Anesthesiology 2004; 100:386 –94 © 2004 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Dose-dependent Effects of Propofol on the Central Processing of Thermal Pain Robert K. Hofbauer, Ph.D.,* Pierre Fiset, M.D.,† Gilles Plourde, M.D., M.Sc.,‡ Steven B. Backman, M.D., Ph.D.,§ M. Catherine Bushnell, Ph.D. Background: Anatomic and physiologic data show that mul- tiple regions of the forebrain are activated by pain. However, the effect of anesthetic level on nociceptive input to these re- gions 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 g/ml (alert control), 0.5 g/ml (mild sedation), 1.5 g/ml (moderate sedation), and 3.5 g/ml (unconsciousness). Results: During the 0.5-g/ml target propofol concentration (mild sedation), the subjects’ pain ratings increased relative to the alert control condition; correspondingly, pain-evoked re- gional cerebral blood flow increased in the thalamus and the anterior cingulate cortex. In contrast, when subjects lost con- sciousness (3.5 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 in- sular cortex. Conclusion: These data show that propofol has a dose-depen- dent effect on thalamocortical transfer of nociceptive informa- tion but that some pain-evoked cortical activity remains after loss of consciousness. ADVANCES in human brain–imaging techniques have led to the identification of multiple brain regions that are activated by painful stimuli. 1–3 However, images ac- quired using both positron emission tomography (PET) and functional magnetic resonance imaging may not reflect only neuronal activity related to the perception of pain, but also coupled epiphenomena of the pain expe- rience, such as autonomic, homeostatic, or behavioral reactions. Anatomic and physiologic evidence repeatedly points toward a network of cortical regions that subserve the pain experience. Nociceptive input is communicated via the somatosensory thalamus to the primary and sec- ondary somatosensory cortices (S1 and S2), 4,5 where information related to stimulus intensity, location, and temporal aspects are thought to be encoded. 6 –10 How- ever, the anterior cingulate cortex (ACC) and the insular cortex (IC) also respond to pain stimuli in a graded manner, 9 suggesting their possible importance in pain perception. Both ACC and IC receive direct input from thalamic nuclei, 11,12 and single-unit recordings within the ACC of rabbits, 13 monkeys, 14 and humans 15 have revealed nociceptive neurons. Pain-related activity in ACC may be particularly important for the affective di- mension of pain because ACC activity correlates with pain unpleasantness more strongly than other cortical regions. 16 The IC has been implicated in nociceptive and innocuous thermal processing, but other data suggest its importance in autonomic regulation, cardiovascular functioning, and homeostatic regulation. 12,17,18 To evaluate the possible participation of sensory and limbic regions in pain processing, we examined nocicep- tive transmission during different levels of propofol an- esthesia, which alters pain perception at subanesthetic doses. We have previously shown that propofol sedation and anesthesia interfere with thalamocortical informa- tion transfer of a vibrotactile stimulus. 19 However, be- cause noxious stimuli induce a wide range of physiologic responses, we hypothesized that the activation of only some anatomically discrete forebrain regions would cor- respond with propofol-induced changes in pain percep- tion. Further, these activations would be distinguishable from other pain-evoked forebrain activations that could correspond to the broader epiphenomena of pain pro- cessing and would be less directly influenced by the level of sedation (e.g., autonomic function, homeostasis, behavioral reactions). Therefore, in the current study, we used the anesthetic propofol to induce sedation and loss of consciousness and examined its influence on pain-evoked neural activation. Materials and Methods Subjects Fifteen healthy subjects (six men, nine women; all right-handed) aged between 18 and 33 yr (mean, 24.0 yr) participated. Before the study, all subjects underwent a thorough medical evaluation. They were pain-free and had no history of neurologic disorders. All procedures were approved by the Ethics and Research Committee of the Montreal Neurologic Institute and Hospital (Mon- treal, Quebec, Canada). Before initiating study-specific procedures, subjects signed a written consent form. * Research Scientist, Department of Neurology and Neurosurgery, † Assistant Professor, ‡ Professor, § Associate Professor, Department of Anesthesia,  Pro- fessor, Department of Neurology and Neurosurgery and Department of Anesthesia. Received from the Department of Neurology and Neurosurgery and the De- partment of Anesthesia, McGill University, Montreal, Quebec, Canada. Submitted for publication January 29, 2003. Accepted for publication September 22, 2003. Supported by the Medical Research Council of Canada, Ottawa, Ontario, Canada. Dr. Hofbauer was funded by the Fonds pour la recherche en santé du Québec, Quebec City, Quebec, Canada, and the Royal Victoria Hospital Research Institute, Montreal, Quebec, Canada. Address reprint requests to Dr. Bushnell: McGill Centre for Research on Pain, 3640 University Street, Room M19, Montreal, Quebec, Canada H3A 2B2. Address electronic mail to: catherine.bushnell@mcgill.ca. Individual article reprints may be purchased through the Journal Web site, www.anesthesiology.org. Anesthesiology, V 100, No 2, Feb 2004 386 Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/100/2/386/646026/0000542-200402000-00031.pdf by guest on 15 September 2022