.
Bootzin RR, Stevens SJ.
Department of Psychology, Box 210068, University of Arizona, Tucson, AZ 85721-0068, United States. Bootzin@u.arizona.edu

Adolescence is a time of change that can be both exciting and stressful. In this review, we focus on the central role that disturbed sleep and daytime sleepiness occupies in interactions involving substance abuse and negative health, social, and emotional outcomes. As a means of improving sleep and lowering risk for recidivism of substance abuse, we developed and implemented a six-session group treatment to treat sleep disturbances in adolescents who have received treatment for substance abuse. The components of the treatment are stimulus control instructions, use of bright light to regularize sleep, sleep hygiene education, cognitive therapy, and Mindfulness-Based Stress Reduction. Preliminary evidence indicates that participants who completed four or more sessions in the treatment program showed improved sleep and that improving sleep may lead to a reduction in substance abuse problems at the 12-month follow-up.

-----

J Am Geriatr Soc. 2005 Jun;53(6):955-62.
Insomnia and hypnotic use, recorded in the minimum data set, as predictors of falls and hip fractures in Michigan nursing homes.
Avidan AY, Fries BE, James ML, Szafara KL, Wright GT, Chervin RD.
Sleep Disorders Center, Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA. avidana@umich.edu

OBJECTIVES: To examine the relationship between insomnia, hypnotic use, falls, and hip fractures in older people. DESIGN: Secondary analysis of a large, longitudinal, assessment database. SETTING: Four hundred thirty-seven nursing homes in Michigan. PARTICIPANTS: Residents aged 65 and older in 2001 with a baseline Minimum Data Set assessment and a follow-up 150 to 210 days later. MEASUREMENTS: Logistic regression modeled any follow-up report of fall or hip fracture. Predictors were baseline reports of insomnia (previous month) and use of hypnotics (previous week). Potential confounds taken into account included standard measures of functional status, cognitive status, intensity of resource utilization, proximity to death, illness burden, number of medications, emergency room visits, nursing home new admission, age, and sex. RESULTS: In 34,163 nursing home residents (76% women, mean age+/-standard deviation 84+/-8), hypnotic use did not predict falls (adjusted odds ratio (AOR)=1.13, 95% confidence interval (CI)=0.98, 1.30). In contrast, insomnia did predict future falls (AOR=1.52, 95% CI=1.38, 1.66). Untreated insomnia (AOR=1.55, 95% CI=1.41, 1.71) and hypnotic-treated (unresponsive) insomnia (AOR=1.32, 95% CI=1.02, 1.70) predicted more falls than did the absence of insomnia. After adjustment for confounding variables, insomnia and hypnotic use were not associated with subsequent hip fracture. CONCLUSION: In elderly nursing home residents, insomnia, but not hypnotic use, is associated with a greater risk of subsequent falls. Future studies will need to confirm these findings and determine whether appropriate hypnotic use can protect against future falls.

-----

J Occup Rehabil. 2005 Jun;15(2):177-90.
Cognitive-behavioral group therapy as an early intervention for insomnia: a randomized controlled trial.
Jansson M, Linton SJ.
Department of Occupational and Environmental Medicine, Orebro Medical Center, S-701 85 Orebro, Sweden.

A randomized controlled design was used with a 1-yr follow-up. The purpose was to compare the effects of two early interventions, a cognitive-behavioral group intervention and a self-help information package, in patients with insomnia. In sum, 165 individuals seeking care for insomnia of 3-12 months duration were randomized to either a group receiving a CBT intervention or a group receiving a self-help information package. At the 1-yr follow-up, 136 participants had completed the entire study. At the 1-yr follow-up, the CBT group intervention was, compared with the control group, effective in producing reductions in dysfunctional beliefs and attitudes about sleep, negative daytime symptoms, as well as vital improvements in sleep (i.e. sleep onset latency, time awake after sleep onset, total sleep time, sleep quality, and sleep efficiency). In comparison with the control group, significantly more participants in the CBT group met criteria at the 1-yr follow-up for clinically meaningful improvements in sleep onset latency, time awake after sleep onset, and sleep efficiency. A CBT group intervention may well be a viable early intervention for patients with insomnia in a wide range of health services.

-----

J Clin Psychiatry. 2005 Apr;66(4):469-76.
A review of the evidence for the efficacy and safety of trazodone in insomnia.
Mendelson WB.
From the University of Chicago, Chicago, Ill.

OBJECTIVE: Trazodone, a triazolopyridine antidepressant, is currently the second most commonly prescribed agent for the treatment of insomnia due to its sedating qualities. Given trazodone's widespread use, a careful review of the literature was conducted to assess its efficacy and side effects when given for treatment of insomnia. DATA SOURCES: In April 2003, a MEDLINE search was conducted using the search terms trazodone and insomnia and trazodone and sleep and restricted to 1980-2003, human subjects, and English language. As trazodone has been implicated in cardiac disorders, a further search was conducted using the term cardiac and trazodone. STUDY SELECTION: All clinical trials that measured any endpoint for insomnia efficacy were included in the assessment. A total of 18 studies were identified from the literature search. In addition, commonly used texts were consulted for information regarding adverse effects related to trazodone. DATA EXTRACTION: Because so few studies were identified by the literature search, all were evaluated and described. DATA SYNTHESIS: Evidence for the efficacy of trazodone in treating insomnia is very limited; most studies are small, conducted in populations of depressed patients, raise issues of design, and often lack objective efficacy measures. Side effects associated with trazodone are not inconsequential, with a high incidence of discontinuation due to side effects, such as sedation, dizziness, and psychomotor impairment, which raise particular concern regarding its use in the elderly. There is also some evidence of tolerance related to use of trazodone. CONCLUSION: Given the relative absence of efficacy data in patients with insomnia and the adverse events associated with trazodone's use in general, it is uncertain whether the risk/benefit ratio warrants trazodone's use in nondepressed patients with insomnia.

-----

J Manipulative Physiol Ther. 2005 Mar-Apr;28(3):179-86.
Insomnia: does chiropractic help?
Jamison JR.
Division of Health Sciences, Murdoch University, School of Chiropractic, Perth, Western Australia 6849, Australia. j.jamison@murdoch.edu.au

OBJECTIVE: To evaluate the effect of chiropractic care on insomnia. DESIGN: Tripartite pilot study. METHODS: The expectations of the chiropractic community were canvassed, a retrospective study to recall changes in sleep patterns was undertaken, and a prospective pilot study to monitor sleep patterns after chiropractic care was carried out. Convenience sampling was used. RESULTS: The 221 patients and 15 chiropractors who completed the expectation study tended to believe that patients with sleeping difficulties benefited from chiropractic care. The chiropractors were more guarded in their expectations than participating patients. One third of the 154 patients who completed the semistructured interview reported their sleep pattern was changed immediately after their chiropractic adjustment. All but 1 of these 52 patients reported improvement. Twenty patients with insomnia participated in the prospective study. Although compared with the report in their screening questionnaire, improvement was noted in certain sleep parameters in the 6 days after their adjustment, no temporal trends emerged in the days and/or weeks after the chiropractic consultation. Most patients reported experiencing less or no discomfort during the duration of the study. CONCLUSION: Although a number of patients do perceive chiropractic care offers temporary respite from their insomnia problem, when changes were more objectively monitored, improvements were erratic and no consistent temporal trends were detectable. Convincing evidence has yet to be produced before routine chiropractic care can be considered adequate intervention for patients with sleeping difficulties. More definitive answers may result from future research being undertaken in sleep laboratories.

-----

Drug Saf. 2005;28(4):301-18.
Benefit-risk assessment of zaleplon in the treatment of insomnia.
Barbera J, Shaprio C.
Sleep Research Unit, University Health Network, TWH, Toronto, Ontario, Canada. joseph.barbera@utoronto.ca

Insomnia is a heterogeneous, highly prevalent condition that is associated with a high level of psychiatric, physical, social and economic morbidity. The treatment of insomnia involves pharmacological and non-pharmacological interventions. The mainstay of pharmacological treatment of insomnia has been the benzodiazepines, the introduction of which represented a significant improvement over the barbiturates and chloral hydrate. Although benzodiazepines have been shown to be efficacious in treating insomnia, they have also been associated with a number of adverse effects including tolerance, dependence, withdrawal and abuse potential, impairment in daytime cognitive and psychomotor performance (including an increased risk of accidents and falls), adverse effects on respiration and the disruption of normal sleep architecture with reduction in both slow wave sleep and rapid eye movement. In the last decade, the treatment of insomnia has been supplemented by the introduction of a number of non-benzodiazepine hypnotics including zolpidem, zopiclone and, most recently, zaleplon. Zaleplon possesses a unique pharmacological profile, with an ultra-short half-life of about 1 hour, and selective binding to the BZ1(omega1) receptor subtypes of the GABA(A) receptor. This unique pharmacological profile predicts a number of pharmacodynamic properties that account for a unique benefit-risk profile. Consistent with these predictions, zaleplon has been shown in a number of studies to be efficacious in promoting sleep initiation, but less so in promoting sleep maintenance. The adverse effects associated with zaleplon have been shown to be more rapidly resolved and/or lesser in magnitude than those associated with benzodiazepines (including triazolam) and the longer acting non-benzodiazepine hypnotics (zolpidem and zopiclone). This improved risk profile includes: the effects of zaleplon on psychomotor and cognitive performance; tolerance, withdrawal and rebound; respiratory depression; sleep architecture; and other treatment-emergent adverse effects. The unique benefit-risk profile of this agent may be particularly suitable for certain patients with insomnia and provides yet another option in the management of this impairing condition.

-----

J Clin Psychiatry. 2005 Mar;66(3):384-90.
The efficacy and safety of the melatonin agonist beta-methyl-6-chloromelatonin in primary insomnia: a randomized, placebo-controlled, crossover clinical trial.
Zemlan FP, Mulchahey JJ, Scharf MB, Mayleben DW, Rosenberg R, Lankford A.
Phase 2 Discovery, Inc., Cincinnati, OH 45219, USA. Fzemlan@phase2D.com

BACKGROUND: While melatonin agonists are known to regulate circadian sleep rhythms, it is not clear whether melatonin agonists have a direct soporific effect. It has been suggested that melatonin's soporific effect is secondary to its ability to induce hypothermia. beta-Methyl-6-chloromelatonin is a high-affinity melatonin receptor agonist that is not associated with hypothermia. The purpose of the present study was to determine if the melatonin agonist beta-methyl-6-chloromelatonin has a direct soporific effect in subjects with primary insomnia. METHOD: A double-blind, placebo-controlled, crossover safety and efficacy study of 20 mg, 50 mg, and 100 mg of beta-methyl-6-chloromelatonin and placebo was conducted in subjects with DSM-IV-TR primary insomnia. Of 84 subjects screened, 40 progressed to randomly receive each of 3 beta-methyl-6-chloromelatonin doses or placebo on each of 2 consecutive nights with 5-day washout periods between treatments. The effect of treatment on both polysomnographic and subjectively measured sleep parameters, next-morning psychomotor performance, and safety measures was determined. The primary outcome measure was latency to persistent sleep measured by polysomnography. RESULTS: A significant effect of beta-methyl-6-chloromelatonin on the primary efficacy variable, latency to persistent sleep, was observed (p = .0003). The 20-mg dose resulted in a significant 31% improvement in sleep latency compared with placebo, while significant 32% and 41% improvements were observed at the 50-mg and 100-mg doses, respectively (20 mg, p = .0082; 50 mg, p = .0062; 100 mg, p < .0001). Similarly, a significant effect of beta-methyl-6-chloromelatonin on subjective measures of time to fall asleep occurred (p = .0050), with significant improvement observed at both the 50-mg and 100-mg doses (p = .0350 and .0198, respectively) and a trend toward improvement observed at the 20-mg dose (p = .0582). Adverse events were mild to moderate in severity and did not differ in frequency between beta-methyl-6-chloromelatonin and placebo treatments. CONCLUSION: beta-Methyl-6-chloromelatonin significantly decreases both objective and subjective measures of sleep latency in subjects with primary insomnia. Thus, these data suggest that mel-atonin agonists may exert a direct soporific effect, as previous research indicates that beta-methyl-6-chloromelatonin is not associated with changes in body temperature, heart rate, or blood pressure.

-----

Psychiatr Serv. 2005 Mar;56(3):332-43.
Diagnosis and treatment of chronic insomnia: a review.
Benca RM.
Department of Psychiatry, University of Wisconsin, Madison, Wisconsin 53719, USA. rbenca@med.wisc.edu

OBJECTIVE: Insomnia has high prevalence rates and is associated with significant personal and socioeconomic burden, yet it remains largely underrecognized and inadequately treated. METHODS: A PubMed search for English-language articles covering randomized controlled trials published between 1970 and 2004 was conducted. Search terms used were "insomnia," "behavioral therapy," and the generic names of agents commonly used to treat insomnia (the Food and Drug Administration-approved benzodiazepines and nonbenzodiazepines, trazodone, and over-the-counter agents). RESULTS: Evidence from epidemiologic studies, physician surveys, and clinical studies suggests that numerous patient and physician factors contribute to the fact that the needs of patients with insomnia remain unmet, including low reporting of insomnia by patients, limited physician training, and office-based time constraints, as well as misconceptions about the seriousness of insomnia, the advantages of treatment, and the risks associated with hypnotic use. Nonpharmacologic therapies produce long-lasting and reliable changes among people with chronic insomnia and have minimal side effects. Pharmacologic therapies have proven effective with improving wake time after sleep onset and sleep maintenance and reducing the number of nighttime awakenings. However, pharmacologic therapy has a greater chance of producing side effects. No conclusive evidence exists to favor either pharmacologic therapy or behavioral therapy. CONCLUSIONS: Insomnia is particularly challenging for clinicians because of the lack of guidelines and the small number of studies conducted in patient populations with behavioral and pharmacologic therapies. Current treatment options do not address the needs of difficult-to-treat patients with chronic insomnia, such as the elderly, and those with comorbid medical and psychiatric conditions. More research is necessary to determine the long-term effects of insomnia treatments.

-----

Sleep Med. 2005 Mar;6(2):107-13. Epub 2005 Jan 26.
Long-term use of sedative hypnotics in older patients with insomnia.
Ancoli-Israel S, Richardson GS, Mangano RM, Jenkins L, Hall P, Jones WS.
Department of Psychiatry 116A, University of California San Diego and Veterans Affairs, San Diego Healthcare System, 3350 La Jolla Village Dr., San Diego, CA 92161, USA. sancoliisrael@ucsd.edu

BACKGROUND AND PURPOSE: Insomnia is a common problem that increases with age and can last months to years. While substantial data establish the efficacy and safety of short-acting hypnotic therapy for the management of short-term insomnia using benzodiazepines receptor agonists (BzRAs), there are few studies on the continued efficacy and safety of these drugs when used for sustained periods. This paper reports the results of a 1-year open-label extension phases of two randomized, double-blind trials of zaleplon. PATIENTS AND METHODS: In the open-label phase, older patients self-administered zaleplon nightly from 6 to 12 months and were then followed through a 7-day single-blind placebo-controlled run-out period. RESULTS: The safety profile in this population of older adults was similar to that observed in a short-term trial of an equivalent population. The data also suggested that long-term therapy produced and maintained statistically significant improvement in time to persistent sleep onset, duration of sleep and number of nocturnal awakenings (P<0.001 for each variable) for treatment durations of up to 12 months. Discontinuation was not associated with rebound insomnia. CONCLUSION: The open-label trial of long-term hypnotic therapy with zaleplon 5 and 10 mg suggests that they are safe and effective for the treatment of insomnia in older patients. Placebo-controlled, double-blind trials are needed in zaleplon and other BzRAs to confirm these results.

