Imaging Human Cerebral Pain Modulation by Dose-dependent Opioid Analgesia: A Positron Emission Tomography Activation Study Using Remifentanil

Background: Previous imaging studies have demonstrated a number of cortical and subcortical brain structures to be activated during noxious stimulation and infusion of narcotic analgesics. This study used 15O-water and positron emission tomography to investigate dose-dependent effects of the short-acting [mu]-selective opioid agonist remifentanil on regional cerebral blood flow during experimentally induced painful heat stimulation in healthy male volunteers.

Methods: Positron emission tomography measurements were performed with injection of 7 mCi 15O-water during nonpainful heat and painful heat stimulation of the volar forearm. Three experimental conditions were used during both sensory stimuli: saline, 0.05 [mu]g [middle dot] kg-1 [middle dot] min-1 remifentanil, and 0.15 [mu]g [middle dot] kg-1 [middle dot] min-1 remifentanil. Cardiovascular and respiratory parameters were monitored noninvasively. Across the three conditions, dose-dependent effects of remifentanil on regional cerebral blood flow were analyzed on a pixel-wise basis using a statistical parametric mapping approach.

Results: During saline infusion, regional cerebral blood flow increased in response to noxious thermal stimulation in a number of brain regions as previously reported. There was a reduction in pain-related activations with increasing doses of remifentanil in the thalamus, insula, and anterior and posterior cingulate cortex. Increasing activation occurred in the cingulofrontal cortex (including the perigenual anterior cingulate cortex) and the periaqueductal gray.     

Neural mechanisms of antinociceptive effects of hypnosis

BACKGROUND: The neural mechanisms underlying the modulation of pain perception by hypnosis remain obscure. In this study, we used positron emission tomography in 11 healthy volunteers to identify the brain areas in which hypnosis modulates cerebral responses to a noxious stimulus. METHODS: The protocol used a factorial design with two factors: state (hypnotic state, resting state, mental imagery) and stimulation (warm non-noxious vs. hot noxious stimuli applied to right thenar eminence). Two cerebral blood flow scans were obtained with the 15O-water technique during each condition. After each scan, the subject was asked to rate pain sensation and unpleasantness. Statistical parametric mapping was used to determine the main effects of noxious stimulation and hypnotic state as well as state-by-stimulation interactions (i.e., brain areas that would be more or less activated in hypnosis than in control conditions, under noxious stimulation). RESULTS: Hypnosis decreased both pain sensation and the unpleasantness of noxious stimuli. Noxious stimulation caused an increase in regional cerebral blood flow in the thalamic nuclei and anterior cingulate and insular cortices. The hypnotic state induced a significant activation of a right-sided extrastriate area and the anterior cingulate cortex. The interaction analysis showed that the activity in the anterior (mid-)cingulate cortex was related to pain perception and unpleasantness differently in the hypnotic state than in control situations. CONCLUSIONS: Both intensity and unpleasantness of the noxious stimuli are reduced during the hypnotic state. In addition, hypnotic modulation of pain is mediated by the anterior cingulate cortex.     

Neural Mechanisms of Antinociceptive Effects of Hypnosis

Background: The neural mechanisms underlying the modulation of pain perception by hypnosis remain obscure. In this study, we used positron emission tomography in 11 healthy volunteers to identify the brain areas in which hypnosis modulates cerebral responses to a noxious stimulus.

Methods: The protocol used a factorial design with two factors: state (hypnotic state, resting state, mental imagery) and stimulation (warm non-noxious vs. hot noxious stimuli applied to right thenar eminence). Two cerebral blood flow scans were obtained with the 15O-water technique during each condition. After each scan, the subject was asked to rate pain sensation and unpleasantness. Statistical parametric mapping was used to determine the main effects of noxious stimulation and hypnotic state as well as state-by-stimulation interactions (i.e., brain areas that would be more or less activated in hypnosis than in control conditions, under noxious stimulation).

Results: Hypnosis decreased both pain sensation and the unpleasantness of noxious stimuli. Noxious stimulation caused an increase in regional cerebral blood flow in the thalamic nuclei and anterior cingulate and insular cortices. The hypnotic state induced a significant activation of a right-sided extrastriate area and the anterior cingulate cortex. The interaction analysis showed that the activity in the anterior (mid-)cingulate cortex was related to pain perception and unpleasantness differently in the hypnotic state than in control situations.     

