Gilda Boroumand, MS4
Faculty Peer Reviewed
Chronic insomnia, defined as difficulty with the initiation, maintenance, duration, and quality of sleep for at least one month, is a common complaint with significant impact on an individual’s daytime functioning and quality of life. It is particularly prevalent in the elderly, affecting between 23% to 34% of individuals over the age of 64.[1] This same group is also more likely to experience adverse effects from various treatment regimens, thus leaving physicians with the task of weighing possible benefits against the risk of side effects. This is a difficult task, for the assessment of treatment efficacy is complicated by insomnia’s overlap with medical and psychiatric conditions, lack of consistency in diagnostic criteria, variation in methods used to assess treatments, and paucity of long-term follow-up in clinical trials.
Patients often turn to nonprescription antihistamines marketed as sleep aids for initial treatment of insomnia. Physicians, too, commonly prescribe such medications for their sedative-hypnotic effects. The 2005 NIH State of the Science Conference cautioned, however, that there is no systematic evidence for their efficacy despite their widespread use.[2,3] A randomized, controlled trial of the histamine-1 antagonist diphenhydramine demonstrated modest improvement of subjective sleep, but its conclusions are limited by a small number of subjects and short duration of treatment (fourteen days).[4] Moreover, the risks of antihistamine use are numerous and significant. A prospective cohort study of over 1600 elderly subjects with 10-year follow-up showed that extended use of diphenhydramine was associated with impairment on the Mini Mental Status Examination (individuals with dementia were excluded from analysis).[5] Indeed, expert consensus reports have advised against the use of diphenhydramine in the elderly due to its significant anticholinergic side effects, daytime sedation, and cognitive impairment noted in multiple clinical trials.[6,7]
Other frequently used medications include FDA-approved benzodiazepines and the newer nonbenzodiazepines, also known as benzodiazepine receptor agonists: zaleplon (Sonata), zolpidem (Ambien), and eszopiclone (Lunesta). The use of benzodiazepines for insomnia in the elderly is controversial given the uncertainty regarding their risk-to-benefit ratio. The efficacy of benzodiazepines in improving sleep latency, sleep maintenance, and total sleep duration was initially demonstrated by a meta-analysis performed in 1997, but more recent work by Holbrook et al. supports only a benefit in sleep duration (by approximately 60 minutes), with no difference in outcome when compared with antihistamines.[8,9] This benefit is countered by a number of adverse effects, including memory, cognitive function, psychomotor impairment, daytime drowsiness, and an increased risk of falling.[4] Additionally, benzodiazepines are only approved for short-term treatment of insomnia and the vast majority of studies evaluating their efficacy provide only two-week follow-up. Certainly their benefits cannot be expected to persist long after discontinuation.
The general consensus among researchers thus appears to favor nonbenzodiazepine agents for their relatively brief half-life and superior side-effect profile, though these, too, are riddled with problems. As compared to the benzodiazepines, longer clinical trials have been performed with the nonbenzodiazepines, with improved subjective sleep demonstrated after six months of treatment with zolpidem and eszopiclone.[10,11] Nonetheless, a 2005 meta-analysis of sedative hypnotics in elderly patients challenges the prevalent belief that nonbenzodiazepines have fewer adverse effects. A review of six studies comparing the two drug classes reported little difference in the number of adverse events and, specifically, no significant difference in cognitive or psychomotor adverse events.[12] Furthermore, the number needed to treat for improved sleep quality was 13 whereas the number needed to harm for any adverse event was 6. Though only a rough indicator, this ratio suggests that sedative medications may not benefit the elderly to the same degree as other adults. The common occurrence of adverse events in the elderly may not justify the subjectively improved sleep quality and increase of approximately 25 minutes in total sleep duration.
The armamentarium of pharmacologic treatments for insomnia includes one agent that does not appear to be associated with hypnotic side effects – but is of rather limited value. Ramelteon (Rozarem), a recently-approved melatonin receptor agonist, is said to provide its greatest benefit to patients with sleep-onset insomnia. One of the first randomized trials to test its efficacy demonstrated a subjective decrease of 10 to 15 minutes in sleep latency and increase of 10 to 15 minutes in total sleep time. [13] Similar results have been reported in studies of elderly patients.[14] Ramelteon is much better tolerated than hypnotic medications, with its side effects of headache, somnolence, and sore throat occurring in less than 1% of patients. Though safe, its gain of a mere 10 to 15 minutes of sleep can hardly be considered ground-breaking.
Surprisingly (or perhaps predictably), behavioral therapies may provide the best results for the treatment of insomnia. Cognitive behavioral therapy (CBT) has been shown to be the most effective. It combines multiple behavioral approaches, usually incorporating stimulus control (which reestablishes the bed as the space where sleep occurs), sleep restriction (which works to increase sleep time by inducing temporary sleep deprivation by reducing time in bed), relaxation therapies (predicated on the idea that insomnia is associated with hyperarousal), and a cognitive component that educates the patient about sleep needs and corrects unrealistic expectations.[15] Several trials have demonstrated the efficacy of CBT in older adults. [16]Moreover, a randomized, controlled trial of elderly patients showed that CBT provided greater benefit than a benzodiazepine, with a sustained therapeutic effect at two-year follow-up.[17] Combined CBT and pharmacotherapy were most efficacious in this study, but this result is challenged by a subsequent trial in which combined therapy provided no advantage over CBT alone, with benzodiazepines producing only moderate benefits during drug administration, with return to baseline after their discontinuation.[18] Researchers in this study concluded that perhaps patients are less committed to learning and practicing CBT if they know they can “control” their insomnia with medications. Of note, although CBT has been administered by psychologists in most studies, successful results have also been reported when therapy was delivered by primary care physicians who received brief training.[19] Perhaps the widespread use of CBT is a possibility for future therapy.