-----

CNS Drugs. 2005;19(1):65-89.
Zolpidem : a review of its use in the management of insomnia.
Swainston Harrison T, Keating GM.
Adis International Limited, Auckland, New Zealand.

Zolpidem (Ambien((R)), Stilnox((R)), Myslee((R))), an imidazopyridine, is a nonbenzodiazepine hypnotic indicated for the short-term treatment of insomnia. Zolpidem improves sleep in patients with insomnia. Its overall tolerability is favourable when administered according to the manufacturer's prescribing information, with a low propensity to cause clinical residual effects, withdrawal, dependence or tolerance. In addition, most evidence suggests that the drug is associated with minimal rebound insomnia. In the only clinical trials that investigated the use of a hypnosedative drug in an 'as-needed' regimen, zolpidem produced a global improvement in sleep. Thus, zolpidem continues to be a useful therapeutic option in the pharmacological treatment of patients with insomnia.

-----

Neuropsychopharmacology. 2004 Dec 15; [Epub ahead of print]
Effect of Repeated Gaboxadol Administration on Night Sleep and Next-Day Performance in Healthy Elderly Subjects.
Mathias S, Zihl J, Steiger A, Lancel M.
1Section of Sleep Pharmacology, Max-Planck-Institute of Psychiatry, Munich, Germany.

Aging is associated with dramatic reductions in sleep continuity and sleep intensity. Since gaboxadol, a selective GABA(A) receptor agonist, has been demonstrated to improve sleep consolidation and promote deep sleep, it may be an effective hypnotic, particularly for elderly patients with insomnia. In the present study, we investigated the effects of subchronic gaboxadol administration on nocturnal sleep and its residual effects during the next days in elderly subjects. This was a randomized, double-blind, placebo-controlled, balanced crossover study in 10 healthy elderly subjects without sleep complaints. The subjects were administered either placebo or 15 mg gaboxadol hydrochloride at bedtime on three consecutive nights. Sleep was recorded during each night from 2300 to 0700 h and tests assessing attention (target detection, stroop test) and memory function (visual form recognition, immediate word recall, digit span) were applied at 0900, 1400, and 1700 h during the following days. Compared with placebo, gaboxadol significantly shortened subjective sleep onset latency and increased self-rated sleep intensity and quality. Polysomnographic recordings showed that it significantly decreased the number of awakenings, the amount of intermittent wakefulness, and stage 1, and increased slow wave sleep and stage 2. These effects were stable over the three nights. None of the subjects reported side effects. Next-day cognitive performance was not affected by gaboxadol. Gaboxadol persistently improved subjective and objective sleep quality and was devoid of residual effects. Thus, at the employed dose, it seems an effective hypnotic in elderly subjects.Neuropsychopharmacology advance online publication, 15 December 2004; doi:10.1038/sj.npp.1300641.

-----

Prog Neuropsychopharmacol Biol Psychiatry. 2004 Nov;28(7):1071-8.
Nefazodone in primary insomnia: an open pilot study.
Wiegand MH, Galanakis P, Schreiner R.
Department of Psychiatry and Psychotherapy, Technical University of Munich, Ismaninger Str. 22, D-81675 Munich, Germany. mhwiegand@lrz.tum.de

The present study is the first to investigate the effect of the antidepressant nefazodone on sleep in patients with primary (psychophysiological) insomnia. Following baseline assessment of sleep (polysomnography and subjective sleep parameters), 32 patients received initially 100 mg nefazodone in a single dose at bedtime; according to efficacy and tolerability, the dose could be increased up to 400 mg. Polysomnography and assessment of subjective sleep parameters were repeated after 4 weeks' administration. 12 patients dropped out, 11 of them due to lack of efficiency or intolerable side effects. In 20 patients who completed, the authors observed a lengthened sleep onset latency, decreases in stage 1 and slow wave sleep, and increases in stages 2 and REM under nefazodone. Subjective measures of sleep mirrored a clearer improvement: there was a significant reduction of the PSQI total score and all subscores except sleep latency. We suppose that the dose range chosen was too high for this patient population, thus accounting for the high proportion of dropouts and the partly unfavorable effects on objective sleep parameters. For a definite evaluation of the possible role of nefazodone in the treatment of primary (psychophysiological) insomnia, double-blind, placebo-controlled, randomized studies with lower doses are needed.

-----

Lancet. 2004 Nov 27;364(9449):1959-73.
Insomnia.
Sateia MJ, Nowell PD.
Dartmouth Medical School, Dartmouth-Hitchcock Sleep Disorders Center, Lebanon, NH 03756, USA. michael.j.sateia@dartmouth.edu

Effective management of insomnia begins with recognition and adequate assessment. Family doctors and other health care providers such as practice nurses and psychologists should routinely enquire about sleep habits as a component of overall health assessment. Identification and treatment of primary psychiatric disorders, medical conditions, circadian disorders, or specific physiological sleep disorders--eg, sleep apnoea and periodic limb movement disorder--are essential steps in management of insomnia. Conditioned aspects of insomnia can be primary (psychophysiological insomnia) or may complicate sleep disturbance owing to other causes. Approved hypnotic drugs have clearly been shown to improve subjective and objective sleep measures in various short-term situations. Despite widespread use of standard hypnotics and sedating antidepressants for chronic insomnia, their role for this indication still remains to be further defined by research evidence. Non-pharmacological treatments, particularly stimulus control and sleep restriction, are effective for conditioned aspects of insomnia and are associated with durable long-term improvement in sleep.

-----

Behav Sleep Med. 2004;2(2):94-112.
Sequential treatment for chronic insomnia: a pilot study.
Vallieres A, Morin CM, Guay B, Bastien CH, LeBlanc M.
Ecole de Psychologie, Universite Laval, Quebec, Canada.

This article explores the efficacy of sequential treatment involving medication and cognitive behavioral treatment (CBT) for insomnia. In a multiple baseline across-subjects design, 6 participants with primary chronic insomnia received 1 of the following treatment sequences: (a) concurrent combination of medication and CBT for the 10-week treatment duration (Combined); (b) medication for the first 5 weeks, with introduction of CBT at week 4 and medication withdrawal after the 5th week resulting in treatment overlap during weeks 4 and 5 (Overlapping: Medication --> Combined --> CBT); and (c) medication alone for the first 5 weeks followed by CBT alone for an additional 5 weeks (Medication --> CBT). Each sequence led to significant sleep improvements, but these improvements occurred at different times during the intervention. Participants in the Combined and in the Overlapping sequences improved their sleep during the 1st phase of treatment, whereas those in the Medication --> CBT sequence improved mostly during the 2nd phase of treatment. These preliminary results suggest that a sequential treatment is effective for chronic insomnia. In addition, the results suggest that sleep improvements are more likely to emerge when CBT is introduced, with an Overlapping sequence showing a slight advantage over the other sequences. Additional clinical trials should be conducted with larger samples to replicate these preliminary findings.

-----

Clin Ther. 2004 Oct;26(10):1578-86.
Effect of zolpidem on sleep in women with perimenopausal and postmenopausal insomnia: a 4-week, randomized, multicenter, double-blind, placebo-controlled study.
Dorsey CM, Lee KA, Scharf MB.
Harvard Medical School, Boston, Massachusetts, USA. cynthia_dorsey@hms.harvard.edu

BACKGROUND: Although most adults in the United States obtain less sleep than they need, women report more sleep deprivation throughout their lifetime than do men. The prevalence of self-reported sleep difficulty increases as women make the transition from the premenopausal to the postmenopausal period. OBJECTIVE: The purpose of this study was to assess the clinical efficacy and safety of zolpidem as a treatment for insomnia in perimenopausal and postmenopausal women. METHODS: Women who were perimenopausal or postmenopausal for >or=6 months, who had developed insomnia in conjunction with menopausal symptoms, and who had difficulty maintaining sleep or had nonrestorative sleep for >or=6 months were eligible for this 4-week, multicenter study. Sleep maintenance difficulty had to occur an average of >or=3 nights per week and had to be accompanied by >or=2 nocturnal hot flashes, hot flushes, or night sweats. Patients were randomized in a double-blind fashion to 1 of 2 treatment groups--zolpidem 10 mg or placebo. Capsules were provided in weekly blister cards, and patients were instructed to take 1 capsule each night at bedtime. Patients recorded estimates of their sleep quality and quantity and daytime functioning on daily morning and evening questionnaires, and made weekly global assessments of sleep. RESULTS: The study included 141 women (mean age +/- SD, 50.8 +/- 4.5 years; age range, 39-60 years). Increases in reported total sleep time were significantly greater in the zolpidem group than in the placebo group (P < 0.01) for each treatment week. Wake time after sleep onset and number of awakenings decreased significantly in the zolpidem group compared with the placebo group (P < 0.05). Each week, approximately twice as many patients in the zolpidem group as in the placebo group reported improved sleep (P < 0.001 for each week). The improvement in sleep-related difficulty with daytime functioning was significantly greater in the zolpidem group than in the placebo group (P < 0.05). The effects of zolpidem did not diminish with the duration of treatment. CONCLUSIONS: Zolpidem 10 mg/d was effective and well tolerated in the treatment of menopause-related insomnia in perimenopausal and postmenopausal women.

-----

J Clin Psychiatry. 2004;65 Suppl 16:41-5.
Pharmacologic management of insomnia.
Walsh JK.
Sleep Medicine and Research Center, St. John's Mercy and St. Luke's Hospitals, Department of Psychiatry, Saint Louis University, St. Louis, MO, USA. walsjk@stlo.mercy.net

Pharmacotherapy is indicated for many types of insomnia, most notably transient insomnia associated with stress, acute illness, or jet lag. Many patients with chronic insomnia, including primary insomnia and insomnia secondary to a variety of medical and psychiatric disorders, also benefit from pharmacotherapy. Relatively few individuals receive prescription medication to help them sleep, and the majority use medication for a few nights to several weeks, as opposed to continuous use for months or years. The hypnotics available on the U.S. market today are benzodiazepine receptor agonists (BZRAs). The BZRAs are efficacious in reducing sleep latency, increasing total sleep time, reducing awakenings, and improving sleep quality without the development of tolerance in studies as long as 6 months. Side effects of the BZRAs are infrequent, dose-related, and related to the sedative properties of the drug. Sedating antidepressants are also frequently prescribed to promote sleep despite inadequate data to support their efficacy for this indication and a greater potential for clinically troublesome side effects.

-----

J Clin Psychiatry. 2004;65 Suppl 16:33-40.
Cognitive-behavioral approaches to the treatment of insomnia.
Morin CM.
Sleep Disorders Center, Laval University, Quebec, Canada. cmorin@psy.ulaval.ca

Insomnia is a pervasive condition with various causes, manifestations, and health consequences. Regardless of the initial cause or event that precipitates insomnia, it is perpetuated into a chronic condition through learned behaviors and cognitions that foster sleeplessness. This article reviews the rationale and objectives of cognitive-behavioral therapy (CBT), a safe and effective treatment for insomnia that may be used to augment hypnotic drugs or as a monotherapy. Cognitive-behavioral management of insomnia includes 3 components--behavioral, cognitive, and educational modules--and is usually presented in a group or individual therapy setting. Each treatment procedure is detailed herein, and recommendations for implementation are given. The evidence supporting this behavioral approach shows that CBT is effective for 70% to 80% of patients and that it can significantly reduce several measures of insomnia, including sleep-onset latency and wake-after-sleep onset. Aside from the clinically measurable changes, this therapy system enables many patients to regain a feeling of control over their sleep, thereby reducing the emotional distress that sleep disturbances cause. Some clinical and practical issues that often arise when implementing this therapeutic approach for insomnia are also discussed.

-----

Sleep Med. 2004 Nov;5(6):523-32.
Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists.
Turek FW, Gillette MU.
Department of Neurobiology and Physiology, Center for Sleep and Circadian Biology, Northwestern University, 2205 Tech Drive, Hogan Hall 2-160, Evanston, IL 60208, USA.

Circadian rhythm sleep disorders (CRSDs), whether chronic or transient, affect a broad range of individuals, including many elderly, those with severe visual impairments, shift workers, and jet travelers moving rapidly across many time zones. In addition, various forms of insomnia affect another large sector of the population. A feature common among CRSDs and some forms of insomnia is sensitivity to the hormone melatonin, which is secreted by the pineal gland. Accumulating evidence suggests that melatonin may regulate the circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Although the light-dark cycle is the primary signal that entrains the circadian clock to environmental cycles, exogenous melatonin has been shown to entrain the clock in individuals with no light perception and free-running circadian rhythms. Furthermore, studies have reported beneficial effects of melatonin for treatment of certain insomnias. Together, these studies suggest that melatonin may be useful for treating some insomnias and CRSDs. In these contexts, use of melatonin as a supplement has been popular in the United States. Unfortunately, the therapeutic potential of melatonin has been difficult to realize in clinical trials, possibly owing to non-specific actions of the agent and its unfavorable pharmacokinetic properties when administered orally. In an attempt to take advantage of the therapeutic opportunities available through the brain's melatonin system, researchers have developed several melatonin agonists with improved properties in comparison to melatonin. Some of these agents are now in clinical trials for treatment of insomnia or CRSDs.

-----

Arch Intern Med. 2004 Sep 27;164(17):1888-96.
Cognitive behavior therapy and pharmacotherapy for insomnia: a randomized controlled trial and direct comparison.
Jacobs GD, Pace-Schott EF, Stickgold R, Otto MW.
Sleep Disorders Center, Beth Israel Deaconess Medical Center, Laboratory of Neurophysiology, Harvard Medical School, Boston, MA 02215, USA. gjacobs@caregroup.harvard.edu

BACKGROUND: Chronic sleep-onset insomnia is a prevalent health complaint in adults. Although behavioral and pharmacological therapies have been shown to be effective for insomnia, no placebo-controlled trials have evaluated their separate and combined effects for sleep-onset insomnia. The objective of this study was to evaluate the clinical efficacy of behavioral and pharmacological therapy, singly and in combination, for chronic sleep-onset insomnia. METHODS: This was a randomized, placebo-controlled clinical trial that involved 63 young and middle-aged adults with chronic sleep-onset insomnia. Interventions included cognitive behavior therapy (CBT), pharmacotherapy, or combination therapy compared with placebo. The main outcome measures were sleep-onset latency as measured by sleep diaries; secondary measures included sleep diary measures of sleep efficiency and total sleep time, objective measures of sleep variables (Nightcap sleep monitor recorder), and measures of daytime functioning. RESULTS: In most measures, CBT was the most sleep effective intervention; it produced the greatest changes in sleep-onset latency and sleep efficiency, yielded the largest number of normal sleepers after treatment, and maintained therapeutic gains at long-term follow-up. The combined treatment provided no advantage over CBT alone, whereas pharmacotherapy produced only moderate improvements during drug administration and returned measures toward baseline after drug use discontinuation. CONCLUSIONS: These findings suggest that young and middle-age patients with sleep-onset insomnia can derive significantly greater benefit from CBT than pharmacotherapy and that CBT should be considered a first-line intervention for chronic insomnia. Increased recognition of the efficacy of CBT and more widespread recommendations for its use could improve the quality of life of a large numbers of patients with insomnia.

