Chronic Insomnia: Comparison of Non-Pharmacological & Pharmacological Treatment Approaches

Chronic Insomnia: Comparison of Non-Pharmacological & Pharmacological Treatment Approaches
Mikaela Leifeld, PharmD
M Health Fairview

Background: Insomnia disorder is characterized by dissatisfaction with sleep quantity or quality related to difficulty initiating (sleep onset) or maintaining sleep (sleep maintenance), which results in associated daytime impairments. Insomnia is a highly prevalent sleep disorder with an estimated impact on 12 to 20% of the general population and is commonly encountered in clinical practice. Chronic insomnia is when sleep difficulties persist for three or more months with a frequency of three or more episodes per week. Uncontrolled chronic insomnia is associated with decreased quality of life; increased risk for depression, anxiety and substance use disorders; and elevated risk for cardiovascular disease and metabolic syndrome. General management measures include treatment of comorbid medical and psychiatric conditions, adjustment of sleep-interfering medications, and modification of behavioral and cognitive factors that may perpetuate insomnia. Despite its prevalence and the availability of approved pharmacotherapy options, a general consensus regarding the optimal approach to treatment of insomnia is lacking. The 2021 American Academy of Sleep Medicine (AASM) Guidelines recommend multicomponent cognitive behavioral therapy for insomnia (CBT-I) as first-line therapy for chronic insomnia. However, factors including lack of trained providers, cost of upfront treatment, delayed symptom relief, and ability and motivation to adhere to treatment recommendations limit its use in practice. Although both non-pharmacological and pharmacological treatment options are available, medications are more frequently used in practice and present safety concerns with significant risks for adverse events. More recently, a novel class of agents, dual orexin receptor antagonists (DORAs), have been brought to market. These agents promote sleep by antagonizing orexin receptors responsible for excitatory responses and the release of neurotransmitters involved in arousal, wakefulness, and appetite. Suvorexant, lemborexant, and daridorexant have been FDA approved for the treatment of insomnia based on phase III randomized controlled trials. However, the clinical application of these agents have not yet been fully recognized. Moreover, optimizing the treatment of insomnia disorder is further complicated by the lack of evidence to support long-term use and the comparative effectiveness of pharmacological agents. 

Evidence: The 2017 AASM Clinical Practice Guidelines recommend CBT-I as a primary intervention in patients with chronic insomnia and limiting the use of medications for patients who are unable to receive CBT-I, have persistent symptoms despite such treatments, or are in need of a temporary adjunct to CBT-I. The therapies applied for CBT-I go beyond traditional sleep hygiene techniques. CBTI-I combines multiple cognitive and behavioral therapy strategies with sleep education to identify and address feelings and behaviors that contribute to sleep disruption. Compared to pharmacological interventions, CBT-I has demonstrated both non-inferior and superior effects in treating chronic insomnia, fewer safety risks, and treatment gains that are potentially durable long-term. However, despite the data, medications continue to be more commonly and inappropriately prescribed in practice. Physicians increasingly prescribe sedating antidepressants, antipsychotics and analgesics “off-label” (i.e., trazodone) despite the lack of evidence to support their effectiveness. Previous meta-analyses of benzodiazepines (BZDs) and non-benzodiazepines (non-BZDs), suggest small to moderate effect sizes for sleep outcomes with significant increases in adverse events, calling into question their relative risk-benefit ratio. A recent systematic review and network meta-analysis from Crescenzo et al. aimed to assess the comparative effects of pharmacological agents for the acute and long-term treatment of insomnia disorder. Provided the basis of evidence for approved insomnia medications are primarily short-term placebo-controlled trials, pharmacotherapies are recommended only for the acute management of insomnia disorder. Crescenzo et al. concluded that, overall, eszopiclone and lemborexant were favorable in terms of long-term effects on sleep quality (>3 months); however, eszopiclone may cause substantial adverse events and safety data available for lemborexant were inconclusive. Comparatively, Zheng et al. established a data-driven pharmacodynamic model to estimate drug efficacy at different time points. Predicted drug efficacy at 24 weeks showed eszopiclone had the greatest reduction in sleep onset latency (SOL) of -16 minutes and increase in total sleep time (TST) of +34 minutes. Suvorexant had the greatest reduction in wake after sleep onset (WASO), a measure of time spent awake from when one falls asleep until awakening in the morning, of -27 minutes. Notably, eszopiclone had smaller effects on WASO reduction of -17 minutes and suvorexant had smaller effects on TST improvements of +20 minutes. Ramelteon was only associated with improvements in SOL of -28 minutes. Low-dose doxepin demonstrated greater reductions in WASO of -37 minutes and increased TST by +62 minutes. The findings of this and other studies call out the need for selection of treatment based on predominant sleep onset versus sleep maintenance symptoms, as well as future studies to examine comparative efficacy and long-term safety of sleep medications. 

Discussion & Clinical Impact: Given the findings of Crescenzo et al., numerous approved medications can be effective for short-term treatment of insomnia, but data to support long-term treatment is limited and inconsistent. Additionally, further randomized-controlled trials that directly compare the effectiveness and safety of sleep medications are needed to better guide the role of pharmacological agents in the treatment of chronic insomnia. The general approach to the treatment of chronic insomnia observed across the literature and guidelines reviewed has been interpreted and outlined below. The table below demonstrates a simplified stepwise approach that may be applied in clinical practice. 

Stepwise Treatment Approach for Chronic Insomnia

(1) Determine appropriateness of CBT-I and other non-pharmacological interventions

Consider: cost, access, ability & motivation to adhere, severity of symptoms & distress 

(2) Evaluate & modify contributing factors when able

Consider: sleep-interfering medications, medical & psychiatric conditions, behavioral & cognitive factors

(3) Risk vs benefit discussion of treatment options

Consider: goals of therapy (reduce daytime impairment, improve quality of life), risk of adverse events (increased in older adults), realistic expectations for efficacy 

(4) Consider appropriateness of melatonin supplement trial 

Consider: primary effect sleep onset, utility in circadian rhythm-based sleep disorders, administration time (1-2 hours vs 30-60 minutes before bedtime), minimal associated risks, quality of supplement

(5) Select agent based on predominant symptoms of sleep onset vs sleep maintenance or mixed 

Consider: age, drug-drug and drug-disease interactions, cost, side effects, previous treatment responses, patient preference

(5a) Sleep onset 

(5b) Sleep maintenance or mixed 

Ramelteon, or

Non-BZD: eszopiclone, zaleplon, zolpidem

DORA: lemborexant, suvorexant, daridorexant, or

Low-dose doxepin, or

Non-BZD: eszopiclone, zolpidem 

(6) Determine plan for monitoring & follow-up 

Consider: (i) effectiveness, (ii) adverse effects, (iii) need for continuation of therapy

(7) Consider future trial off therapy with slow taper 

  • Taper does not result in recurrence of symptoms → discontinue therapy & avoid restarting
  • Taper results in recurrence of symptoms → consider quality of life & option to resume treatment


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