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      Baseline heart rate variability predicts placebo hypoalgesia in men, but not women

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          Abstract

          Introduction

          Placebo hypoalgesic effects vary greatly across individuals, making them challenging to control for in clinical trials and difficult to use in treatment. We investigated the potential of resting vagally-mediated heart rate variability (vmHRV) to help predict the magnitude of placebo responsiveness.

          Methods

          In two independent studies (total N = 77), we administered a placebo paradigm after measuring baseline HRV. In Study I, we delivered heat pain to the forearm, on skin patches treated with “real” and “control” cream (identical inactive creams). In Study II, electrical pulses to the forearm were modulated by sham transcutaneous electrical nerve stimulation. We combined data from both studies to evaluate the relationship between vagally-mediated HRV (vmHRV) parameters and the placebo response size, while also assessing sex differences in this relationship.

          Results and Discussion

          This revealed a positive association between vmHRV and the degree of pain relief, and this effect was driven by men. These results not only reveal new insights into the (sex-specific) mechanisms of placebo hypoalgesia, but also suggest that measuring vmHRV may be helpful in predicting placebo responsiveness. Given that placebo hypoalgesic effects contribute substantially to treatment outcomes, such a non-invasive and easily obtained predictor would be valuable in the context of personalized medicine.

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          Most cited references66

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          Heart rate variability: a review.

          Heart rate variability (HRV) is a reliable reflection of the many physiological factors modulating the normal rhythm of the heart. In fact, they provide a powerful means of observing the interplay between the sympathetic and parasympathetic nervous systems. It shows that the structure generating the signal is not only simply linear, but also involves nonlinear contributions. Heart rate (HR) is a nonstationary signal; its variation may contain indicators of current disease, or warnings about impending cardiac diseases. The indicators may be present at all times or may occur at random-during certain intervals of the day. It is strenuous and time consuming to study and pinpoint abnormalities in voluminous data collected over several hours. Hence, HR variation analysis (instantaneous HR against time axis) has become a popular noninvasive tool for assessing the activities of the autonomic nervous system. Computer based analytical tools for in-depth study of data over daylong intervals can be very useful in diagnostics. Therefore, the HRV signal parameters, extracted and analyzed using computers, are highly useful in diagnostics. In this paper, we have discussed the various applications of HRV and different linear, frequency domain, wavelet domain, nonlinear techniques used for the analysis of the HRV.
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            Kubios HRV--heart rate variability analysis software.

            Kubios HRV is an advanced and easy to use software for heart rate variability (HRV) analysis. The software supports several input data formats for electrocardiogram (ECG) data and beat-to-beat RR interval data. It includes an adaptive QRS detection algorithm and tools for artifact correction, trend removal and analysis sample selection. The software computes all the commonly used time-domain and frequency-domain HRV parameters and several nonlinear parameters. There are several adjustable analysis settings through which the analysis methods can be optimized for different data. The ECG derived respiratory frequency is also computed, which is important for reliable interpretation of the analysis results. The analysis results can be saved as an ASCII text file (easy to import into MS Excel or SPSS), Matlab MAT-file, or as a PDF report. The software is easy to use through its compact graphical user interface. The software is available free of charge for Windows and Linux operating systems at http://kubios.uef.fi. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
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              Sex differences in pain: a brief review of clinical and experimental findings.

              Recent years have witnessed substantially increased research regarding sex differences in pain. The expansive body of literature in this area clearly suggests that men and women differ in their responses to pain, with increased pain sensitivity and risk for clinical pain commonly being observed among women. Also, differences in responsivity to pharmacological and non-pharmacological pain interventions have been observed; however, these effects are not always consistent and appear dependent on treatment type and characteristics of both the pain and the provider. Although the specific aetiological basis underlying these sex differences is unknown, it seems inevitable that multiple biological and psychosocial processes are contributing factors. For instance, emerging evidence suggests that genotype and endogenous opioid functioning play a causal role in these disparities, and considerable literature implicates sex hormones as factors influencing pain sensitivity. However, the specific modulatory effect of sex hormones on pain among men and women requires further exploration. Psychosocial processes such as pain coping and early-life exposure to stress may also explain sex differences in pain, in addition to stereotypical gender roles that may contribute to differences in pain expression. Therefore, this review will provide a brief overview of the extant literature examining sex-related differences in clinical and experimental pain, and highlights several biopsychosocial mechanisms implicated in these male-female differences. The future directions of this field of research are discussed with an emphasis aimed towards further elucidation of mechanisms which may inform future efforts to develop sex-specific treatments.
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                Author and article information

                Contributors
                Journal
                Front Pain Res (Lausanne)
                Front Pain Res (Lausanne)
                Front. Pain Res.
                Frontiers in Pain Research
                Frontiers Media S.A.
                2673-561X
                2673-561X
                20 September 2023
                2023
                : 4
                : 1213848
                Affiliations
                Department of Behavioural and Cognitive Sciences, University of Luxembourg , Esch-sur-Alzette, Luxembourg
                Author notes

                Edited by: Guillaume Leonard, Université de Sherbrooke, Canada

                Reviewed by: Mathieu Roy, McGill University, Canada Dominik Mischkowski, Ohio University, United States Juan Lorenzo Terrasa, University of the Balearic Islands, Spain

                [* ] Correspondence: Joy Krecké kreckejoy@ 123456gmail.com Marian Van der Meulen marian.vandermeulen@ 123456uni.lu
                Article
                10.3389/fpain.2023.1213848
                10547887
                37799824
                5fa0b871-88c9-461a-9e72-4024e6d0599d
                © 2023 Krecké, Dierolf, Rischer, Anton and van der Meulen.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 28 April 2023
                : 31 August 2023
                Page count
                Figures: 3, Tables: 4, Equations: 0, References: 70, Pages: 0, Words: 0
                Funding
                Funded by: National Research Fund, doi 10.13039/501100001866;
                Award ID: C16/BM/11266318/ACHE
                Study II was supported by the Luxembourg National Research Fund (FNR) (grant number: C16/BM/11266318/ACHE). The sponsor had no involvement in the collection, analysis and interpretation of data nor in the writing of the manuscript.
                Categories
                Pain Research
                Original Research
                Custom metadata
                Pain Mechanisms

                cognitive pain inhibition,placebo hypoalgesia,heart rate variability,sex difference,pain

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