Dose-dependent effects of propofol on the central processing of thermal pain

BACKGROUND: Anatomic and physiologic data show that multiple regions of the forebrain are activated by pain. However, the effect of anesthetic level on nociceptive input to these regions is not well understood. METHODS: The authors used positron emission tomography to measure the effect of various concentrations of propofol on pain-evoked changes in regional cerebral blood flow. Fifteen volunteers were scanned while warm and painful heat stimuli were presented to the volar forearm using a contact thermode during administration of target propofol concentrations of 0.0 microg/ml (alert control), 0.5 microg/ml (mild sedation), 1.5 microg/ml (moderate sedation), and 3.5 microg/ml (unconsciousness). RESULTS: During the 0.5-microg/ml target propofol concentration (mild sedation), the subjects' pain ratings increased relative to the alert control condition; correspondingly, pain-evoked regional cerebral blood flow increased in the thalamus and the anterior cingulate cortex. In contrast, when subjects lost consciousness (3.5 microg/ml), pain-evoked responses in the thalamus and the anterior cingulate cortex were no longer observed, whereas significant pain-evoked activation remained in the insular cortex. CONCLUSION: These data show that propofol has a dose-dependent effect on thalamocortical transfer of nociceptive information but that some pain-evoked cortical activity remains after loss of consciousness.     

Dose-dependent regional cerebral blood flow changes during remifentanil infusion in humans: a positron emission tomography study

BACKGROUND: The current study investigated dose-dependent effects of the mu-selective agonist remifentanil on regional cerebral blood flow (rCBF) in volunteers using positron emission tomography (PET). METHODS: Ten right-handed male volunteers were included in a 15O-water PET study. Seven underwent three conditions: control (saline), low remifentanil (0.05 microg x kg(-1) x min(-1)), and moderate remifentanil (0.15 microg x kg(-1) x min(-1)). The remaining three participated in the low and moderate conditions. A semirandomized study protocol was used with control and remifentanil conditions 3 or more months apart. The order of low and moderate conditions was randomized. Cardiovascular and respiratory parameters were monitored. Categoric comparisons between the control, low, and moderate conditions and a pixelwise correlation analysis across the three conditions were performed (P < 0.05, corrected for multiple comparisons) using statistical parametric mapping. RESULTS: Cardiorespiratory parameters were maintained constant over time. At the low remifentanil dose, significant increases in relative rCBF were noted in the lateral prefrontal cortices, inferior parietal cortices, and supplementary motor area. Relative rCBF decreases were observed in the basal mediofrontal cortex, cerebellum, superior temporal lobe, and midbrain gray matter. Moderate doses further increased rCBF in mediofrontal and anterior cingulate cortices, occipital lobe transition, and caudal periventricular grey. Significant decreases were detected in the inferior parietal lobes. These dose-dependent effects of remifentanil on rCBF were confirmed by a correlation analysis. CONCLUSION: Remifentanil induced dose-dependent changes in relative rCBF in areas involved in pain processing. At moderate doses, rCBF responses were additionally detected in structures known to participate in modulation of vigilance and alertness. Insight into the mechanisms of opioid analgesia within the pain-processing neural network may lead to a better understanding of antinociception and opioid treatment.     

In Vivo Imaging of Nitrous Oxide-induced Changes in Cerebral Activation during Noxious Heat Stimuli

Background: Although previous studies have provided some insight into the pharmacologic aspects of nitrous oxide analgesia, the neural circuits mediating its antinociceptive effect remain relatively unexplored. Positron emission tomography was used in nine volunteers to identify the loci of nitrous oxide-modulated cerebral responses to a peripheral noxious stimulus.

Methods: Nitrous oxide-pain interactions were studied by comparing regional cerebral blood flow responses to a 48 degrees Celsius tonic heat stimulus, applied to each volunteer's left forearm, during room air inhalation with those obtained while 20% nitrous oxide was administered. Two cerebral blood flow scans were obtained with the15 O-water technique during each condition. Locations of specific regional activation related to pain, and nitrous oxide, were identified using the statistical parametric mapping method, with a significance level of P < 0.01. Pain was rated by visual analog scale and the values were compared using Wilcoxon rank sum analysis.

