Study objectives: In a randomized controlled non-inferiority trial, we aimed to determine whether low dose Amitriptyline (AM), which is often used off-label, is a safe and effective alternative to cognitive behavioral therapy for insomnia (CBT-I) 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 AM, 10-20 mg (n = 93), or 2) 12 weeks of group CBT-I, 7 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; ISI) at 12 weeks.
Results: Based on a non-inferiority margin of four points on the ISI, AM was non-inferior to CBT-I at 12 weeks of treatment (mean difference of 1.1 points; 95% CI -0.5 to 2.8). Secondary analyses showed that significantly more CBT-I participants reached a clinical response (≥ 8-point reduction on the ISI) than AM participants (58% versus 41%, p=.02). AM participants reported more side-effects (mostly anticholinergic) at 12 weeks treatment (p<.001) than participants who received CBT-I. After discontinuation 68% of the AM participants reported worsening of sleep. In 12% of them this worsening was temporarily.
Conclusions: With a liberal non-inferiority margin, AM is non-inferior to CBT-I in reducing insomnia severity. AM has more side effects and its effect on insomnia may diminish after tapering. CBT-I should remain first-line treatment for patients with medical comorbidity given its broader benefits.
Keywords: amitriptyline; cognitive Behavioral therapy; discontinuation; group; insomnia; medical comorbidity; non-inferiority; pharmacology; side-effects.
© The Author(s) 2025. Published by Oxford University Press on behalf of the Sleep Research Society.