Off-label low dose amitriptyline for insomnia disorder: Patient-reported outcomes.

PURPOSE: Low dose amitriptyline is prescribed off-label to improve sleep maintenance in patients with insomnia disorder. Data on treatment outcomes are limited. We aimed to assess patient-reported treatment effect and side effects of low dose amitriptyline for insomnia in routine care data. METHODS: Cross-sectional study: Seven hundred fifty-two consecutive patients with insomnia disorder having sleep maintenance problems were treated in an outpatient sleep clinic with low dose amitriptyline (10-20 mg based on self-titration). Treatment was intended to improve sleep maintenance. Before the planned follow-up consultation (approximately 6 weeks after start treatment) patients completed an online treatment evaluation questionnaire. Treatment (dose, adherence), sleep, fatigue, satisfaction and side effects were assessed by multiple-choice questions with room for free-text elaboration. RESULTS: 53.7% of the patients reported to use amitriptyline up to 10 mg/day, 42.9% used a self-increased dose of mostly 20 mg/day, while 3.5% had discontinued treatment. 73.9% of the total study population reported improvement of sleep maintenance, 31.3% improved sleep onset, 35.2% improved daytime fatigue, and 45.8% reported to be (very) satisfied with treatment results. 66.1% reported at least one side effect. The reported side effects were generally the already known side effects of amitriptyline. CONCLUSION: These patient-reported outcomes support the clinical observations that low dose amitriptyline improves sleep maintenance on the short term and that it is generally well tolerated. This further justifies randomized controlled trials in patients with insomnia disorder and sleep maintenance problems to assess the effectiveness and safety of low dose amitriptyline on the short and long term.

Insomnia management in Dutch general practice: a routine care database study.

OBJECTIVE: To explore insomnia management in general practice, with a focus on sleep medication prescription. DESIGN: Descriptive analysis of anonymized routine general practice care data extracted from electronic medical records (EMRs), including demographics, free text annotations from sleep consultations and sleep medication prescriptions covering one year before up to two years after the registration of the International Classification for Primary Care (ICPC) code P06 'Sleep disturbance'. SETTING: Twenty-one general practices in an urban area of the Netherlands. PATIENTS: Adults (18-85 year) with a first sleep consultation with their GP. OUTCOMES: Documented non-pharmacological and sleep medication treatment. RESULTS: Of the 1,089 patients who consulted their general practitioner (GP) for sleep disturbance for the first time, about 50% had one more sleep consultation during the two years follow-up. Over two years including the first consultation, GPs documented a non-pharmacological intervention for 48.4% of the patients and prescribed sleep medication to 77.0%. 64.6% of the patients received a sleep medication prescription in the first consultation. Among patients receiving medication (N = 838); 59.6% received more than one prescription; 76.8% received one or more short-acting benzodiazepine receptor agonist (BZRA), 39.5% one or more unrecommended drugs and 14.7% >180 pills of BZRAs in two years. CONCLUSION: Although the guidelines advocate non-pharmacological treatment and warn against unwarranted sleep medication, it is still very common in Dutch general practice to prescribe medication, even at the first sleep consultation. Prescriptions frequently include unrecommended and off-label drugs or repeated BZRA prescriptions.

Short statementThere are concerns about the prescription rate and nature of sleep medication prescribed for patients with sleep disturbance. Analysis of routine care data can provide insights in general practitioners (GPs) management of insomnia.3 main statements GPs prescribed sleep medication in the first consultation to 64.6% of the patients who consulted them for sleep disturbance for the first time.Over two years including the first consultation, 48.4% of the patients received a (documented) non-pharmacological intervention, 77.0% a sleep medication prescription.Among patients receiving medication, the majority received short-acting benzodiazepine receptor agonists (BZRAs), but 39.5% (also) received an unrecommended drug.

The challenge of evaluating health effects of organic food; operationalisation of a dynamic concept of health.

