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


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          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-the-counter 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.


          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 meta-regression (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.


          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.

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          Most cited references 37

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          Explicit criteria for determining potentially inappropriate medication use by the elderly. An update.

          This study updates and expands explicit criteria defining potentially inappropriate medication use by the elderly. Additional goals were to address whether adverse outcomes were likely to be clinically severe and to incorporate clinical information on diagnoses when available. These criteria are meant to serve epidemiological studies, drug utilization review systems, health care providers, and educational efforts. Consensus from a panel of 6 nationally recognized experts on the appropriate use of medication in the elderly was sought. The expert panel agreed on the validity of 28 criteria describing the potentially inappropriate use of medication by general populations of the elderly as well as 35 criteria defining potentially inappropriate medication use in older persons known to have any of 15 common medical conditions. Updated, expanded, and more generally applicable criteria are now available to help identify inappropriate use of medications in elderly populations. These criteria define medications that should generally be avoided in the ambulatory elderly, doses or frequencies of administrations that should generally not be exceeded, and medications that should be avoided in older persons known to have any of several common conditions.
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            A refined method for the meta-analysis of controlled clinical trials with binary outcome.

            For the meta-analysis of controlled clinical trials with binary outcome a test statistic for testing an overall treatment effect is proposed, which is based on a refined estimator for the variance of the treatment effect estimator usually used in the random-effects model of meta-analysis. In simulation studies it is shown that the proposed test keeps the prescribed significance level much better than the commonly used tests in the fixed-effects and random-effects model, respectively. Moreover, when using the test it is not necessary to choose between fixed effects and random effects approaches in advance. The proposed method applies in the same way to the analysis of a controlled multi-centre study with binary outcome, including a possible interaction between drugs and centres. Copyright 2001 John Wiley & Sons, Ltd.
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              Anticholinergic activity of 107 medications commonly used by older adults.

              The objective of this study was to measure the anticholinergic activity (AA) of medications commonly used by older adults. A radioreceptor assay was used to investigate the AA of 107 medications. Six clinically relevant concentrations were assessed for each medication. Rodent forebrain and striatum homogenate was used with tritiated quinuclidinyl benzilate. Drug-free serum was added to medication and atropine standard-curve samples. For medications that showed detectable AA, average steady-state peak plasma and serum concentrations (C(max)) in older adults were used to estimate relationships between in vitro dose and AA. All results are reported in pmol/mL of atropine equivalents. At typical doses administered to older adults, amitriptyline, atropine, clozapine, dicyclomine, doxepin, L-hyoscyamine, thioridazine, and tolterodine demonstrated AA exceeding 15 pmol/mL. Chlorpromazine, diphenhydramine, nortriptyline, olanzapine, oxybutynin, and paroxetine had AA values of 5 to 15 pmol/mL. Citalopram, escitalopram, fluoxetine, lithium, mirtazapine, quetiapine, ranitidine, and temazepam had values less than 5 pmol/mL. Amoxicillin, celecoxib, cephalexin, diazepam, digoxin, diphenoxylate, donepezil, duloxetine, fentanyl, furosemide, hydrocodone, lansoprazole, levofloxacin, metformin, phenytoin, propoxyphene, and topiramate demonstrated AA only at the highest concentrations tested (patients with above-average C(max) values, who receive higher doses, or are frail may show AA). The remainder of the medications investigated did not demonstrate any AA at the concentrations examined. Psychotropic medications were particularly likely to demonstrate AA. Each of the drug classifications investigated (e.g., antipsychotic, cardiovascular) had at least one medication that demonstrated AA at therapeutic doses. Clinicians can use this information when choosing between equally efficacious medications, as well as in assessing overall anticholinergic burden.

                Author and article information

                Syst Rev
                Syst Rev
                Systematic Reviews
                BioMed Central (London )
                17 March 2020
                17 March 2020
                : 9
                [1 ]GRID grid.7839.5, ISNI 0000 0004 1936 9721, Institute of General Practice, , |Johann Wolfgang Goethe University, ; Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany
                [2 ]GRID grid.1033.1, ISNI 0000 0004 0405 3820, Faculty of Health Sciences and Medicine, , Bond University, ; Gold Coast, Australia
                [3 ]GRID grid.7700.0, ISNI 0000 0001 2190 4373, Institute of Medical Biometry and Informatics, , University of Heidelberg, ; Heidelberg, Germany
                [4 ]GRID grid.7839.5, ISNI 0000 0004 1936 9721, Goethe University, Institute of Clinical Pharmacology, ; Frankfurt, Germany
                © The Author(s) 2020

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funded by: German Innovation Fund
                Award ID: 01VSF16034
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                © The Author(s) 2020


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