-----

Sleep Breath. 2004 Sep;8(3):133-40.
Nasal dilator strip therapy for chronic sleep maintenance insomnia: a case series.
Krakow B, Melendrez D, Sisley B, Warner TD, Krakow J.
Sleep and Human Health Institute, Albuquerque, New Mexico 87109, USA. bkrakow@sleeptreatment.com

Sleep-disordered breathing (SDB) is a salient factor in chronic sleep maintenance insomnia. However, many insomnia patients with comorbid SDB may not be interested initially in receiving treatment with continuous positive airway pressure or oral appliance therapy. As an interim pathway, we used Breathe Right nasal dilator strip (NDS) therapy to introduce these patients to the relationship between insomnia and SDB. We hypothesized that NDS-associated improvements might motivate patients to pursue comprehensive SDB therapies. In this open label trial, three men with chronic sleep maintenance insomnia were treated with an educational session about SDB coupled with nightly NDS therapy. At 4-week follow-up, global insomnia severity, difficulty staying asleep, difficulty falling back asleep when awakened, total number of awakenings, and wake time after sleep onset systematically improved. Following NDS therapy, all three insomnia patients elected to pursue comprehensive SDB treatment at local sleep centers.

-----

Prim Care Companion J Clin Psychiatry. 2004;6(1):9-20.
Sleep in the Elderly: Burden, Diagnosis, and Treatment.
McCall WV.
Department of Psychiatry and Behavioral Medicine, Wake Forest University, Winston-Salem, N.C.

Insomnia is commonly seen in elderly populations and is associated with numerous individual and socioeconomic consequences. Elderly patients are more likely to suffer from chronic insomnia characterized by difficulty maintaining sleep than difficulty initiating sleep. Management of insomnia in these patients requires very careful evaluation and exclusion of an underlying medical or psychiatric condition. Nonpharmacologic interventions in elderly patients, especially use of behavioral therapy, have demonstrated some success. Commonly prescribed medications have also been effective, though they have limitations. Newer agents currently under investigation for insomnia hold promise for good efficacy and safety in the elderly population. The following review presents clinical studies, survey results, and guidelines retrieved from peer-reviewed journals in the PubMed database using the search terms elderly, temazepam, trazodone, zolpidem, zaleplon, insomnia, and prevalence and the dates 1980 to 2003. In addition, newer research with emerging agents has been included for completeness.

-----

Int J Psychiatr Nurs Res. 2004 Aug;10(1):1146-50.
"A comparison of the effectiveness of two hypnotic agents for the treatment of insomnia".
Schwartz T, Nihalani N, Virk S, Jindal S, Costello A, Muldoon R, Azhar N, Hussein J, Tirmazi S.
SUNY Upstate Medical University, Department of Psychiatry, 750 East Adams Street, Syracuse, NY 13210, USA.

OBJECTIVE: To compare the effectiveness and tolerability of two hypnotic agents, trazadone (Desyrel) and zaleplon (Sonata) on psychiatric inpatients with insomnia. METHODS: Fifteen patients who were psychiatric inpatients were assigned openly and randomly to receive either trazodone (50-100 mg) or zaleplon (10-20 mg) doses on an "as-needed basis" and followed throughout their hospital stay. Efficacy and side effect profile were subsequently assessed. CONCLUSION: This pilot study suggests that trazodone may be a better agent to promote longer, deeper subjective quality sleep for psychiatric inpatients with insomnia in terms of effectiveness. However, tolerability was much better with zaleplon as daytime residual side effects were less.

-----

Clin Cornerstone. 2004;6 Suppl 1B:S8-18.
Women and insomnia.
Miller EH.
Albert Einstein College of Medicine, New York, USA. EhMiller@nshs.edu

The occurrence of insomnia in women is influenced in great part by the complex hormonal cycles they undergo. Patterns of insomnia in younger women may be physiologically different on a hormonal basis from those found in older women. Although significant objective sleep disturbances have been difficult to demonstrate across the menstrual cycle in normal women, the International Classification of Sleep Disorders (ICSD) includes premenstrual insomnia and premenstrual hypersomnia as sleep disorders within the category of menstrual-associated sleep disorder. On the other hand, during pregnancy and after childbirth, profound fluctuations in steroid and hypothalamic-pituitary-adrenal axis-related hormones produce significant physiological changes, including sleep disruption. During the menopausal transition, significant sleep disruptions are provoked by sleep-disordered breathing, vasomotor disturbance, and mood disorders. Regardless of age, women with chronic insomnia are at higher risk for developing or sustaining depression. Thoughtful management approaches must consider known relationships between menstrual or menopausal status and various sleep disorders, and should rely on pharmacologic, nonpharmacologic, or a combination of treatments to achieve successful relief from insomnia. The off-label, first-line use of antidepressants for treating insomnia in the absence of depression is now considered debatable. The long-term efficacy and safety of the newer benzodiazepine receptor agonists (BZRAs) for insomnia, whether taken nightly or episodically, are supported by existing clinical experience. US Food and Drug Administration guidelines limiting the use of hypnotics to only a few weeks predate the newer generation BZRAs, and, as such, the guidelines may no longer be truly appropriate for these new agents.

-----

J Clin Psychiatry. 2004 Aug;65(8):1128-37.
Long-term, non-nightly administration of zolpidem in the treatment of patients with primary insomnia.
Perlis ML, McCall WV, Krystal AD, Walsh JK.
Sleep and Neurophysiology Laboratory, Department of Psychiatry, University of Rochester, and the University of Rochester Medical Center, Neurosciences Program, Rochester, NY 14642, USA. Michael_Perlis@URMC.Rochester.edu

INTRODUCTION: While it is common practice that hypnotics are used on a non-nightly basis, few investigations have been undertaken to evaluate the efficacy of the intermittent dosing strategy. The present study was designed to further evaluate this issue within a large scale, double-blind, placebo-controlled, long-term trial. METHOD: Patients who met DSM-IV criteria for primary insomnia participated in the study from January 2000 through October 2001. Patients were randomly assigned to 1 of 2 treatment groups (zolpidem 10 mg or placebo) for a period of 12 weeks. Ten pills were provided in foil packs on an every-other-week basis, and patients were instructed to take no fewer than 3 and no more than 5 pills per week. Sleep was evaluated daily with sleep diaries. Pill use was recorded in the sleep diaries. RESULTS: 199 patients (mean +/- SD age = 41.0 +/- 12.8 years; 71% female) were randomly assigned to treatment. On mean, patients receiving zolpidem exhibited (vs. baseline) a 42% decrease in sleep latency, a 52% reduction in number of awakenings, a 55% decrease in wake time after sleep onset, and a 27% increase in total sleep time. These positive clinical gains did not diminish with time and were not associated with dose escalation. There was also no evidence of rebound insomnia. CONCLUSIONS: Over a period of 12 weeks of intermittent treatment with zolpidem, sleep continuity was significantly improved, the clinical gains were sustained, and there was no evidence of subjective rebound insomnia between doses or increases in the amount of medication used during the study interval.

-----

Eur Neuropsychopharmacol. 2004 Aug;14(4):301-6.
Zolpidem is not superior to temazepam with respect to rebound insomnia: a controlled study.
Voshaar RC, Van Balkom AJ, Zitman FG.
Department of Psychiatry, University Medical Centre St Radboud (hp 333), P.O. Box 9101, 6500 HB Nijmegen, Netherlands.

This randomised controlled trial was conducted to compare zolpidem to an equivalent dose of temazepam with respect to subjective rebound insomnia after cessation of 4 weeks of treatment in chronic insomnia (zolpidem 10 mg, n=79; temazepam 20 mg, n=84). Both agents improved total sleep time (TST) as well as sleep onset latency (SOL) significantly during the 4 treatment weeks. Prevalence rates for rebound insomnia, defined as a worsening of TST or SOL of more than 40% compared to baseline, were 27% for TST and 53% for SOL in the Zolpidem condition and 26% and 58%, respectively, in the temazepam condition. No significant differences were found between both agents with respect to rebound insomnia, nor with respect to their efficacy or safety. We conclude that in clinical practice zolpidem has no advantages over temazepam with respect to rebound insomnia.

-----

Hum Psychopharmacol. 2004 Jul;19(5):305-22.
Comparative efficacy of newer hypnotic drugs for the short-term management of insomnia: a systematic review and meta-analysis.
Dundar Y, Dodd S, Strobl J, Boland A, Dickson R, Walley T.
The University of Liverpool, Faculty of Medicine, Liverpool Reviews and Implementation Group, The Sherrington Buildings, Ashton Street, Liverpool L69 3GE, UK.

OBJECTIVES: To compare the clinical effectiveness of zaleplon, zolpidem or zopiclone (Z-drugs) with either benzodiazepines licensed and approved for use in the UK for the short-term management of insomnia (diazepam, loprazolam, lorazepam, lormetazepam, nitrazepam, temazepam) or with each other. METHODS: MEDLINE, EMBASE, PsycINFO, Science Citation Index/Web of Science were searched from 1966 to March 2003 and The Cochrane Library, reference lists of included studies and a number of psychopharmacology journals. Randomized controlled trials comparing either benzodiazepines with the Z-drugs or any two of the Z-drugs in patients with insomnia were included. Outcome measures included: sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia and daytime alertness. RESULTS AND CONCLUSIONS: Twenty four eligible studies were identified with a total study population of 3909 (17 studies comparing a Z-drug with a benzodiazepine and 7 comparing a Z-drug). Insufficient or inappropriately reported data meant that meta-analysis was possible only for a small number of outcomes. There are few clear, consistent differences between the drugs. Some evidence suggests that zaleplon gives shorter sleep latency but shorter duration of sleep than zolpidem, reflecting the pharmacological profiles of the drugs. Copyright 2004 John Wiley & Sons, Ltd.

-----

Eur J Pharmacol. 2004 Jul 8;495(1):1-16.
Adenosine uptake inhibitors.
Noji T, Karasawa A, Kusaka H.
Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., 1188 Shimotogari, Nagaizumi, Sunto, Shizuoka 411-8731, Japan.

Adenosine is a purine nucleoside and modulates a variety of physiological functions by interacting with cell-surface adenosine receptors. Under several adverse conditions, including ischemia, trauma, stress, seizures and inflammation, extracellular levels of adenosine are increased due to increased energy demands and ATP metabolism. Increased adenosine could protect against excessive cellular damage and organ dysfunction. Indeed, several protective effects of adenosine have been widely reported (e.g., amelioration of ischemic heart and brain injury, seizures and inflammation). However, the effects of adenosine itself are insufficient because extracellular adenosine is rapidly taken up into adjacent cells and subsequently metabolized. Adenosine uptake inhibitors (nucleoside transport inhibitors) could retard the disappearance of adenosine from the extracellular space by blocking adenosine uptake into cells. Therefore, it is expected that adenosine uptake inhibitors will have protective effects in various diseases, by elevating extracellular adenosine levels. Protective or ameliorating effects of adenosine uptake inhibitors in ischemic cardiac and cerebral injury, organ transplantation, seizures, thrombosis, insomnia, pain, and inflammatory diseases have been reported. Preclinical and clinical results indicate the possibility of therapeutic application of adenosine uptake inhibitors.

-----

Expert Opin Pharmacother. 2004 Jul;5(7):1573-9.
Advances in the management of insomnia.
Zhdanova IV.
Boston University School of Medicine, Department of Anatomy and Neurobiology, 715 Albany Street R-913, Boston MA 02118, USA. zhdanova@bu.edu

Insomnia is a prevalent disorder, altering night time sleep, daytime mood and performance. Current treatment strategies, used separately or in combination, include pharmacological, circadian, behavioural and cognitive therapy. An increased diversity of available hypnotics with different potency, pharmacodynamic and pharmacokinetic profiles and improved side effect profiles provides more flexibility in designing individual treatment strategies. Melatonin, a pineal hormone with acute sleep-promoting and chronobiotic properties, allows additional possibilities in treating insomnia and circadian sleep disorders. Current studies of processes involved in normal sleep regulation and pathophysiology of insomnia should result in the development of new medications based on physiological mechanisms of sleep.

-----

Curr Treat Options Neurol. 2004 Jul;6(4):319-330.
Sleep Problems Across the Life Cycle in Women.
Moline M, Broch L, Zak R.
Eisai Incorporated, Glenpointe Centre West, 500 Frank W. Burr Boulevard, Teaneck, NJ 07666, USA. margaret_moline@eisai.com

Across the life cycle of women, the quality and quantity of sleep can be markedly impacted by internal (eg, hormonal changes and vasomotor symptoms) and external (financial and child-care responsibilities; marital issue) factors. This paper will outline some of the major phases of the life cycle in women that have been associated with sleep problems. The main messages from this paper include 1) that very little systematic, large-scale research has been performed in virtually every area reviewed; and 2) once identified, the sleep problem is generally best addressed by the standard therapeutic approach, except in the case of pregnant and lactating women in which concern for the fetus and child must be considered in the treatment decision. This paper is organized into sections that address sleep problems associated with the menstrual cycle, pregnancy, postpartum, and perimenopause. Anecdotal reports recommend treatment that addresses the specific physical discomfort experienced by the woman (eg, analgesics for premenstrual pain, pregnancy pillows for backache, and hormone replacement therapy for hot flashes). The importance of developing standard treatment recommendations is stressed because the development of chronic insomnia has been linked to precipitating events. In addition, primary sleep disorders (eg, sleep apnea or restless legs syndrome) have been shown to increase during pregnancy and menopause, but treatment recommendations may be contraindicated or are not specific for women.

-----

Am J Phys Med Rehabil. 2004 Jun;83(6):421-7.
Comparison of lorazepam and zopiclone for insomnia in patients with stroke and brain injury: a randomized, crossover, double-blinded trial.
Li Pi Shan RS, Ashworth NL.
Department of Physical Medicine and Rehabilitation, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.

OBJECTIVES: To determine if lorazepam or zopiclone is more effective in providing a restful night of sleep and to assess the effects of these medications on cognition. DESIGN: A randomized, double-blinded, crossover trial was performed at a tertiary care rehabilitation inpatient unit in a teaching hospital. A total of 18 brain-injured and stroke patients, aged 20-78 yrs, were administered lorazepam, 0.5-1.0 mg, orally at bedtime as needed for 7 days and zopiclone, 3.75-7.5 mg, orally at bedtime as needed for 7 days. Total sleep time and characteristics of sleep were measured. Effects on cognition were also measured using the Folstein Mini Mental Status Exam. RESULTS: There was no difference in average sleep duration or in subjective measures of sleep. Cognition as assessed by the Mini Mental Status Exam revealed no difference in the zopiclone arm compared with the lorazepam arm. CONCLUSION: Zopiclone is equally effective as lorazepam in the treatment of insomnia in stroke and brain-injured patients.