Results: Pain produced cerebral activation in the contralateral thalamus, anterior cingulate, and supplementary motor area. Adding nitrous oxide during pain stimulation abolished activation in these areas but was associated with activation in the contralateral infralimbic and orbitofrontal cortices. In parallel, mean visual analog scale scores decreased significantly from 67 +/- 4 (SEM) to 54 +/- 5 (P < 0.05).     

Effect of remifentanil on intracranial pressure and cerebral blood flow velocity in patients with head trauma

BACKGROUND: Remifentanil, an ultra-short-acting opioid, is used as an on-top analgesic in head trauma patients during transient painful procedures, e.g. endotracheal suctioning, physiotherapy, on the intensive care unit. However, previous studies have shown that opioids may increase intracranial pressure and decrease cerebral blood flow. METHODS: The present study investigates the effect of remifentanil on mean arterial blood pressure, intracranial pressure measured with intraparenchymal or epidural probes, and on cerebral blood flow velocity assessed by transcranial Doppler flowmetry in 20 head trauma patients sedated with propofol and sufentanil. Ventilation was adjusted for a target PaCO2 of 4.7-5.1 kPa. After baseline measurements a bolus of remifentanil (0.5 microg x kg(-1) i.v.) was administrated followed by a continuous infusion of remifentanil (0.25 microg x kg(-1) x min(-1) i.v.) for 20 min. RESULTS: There was no change in mean arterial blood pressure, intracranial pressure, and cerebral blood flow velocity in response to remifentanil infusion over time. Statistical analysis was performed using the Wilcoxon Signed Rank test. CONCLUSIONS: These data suggest that remifentanil can be used for on-top analgesia in head trauma patients without adverse effects on cerebrovascular haemodynamics, cerebral perfusion pressure or intracranial pressure.     

Dose-dependent Effects of Propofol on the Central Processing of Thermal Pain

Background: Anatomic and physiologic data show that multiple regions of the forebrain are activated by pain. However, the effect of anesthetic level on nociceptive input to these regions is not well understood.

Methods: The authors used positron emission tomography to measure the effect of various concentrations of propofol on pain-evoked changes in regional cerebral blood flow. Fifteen volunteers were scanned while warm and painful heat stimuli were presented to the volar forearm using a contact thermode during administration of target propofol concentrations of 0.0 [mu]g/ml (alert control), 0.5 [mu]g/ml (mild sedation), 1.5 [mu]g/ml (moderate sedation), and 3.5 [mu]g/ml (unconsciousness).

Results: During the 0.5-[mu]g/ml target propofol concentration (mild sedation), the subjects' pain ratings increased relative to the alert control condition; correspondingly, pain-evoked regional cerebral blood flow increased in the thalamus and the anterior cingulate cortex. In contrast, when subjects lost consciousness (3.5 [mu]g/ml), pain-evoked responses in the thalamus and the anterior cingulate cortex were no longer observed, whereas significant pain-evoked activation remained in the insular cortex.     

Dose-dependent Regional Cerebral Blood Flow Changes during Remifentanil Infusion in Humans: A Positron Emission Tomography Study

Background: The current study investigated dose-dependent effects of the [mu]-selective agonist remifentanil on regional cerebral blood flow (rCBF) in volunteers using positron emission tomography (PET).

Methods: Ten right-handed male volunteers were included in a 15O-water PET study. Seven underwent three conditions: control (saline), low remifentanil (0.05 [mu]g [middle dot] kg-1 [middle dot] min-1), and moderate remifentanil (0.15 [mu]g [middle dot] kg-1 [middle dot] min-1). The remaining three participated in the low and moderate conditions. A semi-randomized study protocol was used with control and remifentanil conditions 3 or more months apart. The order of low and moderate conditions was randomized. Cardiovascular and respiratory parameters were monitored. Categoric comparisons between the control, low, and moderate conditions and a pixelwise correlation analysis across the three conditions were performed (P < 0.05, corrected for multiple comparisons) using statistical parametric mapping.

Results: Cardiorespiratory parameters were maintained constant over time. At the low remifentanil dose, significant increases in relative rCBF were noted in the lateral prefrontal cortices, inferior parietal cortices, and supplementary motor area. Relative rCBF decreases were observed in the basal mediofrontal cortex, cerebellum, superior temporal lobe, and midbrain gray matter. Moderate doses further increased rCBF in mediofrontal and anterior cingulate cortices, occipital lobe transition, and caudal periventricular grey. Significant decreases were detected in the inferior parietal lobes. These dose-dependent effects of remifentanil on rCBF were confirmed by a correlation analysis.     

