Adverse drug reactions associated with amitriptyline — protocol for a systematic multiple-indication review and meta-analysis

Abstract

Background: Unwanted anticholinergic effects are both underestimated and frequently overlooked. Failure to identify adverse drug reactions (ADRs) can lead to prescribing cascades and the unnecessary use of over-thecounter products. The objective of this systematic review and meta-analysis is to explore and quantify the frequency and severity of ADRs associated with amitriptyline vs. placebo in randomized controlled trials (RCTs) involving adults with any indication, as well as healthy individuals. Methods: A systematic search in six electronic databases, forward/backward searches, manual searches, and searches for Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval studies, will be performed. Placebo-controlled RCTs evaluating amitriptyline in any dosage, regardless of indication and without restrictions on the time and language of publication, will be included, as will healthy individuals. Studies of topical amitriptyline, combination therapies, or including < 100 participants, will be excluded. Two investigators will screen the studies independently, assess methodological quality, and extract data on design, population, intervention, and outcomes ((non-)anticholinergic ADRs, e.g., symptoms, test results, and adverse drug events (ADEs) such as falls). The primary outcome will be the frequency of anticholinergic ADRs as a binary outcome (absolute number of patients with/without anticholinergic ADRs) in amitriptyline vs. placebo groups. Anticholinergic ADRs will be defined by an experienced clinical pharmacologist, based on literature and data from Martindale: The Complete Drug Reference. Secondary outcomes will be frequency and severity of (non-)anticholinergic ADRs and ADEs. The information will be synthesized in meta-analyses and narratives. We intend to assess heterogeneity using metaregression (for indication, outcome, and time points) and I 2 statistics. Binary outcomes will be expressed as odds ratios, and continuous outcomes as standardized mean differences. Effect measures will be provided using 95% confidence intervals. We plan sensitivity analyses to assess methodological quality, outcome reporting etc., and subgroup analyses on age, dosage, and duration of treatment. Discussion: We will quantify the frequency of anticholinergic and other ADRs/ADEs in adults taking amitriptyline for any indication by comparing rates for amitriptyline vs. placebo, hence, preventing bias from disease symptoms and nocebo effects. As no standardized instrument exists to measure it, our overall estimate of anticholinergic ADRs may have limitations.

Comorbid Chronic Pain and Depression: Shared Risk Factors and Differential Antidepressant Effectiveness

“…Serotonin noradrenaline reuptake inhibitors (SNRIs; e.g., duloxetine) and selective serotonin reuptake inhibitors (SSRIs; e.g., paroxetine, sertraline) are commonly used antidepressants for the treatment of comorbid chronic pain and depression (60). Other antidepressant options include tricyclic antidepressants (TCAs) such as amitriptyline (61,62). While these medications have been found to reduce the symptoms of both depression and pain partially, no significant differences in efficacy between them have been established so far (63), thus further research is required (60,64).…”

Genetic risk for chronic pain is associated with lower antidepressant effectiveness: Converging evidence for a depression subtype

“…Furthermore, comorbid chronic pain and depression is typically more difficult to treat than either primary condition alone. However, virtually all clinical guidelines and recommendations for either condition (Bates et al, 2019; Brueckle et al, 2020; Haibach et al, 2014; IsHak et al, 2018; Moore et al, 2015; Urits et al, 2019) have failed to adequately address treatment options for this common comorbidity. This major evidence gap can be attributed (in part) to the reliance on pharmacotherapeutic and other interventional trials excluding specific comorbidities (Baune et al, 2019; Cipriani et al, 2018; Kendrick et al, 2019), and are thus not representative of the inherent clinical heterogeneity across psychiatric populations.…”

Are Anticholinergic Symptoms a Risk Factor for Falls in Older General Practice Patients With Polypharmacy? Study Protocol for the Development and Validation of a Prognostic Model

“…The analyses will only consider medication with systemic effect. In accordance with Brueckle et al ( Brueckle et al, 2020 ), the following symptoms available in the RIME trial are considered to be anticholinergic drug reactions and will be included as potential predictors in our analyses: dizziness/vertigo, stomach pain, problems urinating, dry mouth, itching, constipation, drowsiness/fatigue. ACh burden, in particular, will be measured using five differenct scales/equations with the aim of comparing their ability to predict falls.…”