-----

Health Technol Assess. 2004 Jun;8(24):iii-x, 1-125.
Newer hypnotic drugs for the short-term management of insomnia: a systematic review and economic evaluation.
Dundar Y, Boland A, Strobl J, Dodd S, Haycox A, Bagust A, Bogg J, Dickson R, Walley T.
Liverpool Reviews and Implementation Group, University of Liverpool, UK.

OBJECTIVES: To assess the clinical and cost-effectiveness of zaleplon, zolpidem and zopiclone (Z-drugs) compared with benzodiazepines. DATA SOURCES: Electronic databases, reference lists of retrieved articles and pharmaceutical company submissions. REVIEW METHODS: Randomised controlled trials (RCTs) that compared either benzodiazepines to the Z-drugs or any two of the non-benzodiazepine drugs in patients with insomnia were included in the review. Data on the following outcome measures were considered: sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse effects and rebound insomnia. A search was also undertaken for any study designs that evaluated issues related to adverse events (e.g. dependency and withdrawal symptoms). Full economic evaluations that compared two or more options and considered both costs and consequences including cost-effectiveness, cost-utility analysis or cost-benefit analysis undertaken in the context of high-quality RCTs were considered for inclusion in the review. RESULTS: Twenty-four studies, involving a total study population of 3909 patients, met the inclusion criteria. These included 17 studies comparing a Z-drug with a benzodiazepine and seven comparing a Z-drug with another Z-drug. The diversity of possible comparisons and the range of outcome measures in the review may be confusing. Outcomes were rarely standardised and, even when reported, differed in interpretation. In addition, variations in assessment and variety in the level of information provided make study comparisons difficult. As a result, meta-analysis has been possible on only a small number of outcomes. However, some broad conclusions might be reached based on the limited data provided. The existing published economic literature in this area is very limited. No relevant economic evaluations were identified for inclusion in the review. The industry submissions did not include detailed evidence of cost-effectiveness. Given the lack of robust clinical evidence, no economic model describing the costs and benefits of the newer hypnotic drugs for insomnia was developed. The systematic review provided in this report suggests that an agnostic approach to cost-effectiveness is required at this stage. In the short-term, no systematic evidence is available concerning significant outcome variations between either the different classes of drugs or between individual drugs within each class. Within this short-term horizon, the one element that does vary significantly is the acquisition cost of the individual drugs. CONCLUSIONS: The short-acting drugs seem equally effective and safe with minor differences that may lead a prescriber to favour one over another in different patients. There is no evidence that one is more cost-effective than any other. Analysis of the additional costs to the NHS, depending on the rate of change from benzodiazepine prescriptions to Z-drug prescriptions, at current levels of hypnotic prescribing, range from GBP2 million to GBP17 million per year. There are clear research needs in this area; in particular, none of the existing trials adequately compare these medications. It is suggested that further consideration should be given to a formal trial to allow head-to-head comparison of some of the key drugs in a double-blind RCT lasting at least 2 weeks, and of sufficient size to draw reasonable conclusions. We would also recommend that any such trial should include a placebo arm. It should also collect good-quality data around sleep outcomes and in particular quality of life and daytime drowsiness. We do not believe that any formal study of risk of dependency is feasible at present. Finally, the management of long-term insomnia is suggested for further investigation: considering the frequency of this symptom and its recurring course, the short-term trial of medication and lack of long-term follow-up undermine attempts to develop evidence-based guidelines for the use of hypnotics in this condition, or indeed for its whole management.

-----

J Clin Psychiatry. 2004;65 Suppl 8:8-12.
Measuring treatment efficacy in insomnia.
Roth T.
Henry Ford Hospital Sleep Center, Detroit, MI, USA. troth1@hfhs.org

The measurement of insomnia treatment efficacy has evolved over time. Historically, patient report measures were used to assess sleep the previous night, and, although important, these measures were not objectively validated. While the advent of polysomnography complemented patient reports of nocturnal sleep, few studies have evaluated daytime functioning and impact of impaired sleep on comorbid medical and psychiatric illnesses as measures of the efficacy of hypnotics. In the future, therapeutic endpoints will focus on important factors associated with insomnia, such as enhanced alertness, improved outcomes associated with augmentation therapy for depression, reduction in pain severity, and decreased sleep disturbances associated with hot flashes.

-----

J Am Board Fam Pract. 2004 May-Jun;17(3):212-9.
Treatment of primary insomnia.
Ringdahl EN, Pereira SL, Delzell JE Jr.
Department of Family and Community Medicine University of Missouri-Columbia School of Medicine, Columbia.

Ten percent to 40% of adults have intermittent insomnia, and 15% have long-term sleep difficulties. This article provides a review of the classification, differential diagnosis, and treatment options available for insomnia. We performed a MEDLINE search using OVID and the key words "insomnia," "sleeplessness," "behavior modification," "herbs," "medicinal," and "pharmacologic therapy." Articles were selected based on their relevance to the topic. Evaluation of insomnia includes a careful sleep history, review of medical history, review of medication use (including over-the-counter and herbal medications), family history, and screening for depression, anxiety, and substance abuse. Treatment should be individualized based on the nature and severity of symptoms. Nonpharmacologic treatments are effective and have minimal side effects compared with drug therapies. Medications such as diphenhydramine, doxylamine, and trazodone can be used initially, but patients may not tolerate their side effects. Newer medications such as zolpidem and zaleplon have short half-lives and minimal side effects. Both are approved for short-term use in the insomniac.

-----

J Psychosom Res. 2004 May;56(5):537-42.
Twenty minutes versus forty-five minutes morning bright light treatment on sleep onset insomnia in elderly subjects.
Kirisoglu C, Guilleminault C.
Stanford University Sleep Disorders Clinic, 401 Quarry Road, Suite 3301, Stanford, CA 94305, USA. cguil@stanford.edu

OBJECTIVE: To compare the efficacy of 20 min versus 45 min light exposure for relieving psychophysiological insomnia in the elderly. METHODS: Prospective recruitment of subjects 60 years and older with psychophysiological insomnia. Random distribution to 20 or 45 min of daily exposure to 10,000 lux for 60 days. Sleep latency, total sleep time, fatigue and activity were measured at baseline and 3 and 6 months posttreatment. Blind analysis of data and comparison were performed using repeated-measure analysis of variance, independent samples t test and Wilcoxon rank signed test. RESULTS: At 3 months, improvement was significantly higher in the 45-min versus 20-min condition. At 6 months, variables returned toward baseline in the 20-min but not in the 45-min condition. CONCLUSIONS: Twenty minutes of bright light treatment leads to a lesser treatment response than 45 min at 3-month follow-up and to a return toward baseline at 6-month follow-up that was not seen with a 45-min exposure.

-----

Curr Med Res Opin. 2004 Apr;20(4):441-9.
Comparison of temazepam 7.5 mg with temazepam 15 mg for the treatment of transient insomnia.
Erman MK, Loewy D, Scharf MB.
Pacific Sleep Medicine Services, San Diego, CA 92121, USA. erman@pacificsleepmedicine.com

OBJECTIVE: To demonstrate the equivalent efficacy of temazepam 7.5 mg and temazepam 15 mg for the treatment of transient insomnia. RESEARCH DESIGN AND METHODS: This was a double-blind, parallel group, multicenter study. Healthy male and female subjects with previous but not current complaints of transient insomnia were enrolled. Transient insomnia was induced in the sleep laboratory by means of the 'first night' effect and by implementing a 2-h phase advance. The effects of both doses of temazepam on polysomnographic (PSG) measures of sleep were evaluated for one night. Latency to persistent sleep (LPS) and total sleep time (TST) were designated as the primary efficacy endpoints. RESULTS: One hundred and thirty-one subjects completed the study: 65 received the 7.5-mg dose, and 66 received the 15-mg dose. Treatment groups begin with the lowest effective dose, i.e., 7.5 mg. were well matched based on background demographics. No statistically significant differences between doses were detected for LPS, TST,or any other objective (PSG) measure of sleep. Furthermore, both doses were found to be clinically equivalent for LPS and TST based on predetermined criteria. Temazepam was well tolerated, and no significant differences between doses were found for adverse event (AE) incidence, mean score on the Digit Symbol Substitution Task, or mean scores on questions related to tolerability from the Leeds Sleep Evaluation Questionnaire. CONCLUSIONS: The 7.5-mg and 15-mg doses of temazepam were equally effective for the treatment of transient insomnia.

-----

CNS Drugs. 2004;18(5):297-328.
Residual effects of hypnotics: epidemiology and clinical implications.
Vermeeren A.
Experimental Psychopharmacology Unit, Brain & Behaviour Institute, Faculty of Psychology, Maastricht University, Universiteitssingel 40, PO Box 616, ER 6229 Maastricht, The Netherlands. a.vermeeren@psychology.unimaas.nl

The risk of "hangover" effects, e.g. residual daytime sleepiness and impairment of psychomotor and cognitive functioning the day after bedtime administration, is one of the main problems associated with the use of hypnotics. However, the severity and duration of these effects varies considerably between hypnotics and is strongly dependent on the dose administered.This article reviews epidemiological evidence on the effect of hypnotics on patients' risk for accidents such as traffic accidents, falls and hip fractures (i.e. end-points for residual effects). Information on the duration and severity of residual effects of 11 hypnotics (flunitrazepam, flurazepam, loprazolam, lormetazepam, midazolam, nitrazepam, temazepam, triazolam, zaleplon, zolpidem and zopiclone) was derived from expert ratings, a meta-analysis and actual driving studies. Epidemiological studies show that the risks of an accident increase with increasing half-life of the hypnotic, but that the use of hypnotics with a short half-life, such as triazolam, zopiclone and zolpidem, can also be associated with increased risks. A summary of results from experimental studies should enable prescribing clinicians to compare residual effects of the various hypnotics at different doses and select the one considered most favourable in this respect for the individual patient. This information should also enable them to inform patients more adequately about the likelihood and duration of residual effects of a specific hypnotic dose.

-----

CNS Drugs. 2004;18(5):285-96.
Management of insomnia in patients with chronic pain conditions.
Stiefel F, Stagno D.
Psychiatry Service, University Hospital Lausanne, 1011 Lausanne, Switzerland. Frederic.Stiefel@inst.hospvd.ch

The management of insomnia in patients experiencing chronic pain requires careful evaluation, good diagnostic skills, familiarity with cognitive-behavioural interventions and a sound knowledge of pharmacological treatments. Sleep disorders are characterised by a circular interrelationship with chronic pain such that pain leads to sleep disorders and sleep disorders increase the perception of pain. Sleep disorders in individuals with chronic pain remain under-reported, under-diagnosed and under-treated, which may lead--together with the individual's emotional, cognitive and behavioural maladaptive responses--to the frequent development of chronic sleep disorders. The moderately positive relationship between pain severity and sleep complaints, and the specificity of pain-related arousal and mediating variables such as depression, illustrate that insomnia in relation to chronic pain is multifaceted and poorly understood. This may explain the limited success of the available treatments.This article discusses the evaluation of patients with chronic pain and insomnia and the available pharmacological and nonpharmacological interventions to manage the sleep disorder. Non-pharmacological interventions should not be considered as single interventions, but in association with one another. Some non-pharmacological interventions especially the cognitive and behavioural approaches, can be easily implemented in general practice (e.g. stimulus control, sleep restriction, imagery training and progressive muscle relaxation). Hypnotics are routinely prescribed in the medically ill, regardless of their adverse effects; however, their long-term efficacy is not supported by robust evidence. Antidepressants provide an interesting alternative to hypnotics, since they can improve pain perception as well as sleep disorders in selected patients. Sedative antipsychotics can be considered for sleep disturbances in those patients exhibiting psychotic features, or for those with contraindications to benzodiazepines. Low doses of sedative antipsychotics may improve chronic insomnia in the elderly. However, no intervention is likely to be effective unless a good physician-patient relationship is developed.

-----

J Clin Psychiatry. 2004;65 Suppl 5:7-12.
Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound.
Chouinard G.
Centre de Recherche Fernand Seguin, Psychopharmacologie, Departement de Psychiatrie, Universite de Montreal, Hopital Louis-Lafontaine, Montreal, Quebec, Canada. psychopharm.unit@mcgill.ca

Low and medium potency benzodiazepines were initially introduced for the treatment of insomnia and anxiety. Their therapeutic actions as anxiolytics, sedative hypnotics, anticonvulsants, and muscle relaxants (with their low toxicity) have led to their use as first-line treatments, and they have become one of the most prescribed classes of drugs. Novel therapeutic uses of benzodiazepines were discovered with the introduction of the high-potency benzodiazepines (e.g., alprazolam, clonazepam, and lorazepam). They were found to be effective in treating panic disorder and panic attacks with or without agoraphobia, as add-on therapy to selective serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder and panic disorders, and as adjunctive therapy in treating patients with acute mania or acute agitation. High-potency benzodiazepines have replaced low and medium potency benzodiazepines in all benzodiazepine clinical indications due to their greater therapeutic effects and rapid onset of action. Differences in distribution, elimination half-life, and rate of absorption are important considerations when choosing a high-potency benzodiazepine. Typically, a benzodiazepine with long distribution and elimination half-lives is preferred. A maximum dose of 2 mg/day of any of the high-potency benzodiazepines when given for more than 1 week is recommended. Although as a class benzodiazepines act rapidly and are well tolerated, their use presents clinical issues such as dependence, rebound anxiety, memory impairment, and discontinuation syndrome.

-----

J Pain Symptom Manage. 2004 Apr;27(4):316-21.
The prevalence, key causes and management of insomnia in palliative care patients.
Hugel H, Ellershaw JE, Cook L, Skinner J, Irvine C.
Marie Curie Center, Liverpool, United Kingdom.

In a prospective audit, the prevalence, key causes and treatment of insomnia prior to admission were evaluated in a population of hospice patients using a questionnaire based on a review article of key features related to insomnia in the palliative care setting. Seventy-four patients completed the questionnaire. Fifty-two (70%) patients had insomnia symptoms. Uncontrolled physical symptoms, most often pain (15 patients), were the commonest cause of insomnia, cited by 31 (60%) sleep-disturbed patients. Thirteen (62%) of 21 patients who had been prescribed hypnotic medication reported an improvement with the prescribed medication. Twenty (38%) of the 52 patients with insomnia suggested that improved symptom control would improve their sleep, and only two (4%) suggested the need for more hypnotic medication. We conclude that insomnia is a common symptom in terminally ill patients and that improved symptom control should be a priority in the management of insomnia in this group of patients.

-----

Hum Psychopharmacol. 2004 Mar;19(2):129-34.
A randomized clinical trial comparing doses and efficacy of lormetazepam tablets or oral solution for insomnia in a general practice setting.
Ancolio C, Tardieu S, Soubrouillard C, Alquier C, Pradel V, Micallef J, Blin O.
CPCET et Pharmacologie Clinique, Institut des Neurosciences Physiologiques et Cognitives, Faculte de Medecine, FRE 2109 CNRS-Universite de la Mediterranee, Assistance Publique Hopitaux de Marseille-Hopital de la Timone, 13385 Marseille Cedex 5, France.