Functional neuroimaging of gastric distention

This study aimed to measure brain activation during gastric distention as a way to investigate short-term satiety. We estimated regional cerebral blood flow with positron emission tomography (¹⁵O-water) during gastric balloon inflation and deflation in 18 healthy young women. The contrast between inflated minus deflated conditions showed activation in the following four key regions that were identified a priori: dorsal brain stem; left inferior frontal gyrus; bilateral insula; and right subgenual, anterior cingulate cortex. Extant neuroimaging literature provides context for these areas as follows: the brain stem represents vagal projection zones for visceral afferent processing; the inferior frontal gyrus serves as a convergence zone for processing food-related stimuli; and both the insula and subgenual anterior cingulate cortex respond to emotional stimulation. The identification of neural correlates of gastric distention is a key step in the discovery of new treatments for obesity. New therapies could intervene by modifying the perception of gastric distention, an important contributor to meal termination and short-term satiety. This first study of brain activation during nonpainful, proximal gastric distention provides the groundwork for future research to discover novel treatments for obesity. Presented in part at the annual meeting of the Minnesota Surgical Society, Minneapolis, Minnesota, April 19, 2002. Supported by the Mark A. Nugent Foundation, NIDDK (5P30 DK50456-08) and ORWH (R01-DK52291), NARSAD, and the Department of Veterans Affairs.     

Clinical hypnosis modulates functional magnetic resonance imaging signal intensities and pain perception in a thermal stimulation paradigm

OBJECTIVE: This study was designed to describe regional changes in blood oxygenation level dependent signals in functional magnetic resonance images (fMRI) elicited by thermal pain in hypnotized subjects. These signals approximately identify the neural correlates of the applied stimulation to identify neuroanatomic structures involved in the putative effects of clinical hypnosis on pain perception. METHODS: After determination of the heat pain threshold of 12 healthy volunteers, fMRI scans were performed at 1.5 Tesla by using echoplanar imaging technique during repeated painful heat stimuli. Activation of brain regions in response to thermal pain during hypnosis (using a fixation and command technique of hypnosis) was compared with responses without hypnosis. RESULTS: With hypnosis, less activation in the primary sensory cortex, the middle cingulate gyrus, precuneus, and the visual cortex was found. An increased activation was seen in the anterior basal ganglia and the left anterior cingulate cortex. There was no difference in activation within the right anterior cingulate gyrus in our fMRI studies. No activation was seen within the brainstem and thalamus under either condition. CONCLUSION: Our observations indicate that clinical hypnosis may prevent nociceptive inputs from reaching the higher cortical structures responsible for pain perception. Whether the effects of hypnosis can be explained by increased activation of the left anterior cingulate cortex and the basal ganglia as part of a possible inhibitory pathway on pain perception remains speculative given the limitations of our study design.     

High-dose remifentanil does not impair cerebrovascular carbon dioxide reactivity in healthy male volunteers

BACKGROUND: Cerebrovascular carbon dioxide reactivity during high-dose remifentanil infusion was investigated in volunteers by measurement of regional cerebral blood flow (rCBF) and mean CBF velocity (CBFv). METHODS: Ten healthy male volunteers with a laryngeal mask for artificial ventilation received remifentanil at an infusion rate of 2 and 4 microg x kg-1 x min-1 under normocapnia, hypocapnia, and hypercapnia. Stable xenon-enhanced computed tomography and transcranial Doppler ultrasonography of the left middle cerebral artery were used to assess rCBF and mean CBFv, respectively. If required, blood pressure was maintained within baseline values with intravenous phenylephrine to avoid confounding effects of altered hemodynamics. RESULTS: Hemodynamic parameters were maintained constant over time. Remifentanil infusion at 2 and 4 microg x kg-1 x min-1 significantly decreased rCBF and mean CBFv. Both rCBF and mean CBFv increased as the arterial carbon dioxide tension increased from hypocapnia to hypercapnia, indicating that cerebrovascular reactivity remained intact. The average slopes of rCBF reactivity were 0.56 +/- 0.27 and 0.49 +/- 0.28 ml. 100 g-1 x min-1 x mmHg-1 for 2 and 4 microg x kg-1 x min-1 remifentanil, respectively (relative change in percent/mmHg: 1.9 +/- 0.8 and 1.6 +/- 0.5, respectively). The average slopes for mean CBFv reactivity were 1.61 +/- 0.95 and 1.54 +/- 0.83 cm x s-1 x mmHg-1 for 2 and 4 microg x kg-1 x min-1 remifentanil, respectively (relative change in percent/mmHg: 1.86 +/- 0.59 and 1.79 +/- 0.59, respectively). Preanesthesia and postanesthesia values of rCBF and mean CBFv did not differ. CONCLUSION: High-dose remifentanil decreases rCBF and mean CBFv without impairing cerebrovascular carbon dioxide reactivity. This, together with its known short duration of action, makes remifentanil a useful agent in the intensive care unit when sedation that can be titrated rapidly is required.     

