INTRODUCTION: Pain is highly prevalent in critically ill trauma patients, especially those with a traumatic brain injury (TBI). Behavioral pain tools such as the behavioral pain scale (BPS) and critical-care pain observation tool are recommended for sedated noncommunicative patients. Analysis of heart rate variability (HRV) is a noninvasive method to evaluate autonomic nervous system activity. The analgesia nociception index (ANI) device (Physiodoloris((R)), MDoloris Medical Systems, Loos, France) allows noninvasive HRV analysis. The ANI assesses the relative parasympathetic tone as a surrogate for antinociception/nociception balance in sedated patients. The primary aim of our study was to evaluate the effectiveness of ANI in detecting pain in TBI patients. The secondary aim was to evaluate the impact of norepinephrine use on ANI effectiveness and to determine the correlation between ANI and BPS. METHODS: We performed a prospective observational study in 21 deeply sedated TBI patients. Exclusion criteria were nonsinus cardiac rhythm; presence of pacemaker; atropine or isoprenaline treatment; neuromuscular blocking agents; and major cognitive impairment. Heart rate, blood pressure, and ANI were continuously recorded using the Physiodoloris((R)) device at rest (T1), during (T2), and after the end (T3) of the painful stimulus (tracheal suctioning). RESULTS: In total, 100 observations were scored. ANI was significantly lower at T2 (Median [min - max] 54.5 [22-100]) compared with T1 (90.5 [50-100], P < 0.0001) and T3 (82 [36-100], P < 0.0001). Similar results were found in the subgroups of patients with (65 measurements) or without (35) norepinephrine. During procedure, a negative linear relationship was observed between ANI and BPS (r(2) = -0.469, P < 0.001). At the threshold of 50, the sensitivity and specificity of ANI to detect patients with BPS >/= 5 were 73% and 62%, respectively, with a negative predictive value of 86%. DISCUSSION: Our results suggest that ANI is effective in detecting pain in ventilated sedated TBI patients, including those patients treated with norepinephrine.