Pharmacological interventions for insomnia disorder in adults

A meta-analysis published in 2022 by Franco de Crescenzo and colleagues1De Crescenzo F D'Alò GL Ostinelli EG et al.Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis.Lancet. 2022; 400: 170-184Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar suggested poor efficacy of pharmacotherapeutics in the treatment of insomnia disorder, which sits contrary to the outcomes of earlier meta-analyses. Despite such striking findings from transparent and rigorous methodology, there are multiple clinical scenarios and nuances in the pharmacotherapeutic treatment of sleep disorders that should also be considered. At a basic level, there can be a logically precarious assumption that patients' responses to a given intervention are homogeneous, yet insomnia is phenomenologically diverse, with phenotypes that might require different treatment approaches. For example, patients classified according to the short sleep phenotype, a severe phenotype characterised by insomnia with objective short sleep duration, respond poorly to cognitive behavioural therapy (CBT) for insomnia, which is the gold standard non-pharmacological therapeutic that is highly effective for many patients with insomnia who do not share this specific phenotype. However, trials comparing trazadone and CBT for insomnia in objective short sleepers concluded that only trazadone, and not CBT for insomnia, was effective at increasing total sleep time in this population.2Vgontzas AN Puzino K Fernandez-Mendoza J Krishnamurthy VB Basta M Bixler EO Effects of trazodone versus cognitive behavioral therapy in the insomnia with short sleep duration phenotype: a preliminary study.J Clin Sleep Med. 2020; 16: 2009-2019Crossref PubMed Scopus (32) Google Scholar Insomnia has consistently high rates of co-occurrence among medical and psychiatric disorders. Although the meta-analysis used secondary insomnia as an exclusion criterion, the third edition of the International Classification of Sleep Disorders and the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders no longer recognise secondary insomnia, instead classifying all cases, irrespective of comorbidity, as insomnia disorder. This distinction is clinically important because comorbid insomnia often necessitates pharmacological interventions, due to the poor efficacy of non-pharmacological alternatives. Many clinicians might interpret such findings as universal superiority of CBT for insomnia over pharmacotherapy; however, adherence to CBT for insomnia activities (eg, maintaining strict waking times) relies on intact self-efficacy and motivation, which is often not possible for people with psychiatric disorders such as depressive disorders and substance use disorders. Patients with insomnia who rate low in measures of self-efficacy and high in perceptions of boredom or irritation from CBT for insomnia report worse outcomes than patients who rate high in measures of self-efficacy and low in perceptions of boredom or irritation from CBT for insomnia.3Mitchell MD Gehrman P Perlis M Umscheid CA Comparative effectiveness of cognitive behavioral therapy for insomnia: a systematic review.BMC Fam Pract. 2012; 13: 40Crossref PubMed Scopus (350) Google Scholar Drop-out rates in CBT for insomnia trials for people with major depressive disorder have been as high as 64%,4Cheng P Kalmbach DA Tallent G Joseph CL Espie CA Drake CL Depression prevention via digital cognitive behavioral therapy for insomnia: a randomized controlled trial.Sleep. 2019; 42zsz150Crossref Scopus (84) Google Scholar and 50% of patients with post-traumatic stress disorder-associated insomnia still exhibited symptoms following a standardised course of CBT for insomnia.5Zayfert C DeViva JC Residual insomnia following cognitive behavioral therapy for PTSD.J Trauma Stress. 2004; 17: 69-73Crossref PubMed Scopus (258) Google Scholar Furthermore, in a study published in 20226Huhn AS Finan PH Gamaldo CE et al.Suvorexant ameliorated sleep disturbance, opioid withdrawal, and craving during a buprenorphine taper.Sci Transl Med. 2022; 14eabn8238Crossref PubMed Scopus (15) Google Scholar of patients with opioid use disorder undergoing medically supervised withdrawal (published after the meta-analysis was conducted), the dual orexin receptor antagonist suvorexant showed large improvements in subjective total sleep times (76·6% increase), objective total sleep times, and opioid cravings.6Huhn AS Finan PH Gamaldo CE et al.Suvorexant ameliorated sleep disturbance, opioid withdrawal, and craving during a buprenorphine taper.Sci Transl Med. 2022; 14eabn8238Crossref PubMed Scopus (15) Google Scholar Indeed, de Crescenzo and colleagues acknowledge the challenges associated with prescribing opioids in combination with hypnotic agents in their Discussion,1De Crescenzo F D'Alò GL Ostinelli EG et al.Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis.Lancet. 2022; 400: 170-184Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar and such interventions could offer viable alternatives in this population. We encourage clinicians to consider the cases presented here, in which the efficacy of insomnia treatments might be optimally evaluated in study designs that allow for nuance and analysis across multiple levels (eg, biological and behavioural phenotypes). MJR has received research funding from the British Sleep Society. ASH has received research grant funding from The National Institutes of Health and Ashley Addiction Treatment. PHF has received research grant support from the National Institutes of Health. Pharmacological interventions for insomnia disorder in adults – Authors' replyWe thank Matthew J Reid and colleagues for commenting on our systematic review and network meta-analysis.1 Although the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders does not use the term secondary insomnia, the criteria for insomnia disorder are more nuanced than Reid and colleagues suggest. For example, the diagnosis is excluded if a coexisting mental disorder can "adequately explain the predominant complaint of insomnia", which is not always an easy judgement. We agree, however, that the presence of genuine comorbidity is important because, as Reid and colleagues point out, it could have implications for the utility of cognitive behavioural therapy for insomnia versus pharmacotherapy, and thereby aid individual treatment decision making. Full-Text PDF