Remifentanil and the brain

Background and aim: Remifentanil is an ultra-short-acting opioid, increasingly used today in neuroanesthesia and neurointensive care. Its characteristics make remifentanil a potentially ideal agent, but previous data have cast a shadow on this opioid, supporting potentially toxic effects on the ischemic brain. The aim of the present concise review is to survey available up-to-date information on the effects of remifentanil on the central nervous system.
Method: A MEDLINE search within the past seven years for available up-to-date information on remifentanil and brain was performed.
Results: Concise up-to-date information on the effects of remifentanil on the central nervous system was reported, with a particular emphasis on the following topics: cerebral metabolism, electroencephalogram, electrocorticography, motor-evoked potentials, regional cerebral blood flow, cerebral blood flow velocity, arterial hypotension and hypertension, intracranial pressure, cerebral perfusion pressure, cerebral autoregulation, cerebrovascular CO₂ reactivity, cerebrospinal fluid, painful stimulation, analgesia and hyperalgesia, neuroprotection, neurotoxicity and hypothermia.
Conclusion: The knowledge of the influence of remifentanil on brain functions is crucial before routine use in neuroanesthesia to improve anesthesia performance and patient safety as well as outcome.     

Imaging pain modulation by subanesthetic S-(+)-ketamine

Little is known about the effects of low-dose S-(+)-ketamine on the cerebral processing of pain. We investigated the effects of subanesthetic IV S-(+)-ketamine doses on the perception of experimental painful heat stimuli. Healthy volunteers were evaluated with functional magnetic resonance imaging (fMRI) while receiving the painful stimuli in conjunction with placebo and increasing doses (0.05, 0.1, 0.15 mg x kg(-1) x h(-1)) of ketamine infusion. Vital variables were monitored and all subjects rated pain intensity and unpleasantness on a numerical rating scale. Alterations in consciousness were measured using a psycho-behavioral questionnaire. Pain unpleasantness declined as ketamine dosage was increased (55.1% decrease, placebo versus 0.15 mg x kg(-1) x h(-1) ketamine). Pain intensity ratings also decreased with increasing ketamine dosage but to a lesser extent (23.1% decrease). During placebo administration, a typical pain activation network (thalamus, insula, cingulate, and prefrontal cortex) was found, whereas decreased pain perception with ketamine was associated with a dose-dependent reduction of pain-induced cerebral activations. Analysis of the dose-dependent ketamine effects on pain processing showed a decreasing activation of the secondary somatosensory cortex (S2), insula and anterior cingulate cortex. This part of the anterior cingulate cortex (midcingulate cortex) has been linked with the affective pain component that underlines the potency of ketamine in modulating affective pain processing.     

The effect of remifentanil on cerebral blood flow velocity in children anesthetized with propofol