Lormetazepam is a short-acting benzodiazepine hypnotic which is beneficial in shortening the time to onset of sleep. The aim of the study was to assess a new formulation of lormetazepam (oral solution) in comparison with lormetazepam tablets in out-patients with insomnia. This trial was an open randomized parallel group study conducted by 30 general practitioners. One hundred and eight patients took 0.5 mg on the first night and were allowed to increase their dosage by 0.25 mg (for oral solution) and 0.5 mg (for tablets), respectively, each day and every 2 days. The patients assessed the efficacy, acceptability and tolerance of lormetazepam using a diary card and a set of visual analogue scales assessing their sleep. Over 14 days of treatment, the mean daily dose of lormetazepam was lower in the oral solution group than in the tablets group (0.78 mg versus 0.97 mg). The cumulated dose of lormetazepam was lower with the oral solution (18% reduction). No significant difference between the two groups was found in the assessment of sleep characteristics. The occurrence of side effects did not differ between the two groups. These results suggest that a unitary dose as achieved by an oral solution of lormetazepam allows easier determination of the minimal individual effective dose. Copyright 2004 John Wiley & Sons, Ltd.

-----

J Neuropsychiatry Clin Neurosci. 2004 Winter;16(1):19-28.
Acupuncture increases nocturnal melatonin secretion and reduces insomnia and anxiety: a preliminary report.
Spence DW, Kayumov L, Chen A, Lowe A, Jain U, Katzman MA, Shen J, Perelman B, Shapiro CM.
Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

The response to acupuncture of 18 anxious adult subjects who complained of insomnia was assessed in an open prepost clinical trial study. Five weeks of acupuncture treatment was associated with a significant (p = 0.002) nocturnal increase in endogenous melatonin secretion (as measured in urine) and significant improvements in polysomnographic measures of sleep onset latency (p = 0.003), arousal index (p = 0.001), total sleep time (p = 0.001), and sleep efficiency (p = 0.002). Significant reductions in state (p = 0.049) and trait (p = 0.004) anxiety scores were also found. These objective findings are consistent with clinical reports of acupuncture's relaxant effects. Acupuncture treatment may be of value for some categories of anxious patients with insomnia.

-----

Psychiatr Rehabil J. 2004 Winter;27(3):235-42.
Cognitive-behavioral group therapy for insomnia in individuals with serious mental illnesses: a preliminary evaluation.
Dopke CA, Lehner RK, Wells AM.
Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.

Chronic insomnia is a problem among individuals with serious mental illnesses. In an effort to expand treatment options, we examined whether well-established cognitive-behavioral treatments for insomnia developed for individuals in the general population generalize to those for people with serious mental illnesses. Individuals participated in comprehensive sleep evaluations and cognitive-behavioral therapy. Results suggest that sleep problems often began during periods of distress and/or exacerbation of illness but were maintained by environmental, behavioral, and cognitive factors. With the treatment, participants reported improvement in many sleep parameters. Initial indication is that cognitive-behavioral therapy does generalize. More rigorous research seems warranted.

-----

Health Technol Assess. 2004 Feb;8(8):iii-iv, 1-68.
Psychological treatment for insomnia in the regulation of long-term hypnotic drug use.
Morgan K, Dixon S, Mathers N, Thompson J, Tomeny M.
Loughborough Sleep Research Centre, Department of Human Sciences, Loughborough University, UK.

OBJECTIVES: To evaluate the clinical and cost impact of providing, in routine general practice settings, a cognitive-behaviour therapy (CBT) package for insomnia to long-term hypnotic drug users with chronic sleep difficulties; and to identify factors associated with variations in clinical outcomes. DESIGN: A pragmatic cluster randomised controlled trial with two treatment arms (a CBT-treated 'sleep clinic' group, and a 'no additional treatment' control group), with post-treatment assessments starting at 3, 6 and 12 months. SETTING: Twenty-three general practices in Sheffield, UK. PARTICIPANTS: In total, 209 patients (aged 31-92 years) with chronic sleep problems who had been receiving repeat hypnotic drug prescriptions for at least 1 month (mean = 13.4 years) were recruited into the trial. INTERVENTIONS: The intervention consisted of six 50-minute sessions as follows: introduction and sleep assessment, basic sleep hygiene, stimulus control and sleep restriction procedures, progressive relaxation, cognitive treatments, and review and discharge. MAIN OUTCOME MEASURES: These included: global sleep quality [as measured by the Pittsburgh Sleep Quality Index (PSQI)], frequency of hypnotic drug use, mean dose of hypnotics consumed, health-related quality of life [as measured by the Short-Form 36 (SF-36)], NHS service costs and overall cost utility. RESULTS: At 3- and 6-month follow-ups, patients treated with CBT showed improved global PSQI scores as well as improvements in the SF-36 dimensions of vitality at 3 months and physical functioning and mental health at 6 months. CBT-treated patients also reported reductions in the frequency of hypnotic drug use compared with the control group, with many CBT-treated patients reporting zero drug use at the follow-up assessments. Clinical improvements were maintained within the CBT group at the 12-month follow-up, with PSQI scores and the frequency of hypnotic drug use continuing to show significant reductions relative to the control group. Multiple regression analyses of PSQI scores within the sleep clinic group alone indicated that the magnitude of pre- to post-treatment change in overall sleep quality was closely related to Hospital Anxiety and Depression Scale depression scores at 3-, 6-and 12-month follow-ups. In each model higher depression scores at baseline were associated with poorer treatment outcomes. No significant relationship was found between the patient's age and PSQI outcomes in any of these analyses. Within the sleep clinic group, reductions in drug use showed no significant association with the hypnotic product consumed. At the 3-month follow-up low-frequency drug use was reported by 22.9% (8/35) of temazepam users, 33.3% (5/15) of nitrazepam users and 38.9% (7/18) of zopiclone users. The total cost of service provision was GBP154.40 per patient (1999/2000 prices). The mean incremental cost per quality-adjusted life-year (QALY) at 6 months was GBP3418; this figure was insensitive to changes in costs. A simple model also showed that extending the evaluation period beyond 6 months may improve the cost-effectiveness of CBT. The incorporation of hidden costs associated with hypnotic drug treatment (e.g. accidents) also reduces the cost per QALY ratio, although to a much lesser degree. CONCLUSIONS: In routine general practice settings, psychological treatment for insomnia can improve sleep quality, reduce hypnotic drug use, and improve health-related quality of life at a favourable cost among long-term hypnotic users with chronic sleep difficulties. These positive outcomes appear robust over time, persisting for at least 1 year among the more treatment-adherent patients. While these benefits may be reduced among those patients presenting with higher levels of psychological distress, the present study clearly indicates that older age per se presents no barrier to successful treatment outcomes. Further research should assess the long-term clinical and cost-effectiveness of psychological treatments for insomnia among non-hypnotic-using patients, and establish the minimum psychological treatment input required.

-----

Am J Psychiatry. 2004 Feb;161(2):332-42.
Randomized clinical trial of supervised tapering and cognitive behavior therapy to facilitate benzodiazepine discontinuation in older adults with chronic insomnia.
Morin CM, Bastien C, Guay B, Radouco-Thomas M, Leblanc J, Vallieres A.
Ecole de Psychologie, Universite Laval, Sainte-Foy, Quebec, Canada. cmorin@psy.ulaval.ca

OBJECTIVE: This study evaluated the effectiveness of a supervised benzodiazepine taper, singly and combined with cognitive behavior therapy, for benzodiazepine discontinuation in older adults with chronic insomnia. METHOD: Seventy-six older adult outpatients (38 women, 38 men; mean age of 62.5 years) with chronic insomnia and prolonged use (mean duration of 19.3 years) of benzodiazepine medication for sleep were randomly assigned for a 10-week intervention consisting of a supervised benzodiazepine withdrawal program (N=25), cognitive behavior therapy for insomnia (N=24), or supervised withdrawal plus cognitive behavior therapy (N=27). Follow-up assessments were conducted at 3 and 12 months. The main outcome measures were benzodiazepine use, sleep parameters, and anxiety and depressive symptoms. RESULTS: All three interventions produced significant reductions in both the quantity (90% reduction) and frequency (80% reduction) of benzodiazepine use, and 63% of the patients were drug-free within an average of 7 weeks. More patients who received medication taper plus cognitive behavior therapy (85%) were benzodiazepine-free after the initial intervention, compared to those who received medication taper alone (48%) and cognitive behavior therapy alone (54%). The patients in the two groups that received cognitive behavior therapy perceived greater subjective sleep improvements than those who received medication taper alone. Polysomnographic data showed an increase in the amount of time spent in stages 3 and 4 sleep and REM sleep and a decrease in total sleep time across all three conditions from baseline to posttreatment. Initial benzodiazepine reductions were well maintained up to the 12-month follow-up, and sleep improvements became more noticeable over this period. No significant withdrawal symptoms or adverse events were associated with benzodiazepine tapering. CONCLUSIONS: A structured, time-limited intervention is effective in assisting chronic users of benzodiazepine medication to discontinue or reduce their use of medication. The addition of cognitive behavior therapy alleviates insomnia, but sleep improvements may become noticeable only after several months of benzodiazepine abstinence.

-----

Am J Med. 2004 Jan 15;116(2):91-5.
Nocturnal 6-sulfatoxymelatonin excretion in insomnia and its relation to the response to melatonin replacement therapy.
Leger D, Laudon M, Zisapel N.
Centre du Sommeil, Hotel-Dieu de Paris, Paris, France.

PURPOSE: Melatonin, which is produced by the pineal gland at night, is an endogenous sleep regulator. Both sleep disorders and impaired melatonin production are common among the elderly. We examined the excretion of the major melatonin metabolite 6-sulfatoxymelatonin in insomnia patients aged >or=55 years and its relation with the subsequent response to melatonin therapy. METHODS: We studied 517 insomnia patients, along with 29 age-matched and 30 younger healthy volunteers. Nocturnal urinary 6-sulfatoxymelatonin excretion was assessed between 10 pm and 10 am. Three hundred and ninety-six of the insomnia patients were treated for 2 weeks with placebo and for 3 weeks with 2 mg per night of controlled-release melatonin, of which 372 provided complete datasets. Clinical response, assessed with the Leeds Sleep Evaluation Questionnaire, was defined as an improvement of 10 mm or more on the visual analog scales. RESULTS: Mean (+/- SD) 6-sulfatoxymelatonin excretion was lower in the insomnia patients (9.0 +/- 8.3 microg per night) than in volunteers of the same age (18.1 +/- 12.7 microg per night, P <0.05) and in younger volunteers (24.2 +/- 11.9 microg per night, P <0.05). About 30% of patients (112/372) excreted <or=3.5 microg of sulfatoxymelatonin per night, which is considered to be lower than normal for this age group. These "low excretors" had a significantly higher response to melatonin replacement therapy (58% [65/112] vs. 47% [122/260], P <0.05). CONCLUSION: Low nocturnal melatonin production is associated with insomnia in patients aged 55 years or older, and identifies patients who are somewhat more likely to respond to melatonin replacement.

-----

Clin Pharmacokinet. 2004;43(4):227-38.
Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives : zaleplon, zolpidem and zopiclone.
Drover DR.
Department of Anesthesia, Stanford University School of Medicine, Stanford, California, USA.

Benzodiazepines have historically been the mainstay of treatment for sleeping disorders, yet they have many shortcomings. A new group of sedative hypnotic agents has been developed for this purpose. Similar to the benzodiazepines, zaleplon, zolpidem and zopiclone have activity at the GABA receptor complex, yet they appear to have more selectivity for certain subunits of the GABA receptor. This produces a clinical profile that is more efficacious with fewer side effects. Zaleplon, zolpidem and zopiclone are structurally distinct. Due to variation in binding to the GABA receptor subunits, these three compounds show subtle differences in their effect on sleep stages, and as antiepileptics, anxiolytics and amnestics.The duration of action of zaleplon, zolpidem and zopiclone can be related to their individual pharmacokinetic profile, which subsequently determines the time course of drug effect. Each of these compounds has a unique pharmacokinetic profile with different bioavailability, volume of distribution and elimination half-lives. Zaleplon has a rapid elimination so there are fewer residual side effects after taking a single dose at bedtime. By comparison, zolpidem and zopiclone have a more delayed elimination so there may be a prolonged drug effect. This can result in residual sedation and side effects but may be useful for sustained treatment of insomnia with less waking during the night. There are also differences in potency based on plasma concentrations suggesting that there are differences in binding to the GABA receptor complex. Although zaleplon has a much lower bioavailability (30%), the treatment dose is similar to zolpidem and zopiclone (bioavilaibility of 70%) because of the increased potency of zaleplon. The pharmacokinetics and pharmacodynamics of zaleplon, zolpidem and zopiclone are significantly different from benzodiazepines. The new drugs are sufficiently unique from each other to allow customisation of treatment for various types of insomnia. While zaleplon may be best indicated for the delayed onset of sleep, zolpidem and zopiclone may be better indicated for maintaining a complete night's sleep. Only the patient's symptoms and response to treatment will dictate the best course of treatment.

-----

Drug Saf. 2003;26(4):261-82.
New drugs for insomnia: comparative tolerability of zopiclone, zolpidem and zaleplon.
Terzano MG, Rossi M, Palomba V, Smerieri A, Parrino L.
Sleep Disorders Center, University of Parma, Parma, Italy. mterzano@unipr.it

Insomnia affects 30-35% of people living in developed countries. The impact of insomnia on daytime functioning and its relationship with medical and psychiatric illnesses necessitate early treatment to prevent insomnia becoming persistent and to avoid the development of complications. However, pharmacological strategies must achieve a balance between sedative and adverse effects. In the last 30 years, benzodiazepines have been the preferred drugs for the treatment of insomnia. Benzodiazepines act nonselectively at two central receptor sites, named omega(1) and omega(2), which are located in different areas of the CNS. 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. According to their pharmacokinetic profile, benzodiazepines can be classified into three groups: short half-life (<3 hours), medium half-life (8-24 hours) and long half-life (>24 hours). The newer non-benzodiazepine agents zopiclone, zolpidem and zaleplon have a hypnosedative action comparable with that of benzodiazepines, but they display specific pharmacokinetic and pharmacodynamic properties. These three 'Z' agents all share a short plasma half-life and limited duration of action. In addition, 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 characterised by an ultrashort half-life (approximately 1 hour). Zolpidem and zopiclone have longer half-lives (approximately 2.4 and 5 hours, respectively). These properties, together with the low risk of residual effect, may explain the limited negative influences of these agents on daytime performance. Psychomotor tasks and memory capacities appear to be better preserved by non-benzodiazepine agents than by benzodiazepines. When present, cognitive deficits almost exclusively coincide with the peak plasma concentration. In particular, impairment can emerge in the first hours after drug administration, whereas psychomotor and memory tests carried out 7-8 hours later (i.e. in the morning) generally show no relevant alterations. As with benzodiazepines, the three 'Z' non-benzodiazepine agents should be used for a limited period, even in chronic relapsing conditions. Further evaluation is needed of the safety of hypnosedative medications in the long-term management of insomnia.

