Meta-analysis shows benzodiazepine receptor PAMs improve sleep but increase long-term COPD risks in patients with insomnia

ObjectiveGiven the high prevalence and clinical significance of insomnia in COPD patients, and the ongoing controversy surrounding benzodiazepine receptor positive allosteric modulators (PAMs) therapy, this study systematically evaluates the dual-temporal (short- and long-term) safety profile of PAMs through simultaneous assessment of therapeutic benefits and multidimensional risks in COPD-insomnia comorbidity.MethodsA systematic review and meta-analysis was conducted following the PRISMA guidelines. Systematic literature searches were performed in the target databases. The primary indicators for short-term efficacy and safety assessment comprised total sleep time (TST), number of awakenings, sleep efficiency, partial pressure of oxygen (PaO2), oxygen saturation (SaO2), FEV1, and frequency of apnea events. All-cause mortality and Emergency department, Outpatient, and Hospitalization for acute exacerbations of COPD (AECOPD) were employed as indicators for long-term efficacy and safety.ResultsIn COPD patients, PAMs demonstrated significant short-term benefits, with notable improvements in TST (p < 0.00001), frequency of awakenings (p = 0.005), and sleep efficiency (p < 0.00001). Compared with placebo, PAMs did not increase short-term risks in terms of FEV1 (p = 0.59), SaO2 (p = 0.61), and frequency of apnea events (p = 0.45); however, they induced a slight reduction in PaO2 (p = 0.008) during sleep. Notably, long-term use of PAMs was associated with a significant increase in adverse respiratory outcomes, including higher mortality (OR = 1.58, 95% CI: 0.95–2.61, p = 0.08), and elevated frequency of emergency department visits (OR = 1.97, 95% CI: 1.76–2.19, p < 0.00001), outpatient consultations (OR = 2.07, 95% CI: 1.51–2.82, p < 0.00001), and hospitalizations (OR = 1.94, 95% CI: 1.07–3.52, p = 0.03) due to AECOPD.ConclusionIn patients with COPD and comorbid insomnia, the short-term use of PAMs demonstrates therapeutic potential for improving sleep quality and enhancing quality of life, while not imposing additional respiratory burden. However, prolonged administration may potentially accelerate COPD disease progression. Clinical decisions regarding PAMs therapy for COPD patients with insomnia should be made cautiously after thorough evaluation of short-term benefits versus long-term risks.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/recorddashboard, identifier CRD420251035164.