BACKGROUND: Cerebrovascular stability and rapid anesthetic emergence are desirable features of a neuroanesthetic regimen. In this randomized crossover study the effect of a low-dose remifentanil infusion on cerebral blood flow velocity (CBFV) in children anesthetized with propofol was evaluated. METHODS: Twenty healthy children aged 1-6 years undergoing urological surgery were enrolled. Following face mask induction with sevoflurane, anesthesia was maintained with a standardized propofol infusion. Rocuronium was used to facilitate tracheal intubation and normothermia, and normocapnia were maintained. All children received a caudal epidural block, and a transcranial Doppler probe was placed to measure middle cerebral artery blood flow velocity (Vmca). Each patient received a remifentanil regimen of 0.5 microg x kg(-1) followed by 0.2 microg x kg(-1) x min(-1) in a predetermined order of remifentanil + propofol or propofol alone. Vmca, mean arterial pressure (MAP) and heart rate (HR) were recorded simultaneously at equilibrium with and without remifentanil. RESULTS: The combination of remifentanil and propofol caused an 8.1% decrease in MAP (P = 0.0005) and an 11.8% decrease in HR (P < 0.0001) compared with propofol alone. Vmca was not different between the two groups (P = 0.4041). CONCLUSION: The addition of remifentanil to propofol anesthesia in children causes a reduction in MAP and HR without affecting CBFV. This may imply that cerebral blood pressure autoregulation is preserved in children under propofol and remifentanil anesthesia.     

Attention and sentence processing deficits in Parkinson's disease: the role of anterior cingulate cortex.

Parkinson's disease (PD) is a complex neurodegenerative condition involving a motor disorder that is related to reduced dopaminergic input to the striatum. Intellectual deficits are also seen in PD, but the pathophysiology of these difficulties is poorly understood. Regional cerebral blood flow (rCBF) was studied in neurologically intact subjects during the performance of attention-demanding, sentence processing tasks using positron emission tomography (PET). The results demonstrated significantly increased rCBF in a distributed set of cerebral regions during the detection of an adjective or a particular agent in a sentence, including anterior cingulate cortex, left inferior and middle frontal cortex, left inferior temporo-occipital cortex, posterolateral temporal cortex, left caudate, and left thalamus. We identified defects in this cerebral network by studying PD patients with two PET techniques. Resting PET studies revealed a significant correlation between regional cerebral glucose metabolism in anterior cingulate cortex and deficits in attending to subtle grammatical aspects of sentences. Studies of PD patients with the PET activation technique revealed little change in anterior cingulate and left frontal CBF during performance of the adjective detection or agent detection tasks. These data suggest that a defect in anterior cingulate cortex contributes to the cognitive impairments observed in PD.     

Cerebral representation of the anorectum using functional magnetic resonance imaging

BACKGROUND: Anorectal continence depends not only on the organs of continence but also on cerebral control. There are relatively few data regarding cerebral processing of anorectal continence. METHODS: Thirteen healthy subjects underwent rectal distension to cause urge increasing to discomfort during functional magnetic resonance imaging (fMRI). In addition, a painful heat stimulus was applied to the skin of the anterior abdominal wall in the dermatome corresponding to the rectum. Voluntary contraction of the anal sphincter was also performed. Subjective rating of stimulus intensity was recorded. Evaluation of the data used a general linear model with Brain Voyager(trade mark). RESULTS: Subjective sensation of discomfort increased during repeated rectal distension and caused activation in the anterior cingulate gyrus, insula, thalamus and secondary somatosensory cortex seen on fMRI. Perception of rectal urge and discomfort activated the same cerebral regions with differing intensity. Application of a painful thermal stimulus in the corresponding dermatome showed a modification of the response. Voluntary contraction of the anal sphincter led to activation of the motor cortex and increased activity in the supplementary motor cortex and the insula. CONCLUSION: Cerebral representation of the anorectum as mapped by fMRI is intricate and reflects the complexity of the continence mechanism.     

Increased regional cerebral blood flow in the contralateral thalamus after successful motor cortex stimulation in a patient with poststroke pain

The mechanisms underlying poststroke pain have not been clearly identified. Although motor cortex stimulation (MCS) sometimes reduces poststroke pain successfully, the exact mechanism is not yet known. For further investigation of the neural pathways involved in the processing of poststroke pain and in pain reduction by MCS, the authors used positron emission tomography (PET) scanning to determine significant changes in regional cerebral blood flow (rCBF). This 58-year-old right-handed man suffered from right-sided poststroke pain for which he underwent implantation of a stimulation electrode in the right motor cortex. After 30 minutes of stimulation, his pain was remarkably reduced (Visual Analog Scale scores decreased 8 to 1) and he felt warmth in his left arm. The rCBF was studied using PET scanning with 15O-labeled water when the patient was in the following states: before MCS (painful condition, no stimulation) and after successful MCS (painless condition, no stimulation). The images were analyzed using statistical parametric mapping software. State-dependent differences in global blood flow were covaried using analysis of covariance. Comparisons of the patient's rCBF in the painful condition with that in the painless condition revealed significant rCBF increases in the left rectus gyrus (BA11), left superior frontal lobe (BA9), left anterior cingulate gyms (BA32), and the left thalamus (p < 0.05, corrected). On the other hand, there were significant decreases in rCBF in the right superior temporal gyrus (BA22, p < 0.01, corrected) and the left middle occipital gyrus (BA19, p < 0.05, corrected). The efficacy of MCS was mainly related to increased synaptic activity in the thalamus, whereas the activations in the rectus gyrus, anterior cingulate gyrus, and superior frontal cortex as well as the inactivation of the superior temporal lobe may be related to emotional processes. This is the first report in which the contralateral thalamus was significantly activated and pain relief was achieved using MCS.     

