Pharmacologic Treatment of Insomnia Disorder: An Evidence Report for a Clinical Practice Guideline by the American College of Physicians

Sleep problems are common and associated with a decline in overall and sleep-related health (13). Insomnia is more common in women and older adults (4). Aging is often accompanied by disrupted sleep and frequent and early waking (5, 6). Other conditions coexist with, are due to, or lead to poor sleep (7). Insomnia symptoms are typically transient and may not cause distress or impaired activity. However, insomnia disorder as defined by the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, requires sleep problems that are chronic, persistent, and associated with daytime dysfunction. Insomnia disorder includes a predominant symptom of difficulty with sleep initiation, difficulty maintaining sleep, or early-morning waking with inability to return to sleep causing clinically significant distress or impairment in activities, occurring at least 3 nights per week. Current definitions require insomnia symptoms to have persisted for 3 months or more (8). Individuals must have adequate opportunity for sleep, and symptoms must not be better explained by another sleep disorder, effects of a substance, or other medical or mental conditions. Treatment goals include meaningful improvements in sleep-associated distress or dysfunction (global outcomes). The Insomnia Severity Index (ISI) and the Pittsburgh Sleep Quality Index measure both problems and worry about sleep and accompanying distress or dysfunction. Sleep measures are based on specific sleep variables that can be assessed in a sleep laboratory with polysomnography or actigraphy or subjectively with patient-reported sleep diaries. These include sleep-onset latency (SOL), wake after sleep onset (WASO), total sleep time (TST), and sleep efficiency (percentage of time in bed sleeping). In general, insomnia disorder is treated by clinicians on the basis of patient-reported sleep-associated distress, not laboratory assessment. Additionally, polysomnography is not indicated for the diagnosis or treatment of insomnia disorder (9). Prescription medications are often used. Several are approved for insomnia, typically for short-term use, by the U.S. Food and Drug Administration (FDA). Although medication indications often focus on specific sleep variables, it is not known how frequently primary care physicians target medications to specific or global measures of insomnia or prescribe them long term. We evaluated the efficacy, comparative effectiveness, and harms of pharmacologic interventions for insomnia disorder. An accompanying article assesses psychological and behavioral interventions (10). These articles summarize findings from a report conducted by the Agency for Healthcare Research and Quality/Minnesota Evidence-based Practice Center (11). The work served, in part, as the evidence base for an American College of Physicians' clinical practice guideline. Methods We developed and followed a standard protocol. The protocol was registered at www.crd. york.ac. uk/PROSPERO/ (registration number: CRD42014009908) in May 2014 and published at http://effectivehealthcare.ahrq. gov/index.cfm/search-for-guides-reviews-and-reports/? pageaction=displayproduct&productid=1888. Full details of the findings and evidence tables are available in the report (11). Data Sources and Searches We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and PSYCinfo from 2004 through September 2015 for relevant English-language literature (Table 1 of the Supplement), reference lists of pertinent studies, FDA Web sites and product labels, and ClinicalTrials.gov. Supplement. Data Supplement Study Selection Two investigators independently reviewed titles and abstracts of search results and screened the full text of potentially eligible English-language references. We included randomized, controlled trials (RCTs) of pharmacologic therapies available in the United States, regardless of the comparator (placebo, another medication, nonpharmacologic therapy), if they enrolled adults with insomnia disorder, provided at least 4 weeks of follow-up, and reported global or sleep outcomes. We excluded from analysis studies deemed to have high risk of bias. We included observational studies that reported harms if 1) the population included 100 or more adults with chronic insomnia without other major diagnoses, such as cancer and Parkinson disease; 2) the pharmacologic agents evaluated were FDA-indicated for insomnia and probably administered for sleep disorders; 3) study duration was at least 6 months; and 4) harms were reported by drug class. We also examined harms reported in the following: eligible trials; FDA Web sites for nonbenzodiazepine hypnotics, eszopiclone, zaleplon, zolpidem, and the orexin receptor antagonist suvorexant; FDA product labels for all pharmacologic therapies; and systematic reviews. Data Extraction and Quality Assessment One investigator extracted study data, which was