Low-dose amitriptyline versus cognitive behavioral therapy for insomnia in patients with medical comorbidity: results of a randomized controlled multicenter non-inferiority trial

Study objectives In a randomized controlled non-inferiority trial, we aimed to determine whether low-dose amitriptyline, which is often used off-label, is a safe and effective alternative to cognitive behavioral therapy for insomnia in the treatment of insomnia among patients with insomnia and medical comorbidity. Methods A total of 187 participants with insomnia and medical comorbidity were randomly allocated to either: (1) 12 weeks of amitriptyline, 10–20 mg (n=93), or (2) 12 weeks of group cognitive behavioral therapy for insomnia, seven sessions (n=94). Assessments took place at baseline, 6 and 12 weeks after start of treatment. The primary non-inferiority outcome was insomnia severity (Insomnia Severity Index) at 12 weeks. Results Based on a non-inferiority margin of four points on the Insomnia Severity Index, amitriptyline was non-inferior to cognitive behavioral therapy for insomnia at 12 weeks of treatment (mean difference of 1.1 points; 95% confidence interval = −0.5 to 2.8). Secondary analyses showed that significantly more cognitive behavioral therapy for insomnia participants reached a clinical response (≥eight-point reduction on the Insomnia Severity Index) than amitriptyline participants (58 per cent versus 41 per cent, p =.02). Amitriptyline participants reported more side effects (mostly anticholinergic) at 12 weeks treatment (p <.001) than participants who received cognitive behavioral therapy for insomnia. After discontinuation 68 per cent of the amitriptyline participants reported worsening of sleep. In 12 per cent of them this worsening was temporarily. Conclusions With a liberal non-inferiority margin, amitriptyline is non-inferior to cognitive behavioral therapy for insomnia in reducing insomnia severity. Amitriptyline has more side effects and its effect on insomnia may diminish after tapering. Cognitive behavioral therapy for insomnia should remain first-line treatment for patients with medical comorbidity given its broader benefits.