Amitriptyline’s Anticholinergic Adverse Drug Reactions–a Systematic Multiple-Indication Review and Meta-Analysis
Maria-Sophie Brueckle , Elizabeth T. Thomas,Svenja Elisabeth Seide, Maximilian Pilz, Ana I. Gonzalez-Gonzalez, Truc Sophia Dinh, Ferdinand M. Gerlach, Sebastian Harder, Paul P. Glasziou, Christiane Muth
Abstract
Background
Half the US population uses drugs with anticholinergic properties. Their potential harms may outweigh their benefits. Amitriptyline is among the most frequently prescribed anticholinergic medicinal products, is used for multiple indications, and rated as strongly anticholinergic. Our objective was to explore and quantify (anticholinergic) adverse drug reactions (ADRs) in patients taking amitriptyline vs. placebo in randomized controlled trials (RCTs) involving adults and healthy individuals.
Introduction
A cross-sectional study based on a national sample of 2009–2010 Medicare Part D beneficiaries estimated that nearly one-third of nursing home residents in the USA used drugs with a high anticholinergic burden [5], and suffered from physical impairments and reduced ability to perform activities of daily living as a result [6]. Amitriptyline is used to treat major depressive disorder and other forms of depression, chronic pain, migraine, anxiety disorders [7], fibromyalgia [8], neuropathic pain [9], interstitial cystitis [10], nocturnal enuresis [11], eating disorders, and post-herpetic neuralgia [12].
Materials and Methods
Data extraction and quality assessment
As recommended in the PRISMA statement [29], we developed a standardized data extraction sheet [27] from a set of variables defined a priori. We then pilot-tested the extraction sheet in a subsample of 20 studies to ensure inter-observer variation between the two reviewers was acceptably low. One investigator (MSB) extracted details on study design/setting, population, exposure, and outcomes of interest (e.g. all reported ADRs and adverse drug events such as falls), and two other investigators (ETT, MP) cross-checked the data. Conflicts were resolved by discussion or by another author (CM, SES). Efforts to obtain missing data from the authors of the included studies resulted in the addition of no further information.
Results
The results of the analysis of aggregated and individual ADRs were consistent with those of the main analysis, with ADRs, and especially those indicating anticholinergic activity, occurring more frequently in the amitriptyline group than in the placebo group (see Table 2 “Meta-analytical Results of Secondary Outcomes”).
Discussion
To our knowledge, this is the first systematic review to compare ADRs associated with amitriptyline to placebo across all indications. Our results show that amitriptyline predominantly led to more frequent ADRs indicative of anticholinergic activity compared to placebo. Firstly, the odds of experiencing anticholinergic ADRs was about seven times higher overall. In keeping with the main analyses, the secondary analyses also showed a significant increase in ADRs related to dry mouth, genitourinary, coordination, fatigue, cardiovascular, digestion and vision symptoms with descending odds ratios declining from 11.1 to 2.21. The relatively high heterogeneity of 83% in the I2 test in the primary analysis may be partly due to variation in the odds ratios of different combinations of anticholinergic ADRs in our primary outcome. Heterogeneity remained stable after adjustment for gender, indication, mean daily dose, and mode of administration. Secondly, the odds of experiencing general ADRs were four times higher in the amitriptyline than the placebo group, whereby we found no difference in ADR frequency for ADRs that are not indicative of anticholinergic activity
Conclusion
Our multi-indication systematic review provides important evidence for clinical decision making. About one in three patients of about 40 years of age that are treated with amitriptyline will experience ADRs related to anticholinergic activity (RD = 0.35, NNH = 2.89). The potential to cause harm should be carefully weighed against potential benefits, and communicated to patients. Our results may even understate the situation in older individuals, who are generally more sensitive to anticholinergic effects [3]. Furthermore, the wide spectrum of anticholinergic symptoms supports individualized management, as patients may not be equally bothered by their symptoms. Furthermore, patient preferences should be taken into account, as patients differ in their desire for treatment to combat symptoms and negative outcomes. The paucity of studies examining more severe ADRs, such as cognitive decline and falls, may hinder the decision-making process and should be investigated in future studies. They should also seek to extend generalizability to include patients of older age.
Acknowledgments
We would like to thank Justin Clark from Bond University for developing the search strategy and carry out all searches in the various databases. We are also grateful to Phillip Elliott from Johann Wolfgang Goethe University for conducting a language review. Thanks also go to Kiran Chapidi from University of Bielefeld for his support in data management.
Citation: Brueckle M-S, Thomas ET, Seide SE, Pilz M, Gonzalez-Gonzalez AI, Dinh TS, et al. (2023) Amitriptyline’s anticholinergic adverse drug reactions–A systematic multiple-indication review and meta-analysis. PLoS ONE 18(4): e0284168. https://doi.org/10.1371/journal.pone.0284168
Editor: Chi-Shin Wu, NHRI: National Health Research Institutes, TAIWAN
Received: September 27, 2022; Accepted: March 23, 2023; Published: April 5, 2023
Copyright: © 2023 Brueckle et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: FMG, Funding Source: “Evidence-based multimedication program with implementation to practical care” (EVITA; grant number: 01VSF16034) funded by the German Innovation Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