Fentanyl is more effective than remifentanil at preventing increases in cerebral blood flow velocity during intubation in children

PURPOSE: Controlling the cerebral and systemic hemodynamic responses to laryngoscopy and tracheal intubation may play a role in determining clinical outcome in pediatric neurosurgical patients. This study compared the effects of remifentanil and fentanyl on cerebral blood flow velocity (CBFV) and hemodynamic profile during laryngoscopy and tracheal intubation in children under sevoflurane anesthesia. METHODS: Sixty healthy children aged two to six years undergoing dental surgery under general anesthesia were enrolled. Each child was randomly assigned to receive a remifentanil or fentanyl infusion, at a rate of 0.75, 1.0, or 1.5 microg x kg(-1) x min(-1) after induction of anesthesia with 2% sevoflurane. Middle cerebral artery blood flow velocity was measured by transcranial Doppler (TCD) sonography. Once a baseline set of hemodynamic variables and TCD measurements were recorded, the opioid infusion was started. Measurements were taken at two-minute intervals, starting four minutes prior to laryngoscopy until four minutes following naso-tracheal intubation. RESULTS: Remifentanil caused a more significant decrease in mean arterial pressure and CBFV prior to tracheal intubation than did fentanyl (P < 0.001). During laryngoscopy and for two minutes following tracheal intubation, CBFV increased in all remifentanil groups (P < 0.05), whereas it remained stable in all fentanyl groups. CONCLUSION: This study suggests that fentanyl was more effective than remifentanil at preventing increases in CBFV during and immediately following laryngoscopy and tracheal intubation in children undergoing sevoflurane anesthesia. Fentanyl also seemed to provide a more stable hemodynamic profile prior to laryngoscopy and tracheal intubation when compared to remifentanil.     

Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine

BACKGROUND: Remifentanil-induced secondary hyperalgesia has been documented experimentally in both animals and healthy human volunteers, but never clinically. This study tested the hypotheses that increased pain sensitivity assessed by periincisional allodynia and hyperalgesia can occur after relatively large-dose intraoperative remifentanil and that small-dose ketamine prevents this hyperalgesia. METHODS: Seventy-five patients undergoing major abdominal surgery were randomly assigned to receive (1) intraoperative remifentanil at 0.05 microg x kg(-1) x min(-1) (small-dose remifentanil); (2) intraoperative remifentanil at 0.40 microg x kg(-1) x min(-1) (large-dose remifentanil); or (3) intraoperative remifentanil at 0.40 microg x kg(-1) x min(-1) and 0.5 mg/kg ketamine just after the induction, followed by an intraoperative infusion of 5 microg x kg(-1) x min(-1) until skin closure and then 2 microg x kg(-1) x min(-1) for 48 h (large-dose remifentanil-ketamine). Pain scores and morphine consumption were recorded for 48 postoperative hours. Quantitative sensory tests, peak expiratory flow measures, and cognitive tests were performed at 24 and 48 h. RESULTS: Hyperalgesia to von Frey hair stimulation adjacent to the surgical wound and morphine requirements were larger (P < 0.05) and allodynia to von Frey hair stimulation was greater (P < 0.01) in the large-dose remifentanil group compared with the other two groups, which were comparable. There were no significant differences in pain, pressure pain detection threshold with an algometer, peak flow, cognitive tests, or side effects. CONCLUSION: A relatively large dose of intraoperative remifentanil triggers postoperative secondary hyperalgesia. Remifentanil-induced hyperalgesia was prevented by small-dose ketamine, implicating an N-methyl-d-aspartate pain-facilitator process.