-----

J Psychiatry Neurosci. 2003 May;28(3):191-6.
Treatment of primary insomnia with melatonin: a double-blind, placebo-controlled, crossover study.
Almeida Montes LG, Ontiveros Uribe MP, Cortes Sotres J, Heinze Martin G.
Instituto Nacional de Psiquiatria Ramon de la Fuente Muniz, Calzada Mexico Xochimilco No. 101, San Lorenzo Huipulco, Tlalpan Mexico DF, Mexico. almeidal@prodigy.net.mx

OBJECTIVE: To assess the hypnotic effect of melatonin in patients with primary insomnia. METHOD: Ten patients (mean age 50 yr, range 30-72 yr) who met the DSM-IV criteria for primary insomnia received, in random order, 0.3 mg of melatonin, 1.0 mg of melatonin or placebo 60 minutes before bedtime. A crossover design was used so that each patient received each of the 3 treatments for a 7-day period (with a 5-day washout period between). After each 7-day treatment, night time electroencephalographic (EEG) records were collected, and each morning, subjects completed sleep logs and analogue-visual scales to document the amount and subjective quality of sleep. RESULTS: There were no significant differences in sleep EEG, the amount or subjective quality of sleep or side effects between the placebo, 0.3-mg melatonin or 1.0-mg melatonin treatments. CONCLUSION: Melatonin did not produce any sleep benefit in this sample of patients with primary insomnia.

-----

CNS Drugs. 2003;17(7):513-32.
Clinically important drug interactions with zopiclone, zolpidem and zaleplon.
Hesse LM, von Moltke LL, Greenblatt DJ.
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.

Insomnia, an inability to initiate or maintain sleep, affects approximately one-third of the American population. Conventional benzodiazepines, such as triazolam and midazolam, were the treatment of choice for short-term insomnia for many years but are associated with adverse effects such as rebound insomnia, withdrawal and dependency. The newer hypnosedatives include zolpidem, zaleplon and zopiclone. These agents may be preferred over conventional benzodiazepines to treat short-term insomnia because they may be less likely to cause significant rebound insomnia or tolerance and are as efficacious as the conventional benzodiazepines. This review aims to summarise the published clinical drug interaction studies involving zolpidem, zaleplon and zopiclone. The pharmacokinetic and pharmacodynamic interactions that may be clinically important are highlighted.Clinical trials have studied potential interactions of zaleplon, zolpidem and zopiclone with the following types of drugs: cytochrome P450 (CYP) inducers (rifampicin), CYP inhibitors (azoles, ritonavir and erythromycin), histamine H(2) receptor antagonists (cimetidine and ranitidine), antidepressants, antipsychotics, antagonists of benzodiazepines and drugs causing sedation. Rifampicin significantly induced the metabolism of the newer hypnosedatives and decreased their sedative effects, indicating that a dose increase of these agents may be necessary when they are administered with rifampicin. Ketoconazole, erythromycin and cimetidine inhibited the metabolism of the newer hypnosedatives and enhanced their sedative effects, suggesting that a dose reduction may be required. Addition of ethanol to treatment with the newer hypnosedatives resulted in additive sedative effects without altering the pharmacokinetic parameters of the drugs.Compared with some of the conventional benzodiazepines, fewer clinically important interactions appear to have been reported in the literature with zaleplon, zolpidem and zopiclone. The fact that these drugs are newer to the market and have not been as extensively studied as the conventional benzodiazepines may be the reason for this. Another explanation may be a difference in CYP metabolism. While triazolam and midazolam are biotransformed almost entirely via CYP3A4, the newer hypnosedatives are biotransformed by several CYP isozymes in addition to CYP3A4, resulting in CYP3A4 inhibitors and inducers having a lesser effect on their biotransformation.

-----

Am Fam Physician. 2003 Apr 15;67(8):1755-8.
Valerian.
Hadley S, Petry JJ.
Family Practice Division, Middlesex Hospital, Middletown, Connecticut 06457, USA. susan_hadley@midhosp.org

Valerian is a traditional herbal sleep remedy that has been studied with a variety of methodologic designs using multiple dosages and preparations. Research has focused on subjective evaluations of sleep patterns, particularly sleep latency, and study populations have primarily consisted of self-described poor sleepers. Valerian improves subjective experiences of sleep when taken nightly over one- to two-week periods, and it appears to be a safe sedative/hypnotic choice in patients with mild to moderate insomnia. The evidence for single-dose effect is contradictory. Valerian is also used in patients with mild anxiety, but the data supporting this indication are limited. Although the adverse effect profile and tolerability of this herb are excellent, long-term safety studies are lacking.

-----

Acta Clin Belg. 2003 Jan-Feb;58(1):27-36.
Is there a rationale for prescription of benzodiazepines in the elderly? Review of the literature.
Petrovic M, Mariman A, Warie H, Afschrift M, Pevernagie D.
Service of Internal Medicine, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. mirko.petrovic@rug.ac.be

Benzodiazepines (BZDs) constitute the most widely used symptomatic treatment of insomnia and anxiety. Many of these drugs are associated with adverse effects, such as daytime sedation and dependence with continued use. There is a concern about the rationale for and extent of benzodiazepine (BZD) use in the elderly. The sedation due to BZD use is a main risk factor for falls and other accidents. Impaired cognitive function with continuous use appears to be a major side effect. There is a general awareness that BZD use is inappropriate in many patients, and therefore discontinuation should be recommended whenever possible. Moreover, long-term use of these drugs should be actively discouraged. Although no unanimous recommendations concerning the optimal duration of the withdrawal process exist, BZDs may easily be withdrawn during a short period in most patients who are habituated to a low dose, if an initial phase with dose reduction and psychological support are provided. Alternative approaches involve sleep hygiene guidelines, behavioural treatment and psychotherapy tailored to the needs of the individual patient.

-----

Sleep. 2003 Mar 15;26(2):177-82.
A primary care "friendly" cognitive behavioral insomnia therapy.
Edinger JD, Sampson WS.
Psychology Service, VA Medical Center, Durham, NC, USA. jack.edinger@duke.edu

OBJECTIVES: This study was conducted to test the effectiveness of an abbreviated cognitive-behavioral insomnia therapy (ACBT) with primary DESIGN: A single-blind, randomized group design was used in which study patients were randomized to either a brief, 2-session ACBT or a similarly brief intervention (SHC) that included only generic sleep hygiene recommendations. SETTING: A university-affiliated Department of Veterans Affairs medical center. PARTICIPANTS: Twenty (2 women) veteran patients (M(age) = 51.0 yrs., SD = 13.7 years) who met criteria for chronic primary insomnia. MEASUREMENTS AND RESULTS: Participants completed sleep logs for 2 weeks and questionnaires to measures insomnia symptoms, sleep-related self-efficacy, and dysfunctional beliefs about sleep before treatment, during a 2-week posttreatment assessment, and again at a 3-month posttreatment follow-up. Statistical analyses showed that ACBT produced significantly larger improvements across a majority of outcome measures than did SHC. Case-by-case analyses showed that only the ACBT produced consistent positive effects across study patients, and a sizeable proportion of these patients receiving this treatment achieved clinically significant improvements by their study endpoints. Approximately 52% of those receiving the ACBT reported at least a 50% reduction in their wake time after sleep onset, and 55.6% of ACBT-treated patients who entered the study with pathologic scores on an Insomnia Symptom Questionnaire (ISQ), achieved normal ISQ scores by their final outcome assessment. CONCLUSIONS: ACBT is effective for reducing subjective sleep disturbance and insomnia symptoms in primary care patients.

-----

Clin Pediatr (Phila). 2003 Jan-Feb;42(1):51-8.
Melatonin in children and adolescents with insomnia: a retrospective study.
Ivanenko A, Crabtree VM, Tauman R, Gozal D.
Kosair Children's Hospital Research Institute, Division of Pediatric Sleep Medicine, Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA.

Effectiveness and tolerability of melatonin was assessed in 32 children (mean age 9.6 +/- 4.5 years) with chronic sleep initiation and sleep maintenance problems treated naturalistically in a pediatric sleep medicine center. Children received melatonin for an average of 2.1 +/- 2.0 months at a final average dose of 2.0 +/- 1.2 mg administered 1 hour before bedtime. Twenty-nine (90.6%) children exhibited partial improvement to complete resolution of their sleep problems as measured by sleep latency time and number of awakenings reported by parents. Thus, melatonin may be effective, safe, and well tolerated in the treatment of chronic insomnia in children.

-----

Curr Neurol Neurosci Rep. 2003 Mar;3(2):181-4.
Hypnotics: an update.
Roehrs T, Roth T.
Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202, USA. TARoehrs@aol.com

This update reviews recent developments and advances in the therapeutic and side-effect profile of the benzodiazepine receptor agonists (BZRAs), the generally accepted drug class of choice for the symptomatic treatment of insomnia. All the approved BZRAs, depending on their pharmacokinetic profile, improve and maintain sleep. The major recent advance is in the enhanced diversity of the pharmacokinetic profiles of these drugs, and thus in the flexibility available to the clinician in treatment strategy. Also, during the past decade the nature and significance of the side effects associated with the BZRAs and their determinants, dose and half-life, have been identified and clarified. The important remaining question is whether, and how, the efficacy and safety of the BZRAs change with chronic use.

-----

Age Ageing. 2003 Jan;32(1):19-25.
Non-pharmacological management of primary and secondary insomnia among older people: review of assessment tools and treatments.
Petit L, Azad N, Byszewski A, Sarazan FF, Power B.
The Ottawa Hospital Civic Campus, 1053 Carling Avenue Ottawa, Ontario, Canada.

BACKGROUND:primary and secondary insomnia, especially among older adults, is frequently encountered by family physicians. Pharmacological interventions, although effective in some circumstances, can be detrimental in others. Non-pharmacological management of insomnia may allow the patients to self-administer the treatment. OBJECTIVES:review of published literature of assessment tools and treatments for primary and secondary insomnia. RESULTS:two frequently used self-reporting methods for obtaining sleep data are sleep diaries and Pittsburg Sleep Quality Index. A large amount of research supports the use of non-pharmacological treatments such as stimulus control, sleep restriction, sleep hygiene education, cognitive therapy, multi-component therapy and paradoxical intention. CONCLUSION: assessing the nature of insomnia by using an effective assessment tool and providing patients with a non-pharmacological treatment should be the first intervention for insomnia. It is shown that non-pharmacological treatments for primary and secondary insomnia are feasible and effective alternatives to the use of benzodiazepines, and that family physicians should consider these when managing older patients with insomnia.

-----

Hum Psychopharmacol. 2003 Jan;18(1):75-82.
Adverse effects of temazepam in older adults with chronic insomnia.
Morin CM, Bastien CH, Brink D, Brown TR.
Universite Laval, Quebec, Canada. cmorin@psy.ulaval.ca

BACKGROUND: Benzodiazepine-hypnotics are frequently used for treating insomnia in older adults; however, there is little information about adverse effects associated with their usage over several weeks, particularly in this segment of the population. OBJECTIVE: This study reports on the incidence of adverse effects of temazepam in older adults with chronic insomnia and examines whether the addition of cognitive-behaviour therapy (CBT) is associated with less drug used and fewer adverse effects. METHOD: Sixty patients with chronic and primary insomnia were randomized to temazepam (n = 20), placebo (n = 20) or temazepam plus CBT (n = 20). Data from the physicians' weekly assessments and patients' sleep diaries were used to evaluate adverse effects, the dose (7.5-30 mg) at which they occurred, and drug use patterns over the 8-week course of treatment. RESULTS: The incidence of adverse effects was infrequent, as shown by the low percentages of complaints reported by patients in the temazepam (7.8%), placebo (10.8%) and combination groups (8.3%). The severity of adverse events was mild and decreased over the course of treatment. The maximum dose was reached by 10 patients receiving temazepam, 14 placebo and 7 in the combined treatment. The average nightly dosage used was 20 mg for both the temazepam and placebo groups and 16 mg for the combined condition. Patients receiving temazepam plus CBT used less drugs, with approximately the same incidence of adverse effects. CONCLUSION: Temazepam is a safe hypnotic for use by older adults over an 8-week treatment period. There are few adverse effects and behavioural tolerance to those effects develop over time. The addition of cognitive-behavioural intervention reduced both the amount of medication used and the incidence of adverse effects, with comparable sleep improvements. Copyright 2003 John Wiley & Sons, Ltd.

-----

J Psychosom Res. 2003 Jan;54(1):31-7.
Trait anxiety and sleep-onset insomnia: evaluation of treatment using anxiety management training.
Viens M, De Koninck J, Mercier P, St-Onge M, Lorrain D.
School of Psychology, University of Ottawa, CP 450 Stn A, Ottawa, Ontario, Canada.

OBJECTIVES: This study was initially designed to test the notion that generalized anxiety is a predominant factor in the maintenance of psychologically determined sleep-onset insomnia and that a trait anxiety reducing technique can provide significant therapeutic gains. METHODS: Twenty participants (age 19-63) with moderate to severe sleep-onset chronic insomnia were first asked to monitor their sleep-onset latency (SOL) for a 3-week baseline period at home using a SOL clock device. Then, 10 received anxiety management training (AMT) for 9 weeks, while the remaining 10 were trained in the use of progressive relaxation (PR). All participants were measured before and after therapy using sleep laboratory recordings (three nights each), the Spielberger Trait Anxiety Inventory and the Beck Depression Inventory. Daily home sleep-onset measures with the SOL clock device were also taken during therapy. RESULTS: There was no change in SOL over the 3-week baseline period. However, both groups experienced a significant improvement in SOL from pretreatment (end of baseline) to posttreatment periods. In the laboratory, both groups experienced a reduction in Stage 1 sleep as well as an increase in slow wave sleep (SWS) and sleep satisfaction. On the personality measures, both groups experienced a significant reduction in trait anxiety and a decrease in depression. Overall, there was no indication that one of the therapies was significantly better than the other in effecting changes. CONCLUSION: These results suggest that both PR and AMT are efficient therapies for sleep onset insomnia and overall sleep quality. Improvements in the application of the AMT technique are proposed to maximize its usefulness. Copyright 2003 Elsevier Science Inc.

-----

J Community Health Nurs. 2003 Spring;20(1):27-35.
The use of music to promote sleep in older women.
Johnson JE.
Orvis School of Nursing, University of Nevada, Reno 89557, USA.

Fifty-two women over the age of 70 participated in a study to investigate the use of an individualized music protocol to promote sleep onset and maintenance. They were recruited from the practices of physicians and nurse practitioners, and met the inclusion and exclusion criteria of the International Classification of Sleep Disorders (1990), and the Diagnostic and Statistical Manual of Mental Disorders (1994). Results indicated that the use of music decreased time to sleep onset and the number of nighttime awakenings. Consequently, it increased satisfaction with sleep. Nurses may wish to recommend the use of music at bedtime to older women with insomnia.

-----

Tidsskr Nor Laegeforen. 2002 Dec 10;122(30):2857-9.
[Valerian as a sleeping aid?]
[Article in Norwegian]
Pallesen S, Bjorvatn B, Nordhus IH, Skjerve A.
Institutt for samfunnspsykologi Universitetet i Bergen Christiesgate 12 5015 Bergen. staale.pallesen@psysp.uib.no

BACKGROUND: Valeriana is a herbal over-the-counter drug, in Norway mainly used for insomnia. It is estimated that in Norway only, annual sales of valeriana amount to NOK 20 m. With this considerable consumption in mind, we wanted to review the scientific basis for valeriana as a sleep aid. MATERIAL AND METHODS: Through a literature search we identified 18 experimental studies examining the effects of valeriana on human sleep. RESULTS: The majority of studies reported positive effects of valeriana on subjective sleep parameters. Objective sleep measures yielded inconsistent results. All studies covered a short period of time. Few side effects of valeriana were reported. Only two studies compared valeriana to established hypnotics. INTERPRETATION: We conclude that valeriana may have some hypnotic effect. Long-term studies are clearly lacking, as well as studies comparing valeriana to well-established drug treatments for insomnia.