The health benefits of consuming organically produced foods compared with conventional foods are unclear. Important obstacles to drawing clear conclusions in this field of research are (1) the lack of a clear operational definition of health and (2) the inability to distinguish between different levels of health using valid biomarkers. In this paper, some shortcomings of the current definition of health are outlined and the relevance of integrating a more dynamic and functional component is emphasised, which is reflected by the ability to adapt. The state of health could then be determined by challenging an individual with some form of stressor and by subsequent quantification and evaluation of the coherence in recovery of various physiological processes and parameters. A set of relevant parameters includes the activity of the immune system and the activity of the autonomous nervous system. A good recovery towards homeostasis is suggested to reflect a qualitatively good state of health. Furthermore, it would enable objective evaluation of health-optimising strategies, including the consumption of organically produced foods that aim to strengthen health.

Effectiveness of low-dose amitriptyline and mirtazapine for insomnia disorder: study protocol of a randomised, double-blind, placebo-controlled trial in general practice (the DREAMING study).

INTRODUCTION: For over more than a decade, low-dose amitriptyline and mirtazapine are prescribed off-label for insomnia. However, placebo-controlled evidence on these antidepressants for insomnia is still lacking. Therefore, the present trial aims to assess the effectiveness of low-dose amitriptyline (10-20 mg/day) and mirtazapine (7.5-15 mg/day) in patients with insomnia disorder with difficulty maintaining sleep or early-morning awakening problems in general practice. METHODS AND ANALYSIS: The Drug REdiscovery: low-dose Amitriptyline and Mirtazapine for INsomnia disorder in General practice (DREAMING) study is a randomised, double-blind, placebo-controlled trial in about 50 general practices. Adults (18-85 years) with insomnia disorder (Diagnostic and Statistical Manual of Mental Disorders-5) who ask their general practitioner (GP) for sleep medication when non-pharmacological treatment is deemed not effective, are eligible. EXCLUSION CRITERIA: isolated sleep initiation problem, contraindications for or drug-drug interactions with either amitriptyline or mirtazapine. Participants (n=156) will be randomly assigned to three parallel treatment groups of 16-week treatment with either amitriptyline (one or two tablets of 10 mg/day) or mirtazapine (one or two tablets of 7.5 mg/day) or placebo (one or two tablets) alongside usual GP care. All participants start and end with single dose, but dose can be doubled following GP consultation in week 3. Questionnaire assessments will be conducted at baseline, week 6, 12, 20 and 52. The primary study outcome is self-reported insomnia severity at 6 weeks, measured with the Insomnia Severity Index (ISI) in an intention to treat analysis. Secondary outcomes include subjective sleep quality quantified by sleep indices, daytime functioning and symptoms, safety and treatment evaluation and other sleep care consumption. ETHICS AND DISSEMINATION: The Medical Ethics Committee of the VU Medical Centre Amsterdam approved this trial. The results of this trial will be published in peer-reviewed scientific journals and presented at relevant academic conferences and to key stakeholders. TRIAL REGISTRATION NUMBER: NTR7449.

Increased presence of FOXP3+ regulatory T cells in inflamed muscle of patients with active juvenile dermatomyositis compared to peripheral blood.

Juvenile dermatomyositis (JDM) is an immune-mediated inflammatory disease affecting the microvasculature of skin and muscle. CD4+ CD25+ FOXP3+ regulatory T cells (Tregs) are key regulators of immune homeostasis. A role for Tregs in JDM pathogenesis has not yet been established. Here, we explored Treg presence and function in peripheral blood and muscle of JDM patients. We analyzed number, phenotype and function of Tregs in blood from JDM patients by flow cytometry and in vitro suppression assays, in comparison to healthy controls and disease controls (Duchenne's Muscular Dystrophy). Presence of Tregs in muscle was analyzed by immunohistochemistry. Overall, Treg percentages in peripheral blood of JDM patients were similar compared to both control groups. Muscle biopsies of new onset JDM patients showed increased infiltration of numbers of T cells compared to Duchenne's muscular dystrophy. Both in JDM and Duchenne's muscular dystrophy the proportion of FOXP3+ T cells in muscles were increased compared to JDM peripheral blood. Interestingly, JDM is not a self-remitting disease, suggesting that the high proportion of Tregs in inflamed muscle do not suppress inflammation. In line with this, peripheral blood Tregs of active JDM patients were less capable of suppressing effector T cell activation in vitro, compared to Tregs of JDM in clinical remission. These data show a functional impairment of Tregs in a proportion of patients with active disease, and suggest a regulatory role for Tregs in JDM inflammation.