A cortical source localization analysis of resting EEG data after remifentanil infusion.

OBJECTIVE: To explore changes in current source density locations after remifentanil infusion in healthy volunteers using source localization of the electroencephalography (EEG). METHODS: EEG data was collected from 21 males using a 62-electrode system. Additionally, cognitive performance was evaluated by a continuous reaction time paradigm, and pain scores were obtained for experimental bone and heat stimuli. Data were recorded before and during treatment with remifentanil and placebo. Source localization was performed by sLORETA at delta (1-3.9 Hz), theta (4-7.9 Hz), alpha (8-12 Hz), beta1 (12.1-18 Hz), and beta2 (18.1-30 Hz) frequency bands. RESULTS: Pre-treatment recordings demonstrated reproducible source characteristics. The alterations (i.e., pre- versus post-treatment) due to remifentanil were significantly and robustly different from placebo infusions. The results indicated that neurons in several brain areas including inferior frontal gyrus and insula at frontal lobe oscillated more strongly after remifentanil infusion compared to placebo. Furthermore, the source activity at delta band was correlated with continuous reaction time index. CONCLUSIONS: These results indicate that alterations in brain oscillations during remifentanil are mostly localized to frontal, fronto-temporal and fronto-central lobes and related to cognitive function. SIGNIFICANCE: The approach offers the potential to be used for understanding the underlying mechanism of action of remifentanil on brain activity.

Disruption of cortical connectivity during remifentanil administration is associated with cognitive impairment but not with analgesia.

BACKGROUND: The authors investigated the effect of remifentanil administration on resting electroencephalography functional connectivity and its relationship to cognitive function and analgesia in healthy volunteers. METHODS: Twenty-one healthy male adult subjects were enrolled in this placebo-controlled double-blind cross-over study. For each subject, 2.5 min of multichannel electroencephalography recording, a cognitive test of sustained attention (continuous reaction time), and experimental pain scores to bone-pressure and heat stimuli were collected before and after infusion of remifentanil or placebo. A coherence matrix was calculated from the electroencephalogram, and three graph-theoretical measures (characteristic path-length, mean clustering coefficient, and relative small-worldness) were extracted to characterize the overall cortical network properties. RESULTS: Compared to placebo, most graph-theoretical measures were significantly altered by remifentanil at the alpha and low beta range (8 to 18 Hz; all P < 0.001). Taken together, these alterations were characterized by an increase in the characteristic path-length (alpha 17% and low beta range 24%) and corresponding decrements in mean clustering coefficient (low beta range -25%) and relative small-worldness (alpha -17% and low beta range -42%). Changes in characteristic path-lengths after remifentanil infusion were correlated to the continuous reaction time index (r = -0.57; P = 0.009), while no significant correlations between graph-theoretical measures and experimental pain tests were seen. CONCLUSIONS: Remifentanil disrupts the functional connectivity network properties of the electroencephalogram. The findings give new insight into how opioids interfere with the normal brain functions and have the potential to be biomarkers for the sedative effects of opioids in different clinical settings.

Altered frequency distribution in the electroencephalogram is correlated to the analgesic effect of remifentanil.

Opioids alter resting state brain oscillations by multiple and complex factors, which are still to be elucidated. To increase our knowledge, multi-channel electroencephalography (EEG) was subjected to multivariate pattern analysis (MVPA), to identify the most descriptive frequency bands and scalp locations altered by remifentanil in healthy volunteers. Sixty-two channels of resting EEG followed by independent measures of pain scores to heat and bone pain were recorded in 21 healthy males before and during remifentanil infusion in a placebo-controlled, double-blind crossover study. EEG frequency distributions were extracted by a continuous wavelet transform and normalized into delta, theta, alpha, beta and gamma bands. Alterations relative to pre-treatment responses were calculated for all channels and used as input to the MVPA. Compared to placebo, remifentanil increased the delta band and decreased the theta and alpha band oscillations as a mean over all channels (all p ≤ 0.007). The most discriminative channels in these frequency bands were F1 in delta (83.33%, p = 0.0023) and theta bands (95.24%, p < 0.0001), and C6 in the alpha band (80.95%, p = 0.0054). These alterations were correlated to individual changes in heat pain in the delta (p = 0.045), theta (p = 0.038) and alpha (p = 0.039) bands and to bone pain in the alpha band (p = 0.0092). Hence, MVPA of multi-channel EEG was able to identify frequency bands and corresponding channels most sensitive to altered brain activity during remifentanil treatment. As the EEG alterations were correlated to the analgesic effect, the approach may prove to be a novel methodology for monitoring individual efficacy to opioids.

Altered cortical causality after remifentanil administration in healthy volunteers: a novel approach for pharmaco-EEG.

Alterations in cortical causality information flow induced by remifentanil infusion in healthy volunteers was investigated in a placebo-controlled double-blind cross-over study. For each of the 21 enrolled male subjects, 2.5 minutes of resting electroencephalography (EEG) data were collected before and after infusion of remifentanil and placebo. Additionally, to assess cognitive function and analgesic effect, continuous reaction time (CRT) and bone pressure and heat pain were assessed, respectively. The causality information was extracted from the EEG by phase slope index (PSI). Among the features being reproducible between the two baseline recordings, several PSI features were altered by remifentanil administration in comparison to placebo. Furthermore, several of the PSI features altered by remifentanil were correlated to changes in both CRT and pain scores. The results indicate that remifentanil administration influence the information flow between several brain areas. Hence, the EEG causality approach offers the potential to assist in deciphering the cortical effects of remifentanil administration.

A double-blind, placebo-controlled study on the effect of buprenorphine and fentanyl on descending pain modulation: a human experimental study.

OBJECTIVES: The descending pain inhibitory system is impaired in chronic pain and it is important to know how analgesics interact with this system. The aim of this human experimental pain, double-blind, randomized, placebo-controlled, 3 way cross-over study was to investigate the effect of 2 different opioids on descending pain inhibition using conditioning pain modulation (CPM) as a screening tool. METHODS: Twenty-two healthy male volunteers were randomized to 72 hours of treatment with transdermal patches of fentanyl (25 µg/h), buprenorphine (20 µg/h), or placebo. The CPM was induced by immersing the hand into cold (3.0 ± 0.3°C) water and the evoked pain was continuously rated on a visual analogue scale (VAS). The test stimulus [pressure pain tolerance threshold (PPTol)] was applied to the contra-lateral arm. The CPM test was performed at baseline, 24, 48, and 72 hours after application of the patches. RESULTS: The opioid treatments did not significantly (F=2.249; P=0.07) modulate the PPTol over the treatment period compared with placebo. The CPM-evoked PPTol increases (percentage increase from what was obtained at the baseline before patch application) were significantly enhanced by buprenorphine (P=0.004) and fentanyl (P=0.005) compared with placebo, with no differences between the 2 active drugs. Fentanyl significantly attenuated the time to cold water-evoked VAS peak compared with placebo (P=0.005), and the same trend was observed for buprenorphine (P=0.06). The VAS pain intensity was not affected. DISCUSSION: The opioids buprenorphine and fentanyl significantly potentiate the effect of descending pain inhibition in healthy volunteers.