Brain-based measures of nociception during general anesthesia with remifentanil

Keerthana Deepti Karuna karan ,Barry D. Kussman , KePeng, Lino Becerra, Robert Labadie, Rachel Bernier, Delany Berry, Stephen Green, David Zurakowski, Mark E. Alexander, David Borsook



Catheter radiofrequency (RF) ablation for cardiac arrhythmias is a painful procedure. Prior work using functional near-infrared spectroscopy (fNIRS) in patients under general anesthesia has indicated that ablation results in activity in pain-related cortical regions, presumably due to inadequate blockade of afferent nociceptors originating within the cardiac system. Having an objective brain-based measure for nociception and analgesia may in the future allow for enhanced analgesic control during surgical procedures. Hence, the primary aim of this study is to demonstrate that the administration of remifentanil, an opioid widely used during surgery, can attenuate the fNIRS cortical responses to cardiac ablation.


General anesthesia is a reversible drug-induced state characterized by unconsciousness, amnesia, analgesia, and immobility [1]. Surgery results in nociceptor activation, inflammation at the surgical site, and nerve injury [2], thereby triggering central sensitization [3]. However, there are challenges in providing complete and consistent analgesia during the intra- and postoperative period. Opioid analgesics are the mainstay of multimodal general anesthesia for the management of nociception intraoperatively and pain postoperatively [4], but the dosage, timing of administration, and efficacy in preventing nociceptive activity from reaching the brain is not well understood.

Materials and methods


This study is reported as per the Consolidated Standards of Reporting Trials (CONSORT) guideline (S1 Checklist). A CONSORT and SPIRIT Extension for Randomized Clinical Trials in Extenuating Circumstances (CONSERVE) checklist (S2 Checklist) is also provided to report the modifications in the trial caused due to the coronavirus pandemic. The details of participants evaluated for the study (identified, screened, randomized, and analyzed on an intention-to-treat (ITT) basis) are summarized in the flow diagram (Fig 1). Patients were recruited through the normal caseload of Cardiac Surgery at Boston Children’s Hospital. The research team contacted all patients scheduled to undergo elective electrophysiology study with catheter ablation of an arrhythmia under general anesthesia via email. Interested patients were screened and evaluated for eligibility before the preoperative appointment over the phone. A total of 41 patients were enrolled from October 2016 to March 2020; the number of patients is lower than the intended sample size due to the coronavirus pandemic in the United States of America, as all data collection had to be halted in March 2020.


Cortical response to nonpainful stimuli

The demographic and procedural characteristics of the 41 participants recruited and scanned from October 2016 to March 2020 are summarized in Table 1. Catheter-based ablations were performed in all 41 participants; however, 7 participants were excluded due to poor fNIRS signal quality, (i.e., no visible heart rate in signal indicating poor scalp-optode contact) and 2 participants were excluded because they received only cryoablations (to reduce heterogeneity in surgical procedure as cryoablation is reported to be less painful [35–38]). This step was performed before the data set was unblended.


Summary of findings

To the best of our knowledge, this is the first paper to report the analgesic effects of an opioid using fNIRS measures of cortical responses in patients under general anesthesia. During catheter ablation, considered a painful process, responses were observed in the mFPC and S1 consistent with pain as determined by our prior measures of nociceptive evoked responses in awake, sedated, and anesthetized patients. Furthermore, remifentanil resulted in a decrease in the magnitude of these responses consistent with opioid effects similar to that observed in response to morphine in awake participants [17], but remifentanil did not completely abolish the signal. However, the greatest effect of opioid on the fNIRS response to ablation was found for the higher dose (0.5 mcg/kg/min) followed by the lower dose (0.25 mcg/kg/min) of the remifentanil, especially in the S1. Importantly, auditory responses in mFPC were opposite to presumed nociceptive responses (as shown in PL group). As such, the 2 processes suggests that sensory processing is present during general anesthesia.

Citation: Karunakaran KD, Kussman BD, Peng K, Becerra L, Labadie R, Bernier R, et al. (2022) Brain-based measures of nociception during general anesthesia with remifentanil: A randomized controlled trial. PLoS Med 19(4): e1003965.
Academic Editor: Jean-Louis Vincent, Erasme University Hospital, BELGIUM

Received: February 22, 2021; Accepted: March 14, 2022; Published: April 22, 2022

Copyright: © 2022 Karunakaran 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: Data cannot be shared publicly because it contains non-personally identifiable sensitive participant data. Data can be requested from the Children's Hospital Electronic Research Portal ( for researchers who meet the criteria for access to confidential data.Thepreprocessing scripts mentioned in section 2.6 is publicly available at

Funding: This work was supported by a grant from the National Institute of General Medical Science of the National Institutes of Health to DB (R01GM104986, R01GM122405). 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.

Abbreviations: ANOVA, analysis of covariance; Ant. SS1, anterior superior S1; AUC, area under the ΔHbO curve; BIS, bispectral index; CI, confidence interval; CONSERVE, CONSORT and SPIRIT Extension for Randomized Clinical Trials in Extenuating Circumstances; CONSORT, Consolidated Standards of Reporting Trials; FDR, false discovery rate; fMRI, functional magnetic resonance imaging; fNIRS, functional near-infrared spectroscopy; HD, high-dose; Inf. lPFC, inferior lateral prefrontal cortex; Inf. mFPC, inferior medial frontopolar cortex; lPFC, lateral prefrontal cortex; IRB, Institutional Review Board; ITT, intention-to-treat; LD, low-dose; MD, mean difference; mFPC, medial frontopolar cortex; PeakHbO, Peak ΔHbO; PL, placebo; Pos. SS1, posterior superior S1; RF, radiofrequency; ROI, region of interest; S1, primary somatosensory cortex; SMD, standardized mean difference; Sup. lPFC, superior lateral prefrontal cortex; Sup. mFPC, superior medial frontopolar cortex

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