Despite modest treatment efficacy and significant risks of adverse effects, particularly in the elderly population, pharmacotherapy remains the most frequently recommended intervention for insomnia. Long-term use of medications is contraindicated, as remarkably little is known about the effects on sleep, daytime functioning, and quality of life beyond two-week follow-up, but drugs continue to be overused. Behavioral therapies currently hold the greatest promise for the treatment of insomnia, but these techniques have yet to be adopted by primary care physicians. Large-scale, long-term comparative studies of over-the-counter medications, hypnotics, behavioral therapy, and other remedies would be valuable in gaining a clearer understanding of the treatment of insomnia in elderly adults.
Ms. Boroumand is a 4th year medical student at NYU School of Medicine.
Peer reviewed and commentary by Dr. David Sutin, Associate Professor, NYU Division of General Internal Medicine
I strongly agree with trying behavioral therapy before medications and avoiding anti-histamines. Psychiatric and medical conditions, medications, and primary sleep disorders all need to be evaluated and their contribution to the sleep problem assessed. In the elderly person, any presenting symptom often has many etiologies, and the more that are identified and addressed, the better the outcome. The patient with coexisting depression might well benefit from a sedating antidepressant such as trazodone or mirtazapine. Sleep apnea is found in 24-40% of elderly people; interestingly, less oxygen desaturation occurs with the apneic episodes. The presence of sleep apnea is obviously a contraindication to use of many sedatives.
References:
1. Foley DJ, Monjan AA, Brown SL, Simonsick EM, Wallace RB, Blazer DG. Sleep complaints among elderly persons: an epidemiologic study of three communities. Sleep. 1995;18:425-432.
2. National Institutes of Health State of the Science Conference Statement on Manifestations and Management of Chronic Insomnia in Adults. Sleep. 2005;28:1049-1057
3. Bloom HG, Ahmed I, Alessi CA, et al. Evidence-based recommendations for the assessment and management of sleep disorders in older persons. J Am Geriatr Soc. 2009;57:761-789.
4. Morin CM, Koetter U, Bastien C, Ware JC, Wooten V. Valerian-hops combination and diphenhydramine for treating insomnia: a randomized placebo-controlled clinical trial. Sleep 2005;28:1465-1471.
5. Basu R, Dodge H, Stoehr GP, Ganguli M. Sedative-hypnotic use of diphenhydramine in a rural, older adult, community-based cohort: effects on cognition. Am J Geriatr Psychiatry. 2003;11:205-213.
6. Beers, MH. Explicit criteria for determining potentially inappropriate medication use by the elderly: an update. Arch Intern Med. 1997;157:1531-1536.
7. Wolkove N, Elkholy O, Baltzan M, Palayew M. Sleep and aging: 2. Management of sleep disorders in older people. CMAJ. 2007;176:1449-1454.
8. Nowell PD, Mazumdar S, Buysse DJ, Dew MA, Reynolds CF 3rd, Kupfer DJ. Benzodiazepines and zolpidem for chronic insomnia: a meta-analysis of treatment efficacy. JAMA. 1997;278:2170-2177.
9. Holbrook AM, Crowther R, Lotter A, Cheng C, King D. Meta-analysis of benzodiazepine use in the treatment of insomnia. CMAJ. 2000;162:225-233.
10. Walsh JK, Krystal AD, Amato DA, et al. Nightly treatment of primary insomnia with eszopiclone for six months: effect on sleep, quality of life, and work limitations. Sleep. 2007; 30:959-968.
11. Krystal AD, Erman M, Zammit GK, Soubrane C, Roth T; ZOLONG Study Group. Long-term efficacy and safety of zolpidem extended-release 12.5 mg, administered 3 to 7 nights per week for 24 weeks, in patients with chronic primary insomnia: a 6-month, randomized, double-blind, placebo-controlled, parallel-group, multicenter study. Sleep. 2008;31:79-90.
12. Glass J, Lanctot KL, Herrmann N, Sproule BA, Busto UE. Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ. 2005;331:1169.
13. Erman M, Seiden D, Zammit G, Sainati S, Zhang J. An efficacy, safety, and dose-response study of Ramelteon in patients with chronic primary insomnia. Sleep Med. 2006;7:17-24.
14. Mini LJ, Wang-Weigand S, Zhang J. Self-reported efficacy and tolerability of ramelteon 8 mg in older adults experiencing severe sleep-onset difficulty. Am J Geriatr Pharmacother. 2007;5:177-184.
15. Silber, MH. Clinical practice. Chronic insomnia. N Engl J Med. 2005;353:803-810.
16. Morin CM, Bootzin PR, Buysse DJ, Edinger JD, Espie CA, Lichstein KL. Psychological and behavioral treatment of insomnia: update of the recent evidence (1998-2004). Sleep. 2006;29:1398-1414.
17. Morin CM, Colecchi C, Stone J, Sood R, Brink D. Behavioral and pharmacological therapies for late-life insomnia: a randomized controlled trial. JAMA. 1999;281:991-999.
18. Jacobs GD, Pace-Schott EF, Stickgold R, Otto MW. Cognitive behavior therapy and pharmacotherapy for insomnia: a randomized controlled trial and direct comparison. Arch Intern Med. 2004;164:1888-1896.
19. Baillargeon L, Demers M, Ladouceur R. Stimulus-control: nonpharmacologic treatment for insomnia. Can Fam Physician. 1998;44:73-79.