-----

Eur J Med Res. 2002 Nov 25;7(11):480-6.
Efficacy and tolerability of valerian extract LI 156 compared with oxazepam in the treatment of non-organic insomnia--a randomized, double-blind, comparative clinical study.
Ziegler G, Ploch M, Miettinen-Baumann A, Collet W.
Institute fur Psychomatische Forschung, Stuttgart, Germany.

Patients aged 18 to 73 years and diagnosed with non-organic insomnia according to ICD-10 (F 51.0) were treated in a multicentre, double-blind, randomised parallel group comparison with either 600 mg/die valerian extract LI 156 (Sedonium) or 10 mg/die oxazepam taken for 6 weeks. A total of 202 outpatients with a mean duration of insomnia of 3.5 months at baseline were included at 24 study centres (general practices) in Germany. - Sleep quality (SQ) after 6 weeks measured by the Sleep Questionnaire B (SF-B; CIPS 1996) showed that 600 mg/die valerian extract LI 156 was at least as efficacious as a treatment with 10 mg/die oxazepam. Both treatments markedly increased sleep quality compared with baseline (p <0.01). The other SF-B subscales, i.e. feeling of refreshment after sleep (GES), psychic stability in the evening (PSYA), psychic exhaustion in the evening (PSYE), psychosomatic symptoms in the sleep phase (PSS), dream recall (TRME), and duration of sleep confirmed similar effects of both treatments. Clinical Global Impressions scale (CGI) and Global Assessment of Efficacy by investigator and patient, again, showed similar effects of both treatments. Adverse events occurred in 29 patients (28.4%) receiving valerian extract LI 156 and 36 patients (36.0%) under oxazepam, and were all rated mild to moderate. No serious adverse drug reactions were reported in either group. Most patients assessed their respective treatment as very good (82.8% in the valerian group, 73.4% in the oxazepam group). During the 6 week treatment phase Valerian extract LI 156 (Sedonium) 600 mg/die showed a comparable efficacy to 10 mg/die oxazepam in the therapy of non-organic insomnia.

-----

Cochrane Database Syst Rev. 2002;(4):CD003346.
Benzodiazepines and related drugs for insomnia in palliative care.
Hirst A, Sloan R.
Cochrane Cancer Network, Institute of Health Sciences, P O Box 777, Headington, Oxford, UK, OX3 7LF. ahirst@canet.org

BACKGROUND: Insomnia, a subjective complaint of poor sleep and associated impairment in daytime function, is a common problem. Currently, benzodiazepines are the most used pharmacological treatment for this complaint. They are considered helpful for occasional short-term use up to four weeks but longer term use is not advised due to potential problems regarding tolerance, dosing escalation, psychological addiction and physical dependence. There is no consensus on their utility in patients with progressive incurable conditions who may require assistance with sleep for many weeks as their condition deteriorates. OBJECTIVES: To assess the effectiveness and safety of benzodiazepines or benzodiazepine receptor agonists such as Zolpidem, Zopiclone and Zaleplon for insomnia in palliative care. SEARCH STRATEGY: Several electronic databases were searched including Cochrane PaPaS Group specialized register, Cochrane Library Issue 4, 2001, MEDLINE, EMBASE, BNI plus, CINAHL, BIOLOGICAL ABSTRACTS, PSYCINFO, CANCERLIT, HEALTHSTAR, WEB OF SCIENCE, SIGLE, Dissertation Abstracts, ZETOC and the MetaRegister of ongoing trials. These were searched from 1960 to 2001 or as much of this range as possible. Additional articles were sought by handsearching reference lists in standard textbooks and reviews in the field and by contacting academic centres in palliative care and pharmaceutical companies. There were no language restrictions. SELECTION CRITERIA: Studies considered for inclusion were randomized controlled trials of adult patients in any setting, receiving palliative care or suffering an incurable progressive medical condition. (For example, cancers, AIDS, Motor Neurone Disease, Multiple Sclerosis, Parkinson's Disease, Chronic Obstructive Pulmonary Disease). There had to be an explicit complaint of insomnia in study participants, diagnosed by any of the three main classification systems (DSM-IV (APA 1994), ICSD (AASD 1990) or ICD (WHO 1992)), or as described in the study if it involved a subjective complaint of poor sleep. Studies had to compare a benzodiazepine or Zolpidem or Zopiclone or Zaleplon with placebo or active control for the treatment of insomnia. Any duration of therapy were considered. DATA COLLECTION AND ANALYSIS: Abstracts were independently inspected by both reviewers, full papers were obtained where necessary. Where there was uncertainty advice was sought by a third (PW). Data extraction and quality assessments were undertaken independently by both reviewers. MAIN RESULTS: No randomized controlled trials were identified meeting the a priori inclusion criteria. Thirty-seven studies were considered but all were excluded from the review. REVIEWER'S CONCLUSIONS: Despite a comprehensive search no evidence from randomized controlled trials was identified. It was not possible to draw any conclusions regarding the use of benzodiazepines in palliative care.

-----

Aust Fam Physician. 2002 Nov;31(11):995-1000.
Insomnia. Diagnosis and management.
Grunstein R.
Sleep Research Group, Institute of Respiratory Medicine, University of Sydney. rrg@mail.med.usyd.edu.au

BACKGROUND: Insomnia is a complaint of perceived poor sleep quality resulting in impairment of daytime function. It is the commonest clinical sleep disorder with approximately 6-12% of adults complaining of chronic insomnia. OBJECTIVE: To review current knowledge on causes and effects of insomnia and to provide a brief evidence based review of management options for the family practitioner. DISCUSSION: Patients with insomnia are characterised by excessive arousal and an inability to sleep despite reported reduced sleep hours and poor sleep quality. Current management approaches are focussed on reducing this 'hyperarousal' and its behavioural manifestations by a range of behavioural treatments. Good evidence exists for the efficacy of hypnotics for short term insomnia but long term data is currently lacking. Nonbenzodiazepine hypnotics (zopiclone, zolpidem) have less adverse effects and similar efficacy to benzodiazepines.

-----

Prim Care. 2002 Jun;29(2):339-60, vii.
Anxiety, depression, and insomnia.
Larzelere MM, Wiseman P.
Department of Family Medicine, Louisiana State University Health Sciences Center, School of Medicine, 200 West Esplanade Avenue, Suite 510, Kenner, LA 70065, USA. mlarze@lsuhsc.edu

Evidence for alternative treatments for depression, anxiety, and insomnia are reviewed in this article. Treatment of depression with St. John's wort, L-tryptophan, 5-hydroxytryptophan, S-adenosylmethionine, dehydroepiandosterone, folate, exercise, acupuncture, and meditation are examined. Evidence for the efficacy of kava kava, exercise, relaxation therapies, and acupuncture in treatment anxiety is reviewed. The use of valerian, melatonin, chamomile, passionflower, exercise, acupuncture, and behavioral therapies (i.e., sleep restriction, stimulus control, relaxation, and sleep hygiene) for insomnia is discussed.

-----

Seishin Shinkeigaku Zasshi. 2002;104(6):513-28.
[Behavioral treatment for chronic insomnia]
[Article in Japanese]
Adachi Y, Yamagami T.
Faculty of Human and Social Environment, Hiroshima International University, Institute of Behavioral Health.

The efficacy of non-pharmacological intervention for chronic insomnia has been proven by several meta-analytic reviews, an NIH report, an American Academy of Sleep Medicine review, and numerous clinical trials. Behavior therapy for chronic insomnia consists of relaxation, stimulus control, sleep restriction, cognitive restructuring and sleep hygiene education, which has produced reliable and durable changes in total sleep time, sleep onset latency, number and duration of awakening. These studies also showed that the post-treatment effect of behavior therapy is equal to that of hypnotic therapy, and that these effects were maintained for 6 months on follow-up assessment. Elderly insomniac patients would gain considerable benefit from behavioral treatments because there are no adverse physical effects as there are from pharmacological therapy. The authors present the basic theory, techniques of behavior therapy for insomnia, and the results of two important key meta-analytic reviews. Any behavioral approach such as convenient education, self-care enhancement by bibliotherapy, and individual face-to-face counseling, seem to be fruitful not only for American but also Japanese insomnia patients. Nonetheless, there are no currently actual intervention studies using behavior therapy in Japan. We have discussed the methodology of intervention study and published a behavioral self-help manual for people with sleep problems. Development of a behavioral approach to chronic insomnia seemed to be very beneficial and a useful contribution to mental health services.

-----

Pharmacopsychiatry. 2002 Sep;35(5):165-74.
Trimipramine in primary insomnia: results of a polysomnographic double-blind controlled study.
Riemann D, Voderholzer U, Cohrs S, Rodenbeck A, Hajak G, Ruther E, Wiegand MH, Laakmann G, Baghai T, Fischer W, Hoffmann M, Hohagen F, Mayer G, Berger M.
Department of Psychiatry and Psychotherapy, University of Freiburg, Germany. dieter_riemann@psyallg.ukl.uni-freiburg.de

In recent years, sedating antidepressants have been increasingly used to treat primary insomnia. Up to now, only one open pilot study with trimipramine and one double-blind placebo-controlled study with doxepin have provided scientific support for this approach in treating primary insomnia. In order to test the hypothesis that sedating antidepressants are useful in the treatment of primary insomnia, the effect of trimipramine on objectively and subjectively measured parameters of sleep was investigated in a double-blind placebo- and lormetazepam-controlled study in a sample of 55 patients with primary insomnia attending outpatient sleep-disorder clinics. Trimipramine was selected since it has shown positive effects on sleep continuity with a lack of REM sleep suppression in studies on depressed patients and in one pilot study on patients with primary insomnia. Trimipramine at an average dose of 100 mg over a period of 4 weeks significantly enhanced sleep efficiency, but not total sleep time (which had been the primary target variable) compared to placebo as measured by polysomnography. Changes in objective sleep parameters were paralleled by changes in subjective sleep parameters. Trimipramine did not suppress REM sleep. Lormetazepam decreased wake time and sleep stage 3 and increased REM sleep compared to placebo. After switching trimipramine to placebo, sleep parameters returned to baseline. There was no evidence of any rebound effect from trimipramine. Side effects from trimipramine were only marginal. This first double-blind placebo-controlled study with trimipramine suggests its efficacy in the treatment of primary insomnia. However, due to the large intra- and interindividual variance in the parameters of interest before and during treatment a larger sample size would have been necessary to strengthen the validity of our findings.

-----

Cochrane Database Syst Rev. 2002;(2):CD003403.
Bright light therapy for sleep problems in adults aged 60+.
Montgomery P, Dennis J.
The University of Oxford Section of Child and Adolescent Psychiatry, Park Hospital, Old Road, Headington, Oxford, UK, OX3 7LQ. paul.montgomery@psych.ox.ac.uk

BACKGROUND: The prevalence of sleep problems in adulthood increases with age. While not all sleep changes are pathological in later life, severe disturbances may lead to depression, cognitive impairments, deterioration of quality of life, significant stresses for carers and increased healthcare costs. The most common treatment for sleep disorders (particularly insomnia) is pharmacological. The efficacy of non-drug interventions has been suggested to be slower than pharmacological methods, but with no risk of drug-related tolerance or dependency. Bright light treatment involves participants sitting in front of a "light box" which emits very high (typically 10,000 lux) fluorescent light for periods of around two hours daily. The timing of this light treatment will depend on the irregular timing of the participant's sleep pattern. OBJECTIVES: To assess the efficacy of bright light therapy in improving sleep quality (sleep timing in particular) amongst adults aged 60 and above. SEARCH STRATEGY: The following databases were searched: MEDLINE (1966 - January 2001); EMBASE (1980 - January 2001), CINAHL ( 1982 - January 2001; PsychINFO 1970 to 2001; The Cochrane Library (Issue 1, 2001); National Research Register (NRR [2001]). Bibliographies of existing reviews in the area, as well as of all trial reports obtained, were searched. Experts in the field were consulted. SELECTION CRITERIA: Randomised controlled trials of bright light therapy for primary sleep problems where 80% or more of participants were over 60. Participants must have been screened to exclude those with dementia and/or depression. DATA COLLECTION AND ANALYSIS: Abstracts of studies identified in searches of electronic databases were read and assessed to determine whether they might meet the inclusion criteria. MAIN RESULTS: Reviewers found no trials on which to base conclusions for the effectiveness of this treatment. REVIEWER'S CONCLUSIONS: When the possible side-effects of standard treatment (hypnotics) are considered, there is a reasonable argument to be made for clinical use of non-pharmacological treatments. In view of the promising results of bright light therapy in other populations with problems of sleep timing, further research into their effectiveness with older adults would seem justifiable.

-----

Geriatrics. 2002 May;57(5):24-6, 29, 32 passim.
Insomnia. Safe and effective therapy for sleep problems in the older patient.
Schneider DL.
Department of Medicine, Division of General Medicine and Geriatrics, University of California, San Diego, USA.

Insomnia is a problem in all stages of life but is particularly common after age 65. A number of factors--including advanced age, psychosocial influences, medical illness, and the use of medications and alcohol--may disturb sleep architecture. Evaluation of insomnia in the older patient requires a careful history and physical examination, supplemented by a sleep diary. Treatment of underlying conditions and nonpharmacologic improvements in sleep hygiene are first-line therapy, but pharmacologic agents such as benzodiazepines, nonbenzodiazepine hypnotics, or antidepressants may be needed. Nonbenzodiazepines with rapid elimination may offer a lower side-effect profile than other hypnotic agents when used for insomnia in the older population.

-----

Paediatr Drugs. 2002;4(6):391-403.
Insomnia in children: when are hypnotics indicated?
Younus M, Labellarte MJ.
Division of Child and Adolescent Psychiatry, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287-3325, USA.

Insomnia in children is a nonspecific impairing symptom that may be the result of normal developmental changes, psychosocial duress, a sleep disorder, a psychiatric disorder, other medical disorders, substance misuse, or an adverse effect of medication. Careful clinical assessment of insomnia in children may include the use of symptom rating scales, laboratory testing, or other medical assessment. Short- and long-term treatment of insomnia in children involves management of etiological factors and associated syndromes. Controlled treatment studies of pediatric insomnia are limited to <10 published studies of psychosocial and/or psychopharmacological treatment in young children. Directive parent education and behavior modification techniques have been effective in short-term treatment of insomnia in young children, and may be the preferred treatment of extrinsic insomnia, as well as an important adjunctive treatment of any insomnia symptoms. Two benzodiazepines [flurazepam and delorazepam (chlordesmethyldiazepam)], one antihistamine (niaprazine) and one phenothiazine [alimemazine (trimeprazine)] have been shown to be effective in the short-term treatment of insomnia in young children, although none of these agents have US Food and Drug Administration approval for pediatric insomnia. Short-acting benzodiazepines may have a role in the brief treatment of pediatric insomnia associated with an anxiety or mood disorder, psychosis, aggression, medication- induced activation, or anticipatory anxiety associated with a medical procedure. However, tachyphylaxis and risk of misuse preclude the long-term use of benzodiazepines for the treatment of insomnia in children. Newer hypnotics, which appear better tolerated than the benzodiazepines in studies of adults, may have a role when combined with psychosocial treatments of pediatric insomnia. Treatment of intrinsic pediatric insomnia may additionally involve chronotherapy or medical management.

