Newly Published
Pain Medicine  |   September 2018
Brain Dynamics and Temporal Summation of Pain Predicts Neuropathic Pain Relief from Ketamine Infusion
Author Notes
  • From the Division of Brain, Imaging, and Behaviour – Systems Neuroscience, Krembil Brain Institute, Krembil Research Institute (R.L.B., J.C.C., A.R., J.A.K., K.S.H., N.R.O., A.B., K.D.D.) and Department of Anesthesia and Pain Management (L.V.R., A.B.), Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; and Institute of Medical Science (J.C.C., A.R., J.A.K., K.S.H., N.R.O., K.D.D.), Department of Anesthesia (L.V.R., A.B.), Institute of Health Policy Management and Evaluation (A.B.), and Department of Surgery (K.D.D.), University of Toronto, Toronto, Ontario, Canada.
  • Submitted for publication April 11, 2018. Accepted for publication July 27, 2018.
    Submitted for publication April 11, 2018. Accepted for publication July 27, 2018.×
  • Acknowledgments: The authors thank Aaron Kucyi, Ph.D. (Krembil Research Institute, Toronto, Canada) for his help developing the analysis pipeline, Eugen Hlasny, M.R.T. (M.R.) and Keith Ta, M.R.T. (M.R.) (both Toronto Western Hospital, Toronto, Canada) for expert technical assistance in magnetic resonance imaging acquisition, Marie-Andree Coulombe, Ph.D. (Krembil Research Institute, Toronto, Canada) for contributions to set up the study design, and Jamal Kara, B.Sc. and Sabeeh Alvi, H.B.Sc., C.C.R.P. (both Toronto Western Hospital, Toronto, Canada) for study assistance.
    Acknowledgments: The authors thank Aaron Kucyi, Ph.D. (Krembil Research Institute, Toronto, Canada) for his help developing the analysis pipeline, Eugen Hlasny, M.R.T. (M.R.) and Keith Ta, M.R.T. (M.R.) (both Toronto Western Hospital, Toronto, Canada) for expert technical assistance in magnetic resonance imaging acquisition, Marie-Andree Coulombe, Ph.D. (Krembil Research Institute, Toronto, Canada) for contributions to set up the study design, and Jamal Kara, B.Sc. and Sabeeh Alvi, H.B.Sc., C.C.R.P. (both Toronto Western Hospital, Toronto, Canada) for study assistance.×
  • Research Support: Supported by the Academic Health Science Centre Alternative Funding Plan Innovation Fund (Toronto Western Hospital, Toronto, Canada). R.L.B. was supported by a post-doctoral fellowship from the Canadian Institutes of Health Research (Ottawa, Canada).
    Research Support: Supported by the Academic Health Science Centre Alternative Funding Plan Innovation Fund (Toronto Western Hospital, Toronto, Canada). R.L.B. was supported by a post-doctoral fellowship from the Canadian Institutes of Health Research (Ottawa, Canada).×
  • Competing Interests: The authors declare no competing interests.
    Competing Interests: The authors declare no competing interests.×
  • Correspondence: Address correspondence to Dr. Davis: Krembil Brain Institute, Krembil Research Institute, University Health Network, Toronto Western Hospital, 399 Bathurst Street, Room MP12-306, Toronto, Ontario M5T 2S8, Canada. karen.davis@uhnresearch.ca. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Pain Medicine / Central and Peripheral Nervous Systems / Pain Medicine / Pharmacology
Pain Medicine   |   September 2018
Brain Dynamics and Temporal Summation of Pain Predicts Neuropathic Pain Relief from Ketamine Infusion
Anesthesiology Newly Published on September 6, 2018. doi:10.1097/ALN.0000000000002417
Anesthesiology Newly Published on September 6, 2018. doi:10.1097/ALN.0000000000002417
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • Ketamine is an N-methyl-d-aspartate antagonist with growing use in the management of chronic pain

  • Descending pain modulatory circuits are key modulators of chronic pain

What This Article Tells Us That Is New:

  • The infusion of ketamine resulted in meaningful pain relief in about 50% of patients with chronic neuropathic pain

  • The magnitude of temporal summation of pain and the dynamic engagement of the descending pain modulatory circuit predicted treatment efficacy and point to mechanisms by which ketamine can relieve pain

Background: Ketamine is an N-methyl-d-aspartate receptor antagonist that reduces temporal summation of pain and modulates antinociception. Ketamine infusions can produce significant relief of neuropathic pain, but the treatment is resource intensive and can be associated with adverse effects. Thus, it is crucial to select patients who might benefit from this treatment. The authors tested the hypothesis that patients with enhanced temporal summation of pain and the capacity to modulate pain via the descending antinociceptive brain pathway are predisposed to obtain pain relief from ketamine.

Methods: Patients with refractory neuropathic pain (n = 30) and healthy controls underwent quantitative sensory testing and resting-state functional magnetic resonance imaging and then completed validated questionnaires. Patients then received outpatient intravenous ketamine (0.5 to 2 mg · kg−1 · h−1; mean dose 1.1 mg · kg−1 · h−1) for 6 h/day for 5 consecutive days. Pain was assessed 1 month later. Treatment response was defined as greater than or equal to 30% pain relief (i.e., reduction in pain scores). We determined the relationship between our primary outcome measure of pain relief with pretreatment temporal summation of pain and with brain imaging measures of dynamic functional connectivity between the default mode network and the descending antinociceptive brain pathway.

Results: Approximately 50% of patients achieved pain relief (mean ± SD; Responders, 61 ± 35%; Nonresponders, 7 ± 14%). Pretreatment temporal summation was associated with the effect of ketamine (ρ = −0.52, P = 0.003) and was significantly higher in Responders (median [25th, 75th] = 200 [100, 345]) compared with Nonresponders (44 [9, 92]; P = 0.001). Pretreatment dynamic connectivity was also associated with the clinical effect of ketamine (ρ = 0.51, P = 0.004) and was significantly higher in Responders (mean ± SD, 0.55 ± 0.05) compared with Nonresponders (0.51 ± 0.03; P = 0.006). Finally, the dynamic engagement of the descending antinociceptive system significantly mediated the relationship between pretreatment pain facilitation and pain relief (95% CI, 0.005 to 0.065).

Conclusions: These findings suggest that brain and behavioral measures have the potential to prognosticate and develop ketamine-based personalized pain therapy.