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      Dissociative and analgesic properties of ketamine are independent and unaltered by sevoflurane general anesthesia

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          Ketamine-induced dissociation and analgesia are independent and robust to general anesthesia neural circuit alterations, suggesting that ketamine can be refined into a targeted pain therapeutic.



          Ketamine, an anesthetic adjunct, is routinely administered as part of a balanced general anesthetic technique. We recently showed that the acute analgesic and dissociation properties of ketamine are separable to suggest that distinct neural circuits underlie these states.


          We aimed to study whether this finding is robust to the substantial neural circuit alterations associated with general anesthesia.


          We conducted a single-site, open-label, randomized controlled, cross-over study of sevoflurane and sevoflurane-plus-ketamine (SK) general anesthesia in healthy subjects (n = 12). Before and after general anesthesia, we assessed precalibrated cuff pain intensity and nociceptive pain quality as well as dissociation using the Clinician-Administered Dissociative States Scale (CADSS). For statistical inference, we ran a variation of backward elimination repeated-measures analysis of covariance. Models with CADSS as a covariate term were used to assess whether dissociation mediated the effect of ketamine on pain intensity and quality.


          Sevoflurane-plus-ketamine general anesthesia was associated with a significant ( P = 0.0002) pain intensity decline of 3 (SE, 0.44). There was an order effect for dissociation such that SK was associated with a significant ( P = 0.0043) CADSS increase of 17.8 (3.2) when the SK treatment came first. When the pain intensity model was reanalyzed with CADSS as an additional covariate, the effect of CADSS was not significant. These results were also conserved for pain quality.


          Our findings suggest that the analgesic and dissociation properties of ketamine remain separable despite general anesthesia. Thus, ketamine may be used as a probe to advance our knowledge of dissociation independent pain circuits.

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          Most cited references 26

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          Consciousness and anesthesia.

          When we are anesthetized, we expect consciousness to vanish. But does it always? Although anesthesia undoubtedly induces unresponsiveness and amnesia, the extent to which it causes unconsciousness is harder to establish. For instance, certain anesthetics act on areas of the brain's cortex near the midline and abolish behavioral responsiveness, but not necessarily consciousness. Unconsciousness is likely to ensue when a complex of brain regions in the posterior parietal area is inactivated. Consciousness vanishes when anesthetics produce functional disconnection in this posterior complex, interrupting cortical communication and causing a loss of integration; or when they lead to bistable, stereotypic responses, causing a loss of information capacity. Thus, anesthetics seem to cause unconsciousness when they block the brain's ability to integrate information.
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            General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal.

            The mechanisms through which general anaesthetics, an extremely diverse group of drugs, cause reversible loss of consciousness have been a long-standing mystery. Gradually, a relatively small number of important molecular targets have emerged, and how these drugs act at the molecular level is becoming clearer. Finding the link between these molecular studies and anaesthetic-induced loss of consciousness presents an enormous challenge, but comparisons with the features of natural sleep are helping us to understand how these drugs work and the neuronal pathways that they affect. Recent work suggests that the thalamus and the neuronal networks that regulate its activity are the key to understanding how anaesthetics cause loss of consciousness.
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              Measurement of dissociative states with the Clinician-Administered Dissociative States Scale (CADSS).

              The purpose of this study was to develop an instrument for the measurement of present-state dissociative symptoms, the Clinician Administered Dissociative States Scale (CADSS). Reported here are interrater reliability and internal consistency of the CADSS, validity as assessed by comparisons with other instruments for the assessment of dissociation, and sensitivity of the CADSS to discriminate patients with dissociative disorders from patients with other psychiatric disorders and healthy subjects. Initial analyses indicated good interrater reliability and construct validity for the CADSS. Scores on the CADSS discriminated patients with dissociative disorders from the other groups.

                Author and article information

                Pain Rep
                Pain Rep
                Pain Reports
                Wolters Kluwer (Philadelphia, PA )
                Jul-Aug 2021
                03 June 2021
                : 6
                : 2
                [a ]Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA
                [b ]Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
                [c ]División de Anestesiología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
                [d ]Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, USA
                Author notes
                [* ]Corresponding author. Address: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, 55 Fruit St, Grey/Jackson, Rm. 434, Boston, MA 02114. Tel.: 617-724-7200. E-mail address: oluwaseun.akeju@ 123456mgh.harvard.edu (O.Akeju).
                PAINREPORTS-D-20-0148 00007
                Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

                This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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                ketamine, dissociation, pain, analgesia, sevoflurane


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