-----

Neuroendocrinol Lett. 2002 Apr;23 Suppl 1:9-13.
Melatonin in sleep disorders and jet-lag.
Cardinali DP, Brusco LI, Lloret SP, Furio AM.
Departament of Physiology, Faculty of Medicine, University of Buenos Aires, Argentina. cardinal@mail.retina.ar

In elderly insomniacs, melatonin treatment decreased sleep latency and increased sleep efficiency. This is particularly marked in Alzheimer's disease (AD) patients. Melatonin is effective to reduce significantly benzodiazepine use. In addition, melatonin administration synchronizes the sleep-wake cycle in blind people and in individuals suffering from delayed sleep phase syndrome or jet lag. Urinary levels of 6-sulphatoxymelatonin decrease with age and in chronic diseases like AD or coronary heart disease. The effect of melatonin on sleep is probably the consequence of increasing sleep propensity (by inducing a fall in body temperature) and of a synchronizing effect on the circadian clock (chronobiotic effect).

-----

Isr J Psychiatry Relat Sci. 2002;39(1):36-49.
Non-pharmacological treatments of insomnia.
Lushington K, Lack L.
Centre for Sleep Research, University of South Australia, Queen Elizabeth Hospital, Woodville, South Australia.

Insomnia is a prevalent and complex disorder to treat. This article reviews the prevalence, etiology, diagnosis and treatment of insomnia. With regard to treatment, there now exists an extensive literature demonstrating that compared with pharmacological treatments a range of non-pharmacological therapies are of proven clinical efficacy and durability. These include, for example, stimulus control therapy, bedtime restriction therapy, relaxation therapy, cognitive therapy and bright light therapy. These therapies are summarized and evaluated. It is recommended that therapists consider non-drug treatments based on cognitive-behavioral principles when managing a patient with insomnia.

-----

Prog Neuropsychopharmacol Biol Psychiatry. 2002 Apr;26(3):539-45.
Can valerian improve the sleep of insomniacs after benzodiazepine withdrawal?
Poyares DR, Guilleminault C, Ohayon MM, Tufik S.
Sleep Laboratory of the Department of Psychobiology, Universidade Federal de Sao Paulo, Sao Paulo, Brazil.

PURPOSE: The authors studied the sleep of patients with insomnia who complained of poor sleep despite chronic use of benzodiazepines (BZDs). The sample consisted of 19 patients (mean age 43.3+/-10.6 years) with primary insomnia (DSM-IV), who had taken BZDs nightly, for 7.1+/-5.4 years. The control group was composed of 18 healthy individuals (mean age 37+/-8 years). Sleep electroencephalogram (EEG) of the patients was analyzed with period amplitude analysis (PAA) and associated algorithms, during chronic BZD use (Night 1), and after 15 days of a valerian placebo trial (initiated after washout of BZD, Night 2). Sleep of control subjects was monitored in parallel. RESULTS: Valerian subjects reported significantly better subjective sleep quality than placebo ones, after BZD withdrawal, despite the presence of a few side effects. However, some of the differences found in sleep structure between Night 1 and Night 2 in both the valerian and placebo groups may be due to the sleep recovery process after BZD washout. Example of this are: the decrease in Sleep Stage 2 and in sigma count; the increase in slow-wave sleep (SWS), and delta count, which were found to be altered by BZD ingestion. There was a significant decrease in wake time after sleep onset (WASO) in valerian subjects when compared to placebo subjects; results were similar to normal controls. Nonetheless, valerian-treated patients also presented longer sleep latency and increased alpha count in SWS than control subjects. CONCLUSIONS: The decrease in WASO associated with the mild anxiolytic effect of valerian appeared to be the major contributor to subjective sleep quality improvement found after 2-week of treatment in insomniacs who had withdrawn from BDZs. Despite subjective improvement, sleep data showed that valerian did not produce faster sleep onset; the increase in alpha count compared with normal controls may point to residual hyperarousabilty, which is known to play a role in insomnia. Nonetheless, we lack data on the extent to which a sedative drug can improve alpha sleep EEG. Thus, the authors suggest that valerian had a positive effect on withdrawal from BDZ use.

-----

Ann Pharmacother. 2002 May;36(5):852-9.
Safety of zaleplon in the treatment of insomnia.
Israel AG, Kramer JA.
Department of Internal Medicine, School of Medicine, University of California San Diego, 4060 4th Avenue, Suite 505, San Diego, CA 92103-2121, USA. aisrael@pol.net

OBJECTIVE: To evaluate the safety of zaleplon, a quick-acting, rapidly eliminated nonbenzodiazepine (non-BZD) hypnotic, as described in clinical investigations of adult and/or elderly subjects. DATA SOURCES: Published and presented studies evaluating zaleplon, a novel non-BZD, were identified via MEDLINE (1995-July 2001), Current Contents (ISI database), bibliographic reviews, and consultation with sleep specialists who also identified published abstracts containing data not yet published in peer-reviewed journals. DATA SYNTHESIS: Transient and chronic insomnia are common problems that should be clinically evaluated and appropriately treated. BZDs have been a primary pharmacotherapy for treating insomnia, despite their disadvantages. Newer hypnotics, characterized by increased receptor-binding specificity and favorable pharmacokinetics, provide potentially better alternatives to BZDs. Assessments included residual sedation, psychomotor impairment, or cognitive dysfunction during treatment, as well as the occurrence of rebound insomnia and withdrawal effects after discontinuation of therapy. CONCLUSIONS: Zolpidem, the first non-BZD hypnotic, appears to have short- and long-term safety profiles similar to those of the BZD triazolam. Zaleplon, a newer non-BZD sleep medication, has a quick onset of action and undergoes rapid elimination, which results in a better safety profile than previously available agents. Additionally, rebound insomnia and other withdrawal effects have not been demonstrated with zaleplon, and the drug is well tolerated in both young and elderly patients. These characteristics may be clinically advantageous for patients who should not receive BZDs.

-----

MedGenMed. 2002 Mar 14;4(1):9.
Management of insomnia—the role of zaleplon.
Richardson GS, Roth T, Kramer JA.
Sleep Disorders and Research Center, Henry Ford Hospital, Detroit, MI, USA.

CONTEXT: Insomnia is the most frequently reported sleep symptom, severely affecting up to 15% of the US population. The need to effectively treat this disorder is underscored by the significant adverse consequences on the productivity, safety, overall health, and quality of life of the affected individual. Pharmacologic intervention has traditionally involved the use of benzodiazepine receptor agonists (BzRAs), for which efficacy and general safety have been established. OBJECTIVE: The purpose of this paper is to examine the potentially unique role of zaleplon in the treatment of insomnia. DATA SOURCE: The clinical experience of the authors was critically applied to peer-reviewed published papers or abstracts regarding zaleplon, which were identified via MEDLINE (1995-September 2000). RESULTS: Adverse effects, usually related to residual sedation, impose limits on the use of older BzRAs and have prompted the development of new sleep medications with advantageous adverse event profiles. Zaleplon demonstrates a very rapid onset and offset of effect that permits symptomatic rather than prophylactic administration, resulting in comparable efficacy and reduced risk of the adverse effects associated with longer half-life agents. CONCLUSIONS: The characteristics of zaleplon may translate into distinct and significant clinical advances in the treatment of insomnia.

-----

J Clin Psychopharmacol. 2002 Apr;22(2):137-47.
Acute efficacy of fluoxetine versus sertraline and paroxetine in major depressive disorder including effects of baseline insomnia.
Fava M, Hoog SL, Judge RA, Kopp JB, Nilsson ME, Gonzales JS.
Depression Clinical and Research Program, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. mfava@partners.org

This study assessed whether fluoxetine, sertraline, and paroxetine differ in efficacy and tolerability in depressed patients and the impact of baseline insomnia on outcomes. Patients (N = 284) with DSM-IV major depressive disorder were randomly assigned in a double-blind fashion to fluoxetine, paroxetine, or sertraline for 10 to 16 weeks of treatment. Using the Hamilton Rating Scale for Depression (HAM-D) sleep disturbance factor score, patients were categorized into low (<4) or high (>or=4) baseline insomnia subgroups. Changes in depression and insomnia were assessed. Safety assessments included treatment-emergent adverse events (AEs), reasons for discontinuation, and AEs leading to discontinuation. In addition, AEs were evaluated within insomnia subgroups to determine emergence of activation or sedation. Depression improvement, assessed with the HAM-D-17 total score, was similar among treatments in all patients (p = 0.365) and the high (p = 0.853) and low insomnia (p = 0.415) subgroups. Insomnia improvement, assessed with the HAM-D sleep disturbance factor score, was similar among treatments in all patients (p = 0.868) and in the high (p = 0.852) and low insomnia (p = 0.982) subgroups. Analyses revealed no significant differences between treatments in the percentages of patients with substantial worsening, any worsening, worsening at endpoint, or improvement at endpoint in the HAM-D sleep disturbance factor in either insomnia subgroup. Treatments were well tolerated in most patients. No significant differences between treatments in the incidence of AEs suggestive of activation or sedation were seen in the insomnia subgroups. These data show no significant differences in acute treatment efficacy and tolerability across fluoxetine, sertraline, and paroxetine in major depressive disorder patients. Improvement in overall depression and in associated insomnia was achieved by most patients regardless of baseline insomnia.

-----

Br J Clin Pharmacol. 2002 Feb;53(2):196-202.
Noise-induced sleep maintenance insomnia: hypnotic and residual effects of zaleplon.
Stone BM, Turner C, Mills SL, Paty I, Patat A, Darwish M, Danjou P.
QinetiQ Ltd, Centre for Human Sciences, Farnborough, Hampshire, GU14 0LX, UK. bmstone@QinetiQ.com

AIMS: The primary objective of the study was to assess the residual effects of zaleplon in the morning, 4 h after a middle-of-the-night administration. The secondary objective was to investigate the effectiveness of zaleplon in promoting sleep in healthy volunteers with noise-induced sleep maintenance insomnia. METHODS: Thirteen healthy male and female volunteers (aged 20-30 years) with normal hearing, who were sensitive to the sleep-disrupting effects of noise, participated in a double-blind, placebo- and active-drug controlled, four-period cross-over study. The subjects were permitted to sleep for 5 h (22.45-03.45 h) in a quiet environment before they were awoken. At 04.00 h they ingested 10 mg zaleplon, 20 mg zaleplon, 7.5 mg zopiclone (active control), or placebo before a second period of sleep (04.00-08.00 h), during which they were exposed to an 80 dB(A) 1 kHz pure tone pulse with an inter-tone interval of 1 s and a duration of 50 ms. The sound stimulus was stopped after 10 min of persistent sleep or after 2 h if the subject had not fallen asleep. Residual effects were assessed at 08.00 h (4 h after drug administration) using the digit symbol substitution test (DSST), choice reaction time (CRT), critical flicker fusion (CFF), and immediate and delayed free recall of a 20 word list. The data were analysed by analysis of variance. A Bonferroni adjustment was made for the three active treatments compared with placebo. RESULTS: There were no residual effects of zaleplon (10 and 20 mg) compared with placebo. Zopiclone impaired memory by delaying the free recall of words (P = 0.001) and attenuated performance on DSST (P = 0.004) and CRT (P = 0.001), compared with placebo. Zaleplon reduced the latency to persistent sleep (10 mg, P = 0.001; 20 mg, P = 0.014) and the 20 mg dose reduced stage 1 sleep (P = 0.012) compared with placebo. Zopiclone reduced stage 1 sleep (P = 0.001), increased stage 3 sleep (P = 0.0001) and increased total sleep time (P = 0.003), compared with placebo. CONCLUSIONS: Zaleplon (10 mg and 20 mg), administered in the middle of the night 4 h before arising, shortens sleep onset without impairing next-day performance.

-----

Nippon Yakurigaku Zasshi. 2002 Feb;119(2):111-8.
[Pharmacological profile and clinical effect of zolpidem (Myslee tablets), a hypnotic agent]
[Article in Japanese]
Shirakawa K.
Fujisawa Pharmaceutical Co. Ltd., 4-7, Doshomachi 3-chome, Chuo-ku, Osaka 541-8514, Japan. kiyoharu_shirakawa@po.fujisawa.co.jp

Zolpidem is a non-benzodiazepine hypnotic agent with a chemical structure of imidazopyridine. In vitro and in vivo binding studies, zolpidem exhibits selectivity to omega 1 receptors (GABAA-receptor subtypes containing alpha 1 subunits). Unlike benzodiazepines, zolpidem produces sedative effects in preference to anxiolytic, anticonvulsant and myorelaxant effects in behavioral experiments using mice. Double-blind comparative studies with reference drugs such as triazolam and zopiclone show that zolpidem is an effective and highly safe drug for the treatment of insomnia. In addition, zolpidem does not produce next-day residual effects, rebound insomnia and tolerance. This clinical profile of zolpidem may be related to its selectivity and high intrinsic activity for omega 1 receptors.

-----

Int Clin Psychopharmacol. 2002 Jan;17(1):9-17.
Continuous versus non-nightly use of zolpidem in chronic insomnia: results of a large-scale, double-blind, randomized, outpatient study.
Hajak G, Cluydts R, Declerck A, Estivill SE, Middleton A, Sonka K, Unden M.
Department of Psychiatry and Psychotherapy, University of Regensburg, Germany. goeran.hajak@bkr-regensburg.de

New treatment strategies are encouraged in insomnia and, in particular, discontinuous treatment. The aim of this double-blind study was to compare, in a large primary care population of chronic insomniacs (> 4 weeks duration) the efficacy and safety of zolpidem 10 mg 5 nights/week and placebo 2 nights/week, to that of nightly zolpidem. Seven hundred and eighty-nine drug-free insomniacs, with a Total Sleep Time (TST) of 3-6 h/night were enrolled in seven European countries. After a placebo run-in period, treatment lasted 14 days. The primary criterion was the Clinical Global Impression improvement score (CGI-II) which showed that 65.2% of patients in the continuous and 58.6% in the discontinuous groups were rated 'much' or 'very much' improved. Even though the non-inferiority test did not show the equivalence of both regimens, the difference of 7% in responder rates does not appear to be clinically relevant. Other sleep parameters such as TST, number of nocturnal awakenings and Quality of Life scales showed marked, not significantly different, improvements in both groups. Both regimens were well tolerated and no adverse event which could be related to non-treatment nights was reported in the discontinuous group. Non-nightly zolpidem appears to be a feasible and safe additional option for the management of chronic insomnia.

The Insomnia FileSM Compiled and Maintained by    The Center for Current Research, Inc. 708 Aubrey Avenue • Ardmore PA USA 19003 Phone: 610-649-3165 Email: customerservice@lifestages.com Website: www.lifestages.com

©Copyright 1992-date by The Center for Current Research. The Insomnia File is a proprietary compilation of the Center for Current Research. The information in the File is solely for your use, and the use of your family, friends, and doctors. The information is the property of the individual researchers and institutions that produced it. It is an infringement of copyright law to attempt to "resell" the information as it is presented here.