independently checked by a second investigator. Our main outcome of interest was patient-reported global measure of effectiveness: improvement in sleep variables and daytime functioning and distress. The 7-item ISI (score range, 0 to 28) or the 7-component, 19-item Pittsburgh Sleep Quality Index (score range, 0 to 21) were commonly used instruments measuring both problems and worry about sleep and accompanying distress or dysfunction (Table 2 of the Supplement). We also assessed sleep-specific parameters on the basis of patient-recorded sleep diaries, including SOL, TST, WASO, sleep efficiency, sleep quality, function, mood, and quality of life. Risk of bias for RCTs was independently assessed by 2 investigators using an instrument developed for this project (12). We classified overall risk of bias for each study as low, moderate, or high according to a summary of bias risk across domains and confidence that the results were believable given the study's limitations. We excluded studies with high risk of bias from analysis. Data Synthesis and Analysis We grouped studies and rated strength of evidence by drug. Evidence ratings within each comparison were determined as high, moderate, low, or insufficient (13) by at least 2 trained research associates and the principal investigator; final determinations were ascertained through consensus. For assessments of efficacy, we used established minimum important differences for main outcomes if they were available and statistical significance alone if minimum important differences were not established. We pooled results for doses approved by the FDA if more than 1 study assessed that dose, used a similar comparator (such as placebo), involved a similar study population (for example, elderly patients), and assessed similar outcomes (such as the same sleep variable). Data were analyzed in RevMan 5.3 (Nordic Cochrane Center). DerSimonian and Laird random-effects models were used to calculate pooled risk ratios and absolute risk differences with 95% CIs for categorical outcomes. Weighted mean differences or standardized mean differences with 95% CIs were calculated for continuous outcomes. We assessed statistical heterogeneity with the Cochran Q test and measured magnitude with the I 2 statistic (I 2> 75% indicates substantial heterogeneity) (14). We searched several databases to identify and reduce potential publication bias. Role of Funding Source This review was nominated to the Agency for Healthcare Research and Quality Effective Healthcare Program by an anonymous individual and funded by the Agency for Healthcare Research and Quality. Agency staff and key informants representing various perspectives offered suggestions as we developed and refined the scope of the review. A technical expert panel provided input to the protocol and reviewed the draft report. The American College of Physicians provided support for manuscript preparation. The authors are solely responsible for its content. Results Search results are shown in the Appendix Figure. Thirty-five RCTs with acceptable risk of bias evaluated pharmacologic treatments (1546) (Figure). Six were in older adults (4247). We did not find evidence of publication bias in a search of ClinicalTrials.gov through September 2015. Eleven observational studies provided data for long-term harms (4858). Drug doses used in older adults were lower than those used in general populations. Few antidepressant or benzodiazepine trials met inclusion criteria, primarily because of short treatment durations. Patients were typically diagnosed with insomnia disorder according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria, which require symptoms to be present for at least 1 month (current criteria require symptoms for at least 3 months). Appendix Figure. Evidence search and selection. Intervention type totals do not equal total references because several trials were used in the analysis for 2 different types of interventions. RCT= randomized, controlled trial. Figure. Network of pharmacologic treatments for chronic insomnia disorder. The k values refer to number of studies. CBT= cognitive behavioral therapy. The mean symptom duration was rarely reported. Additional enrollment criteria were based on thresholds for SOL, TST, WASO, or number of awakenings per night during a typical night in the month before enrollment. Only 2 trials based enrollment on, or provided baseline scores of, global measures. Most required TST of 6.5 hours or less or SOL of greater than 30 minutes. When WASO was included, thresholds ranged from 30 to 120 minutes. Common exclusion criteria included psychiatric disorders or substance abuse (Tables 3 and 4 of the Supplement). Trials rarely assessed treatments for longer than 4 weeks. Most participants were women, white, and younger than 50 years. Most studies were industry-sponsored. Doses used in some trials exceeded FDA recommended doses, especially for women and older or debilitated adults (Tables 1 and 2). Table 1. Nonbenzodiazepin