Rachael L Bosma1, Joshua C Cheng, Anton Rogachov, Junseok A Kim, Kasey S Hemington, Natalie R Osborne, Lakshmikumar Venkat Raghavan, Anuj Bhatia, Karen D Davis. 1. 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.) Department of Anesthesia and Pain Management (L.V.R., A.B.), Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada 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.) Department of Surgery (K.D.D.), University of Toronto, Toronto, Ontario, Canada.
Abstract
WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: 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 · h; mean dose 1.1 mg · kg · h) 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.
WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: 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 · h; mean dose 1.1 mg · kg · h) 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.
Authors: Alexandra E Koulouris; Robert R Edwards; Kathleen Dorado; Kristin L Schreiber; Asimina Lazaridou; Sharika Rajan; Jeffrey White; Jenniffer Garcia; Christopher Gibbons; Roy Freeman Journal: Pain Med Date: 2020-10-01 Impact factor: 3.750
Authors: Inge Timmers; Jeroen R de Jong; Mariëlle Goossens; Jeanine A Verbunt; Rob J Smeets; Amanda L Kaas Journal: Front Neurosci Date: 2019-09-17 Impact factor: 4.677
Authors: Thomas J P Mangnus; Maaike Dirckx; Krishna D Bharwani; Cecile C de Vos; Sander P G Frankema; Dirk L Stronks; Frank J P M Huygen Journal: Pain Pract Date: 2021-07-24 Impact factor: 3.079
Authors: Karen D Davis; Nima Aghaeepour; Andrew H Ahn; Martin S Angst; David Borsook; Ashley Brenton; Michael E Burczynski; Christopher Crean; Robert Edwards; Brice Gaudilliere; Georgene W Hergenroeder; Michael J Iadarola; Smriti Iyengar; Yunyun Jiang; Jiang-Ti Kong; Sean Mackey; Carl Y Saab; Christine N Sang; Joachim Scholz; Marta Segerdahl; Irene Tracey; Christin Veasley; Jing Wang; Tor D Wager; Ajay D Wasan; Mary Ann Pelleymounter Journal: Nat Rev Neurol Date: 2020-06-15 Impact factor: 42.937
Authors: Junseok A Kim; Rachael L Bosma; Kasey S Hemington; Anton Rogachov; Natalie R Osborne; Joshua C Cheng; Jiwon Oh; Benjamin T Dunkley; Karen D Davis Journal: Neuroimage Clin Date: 2020-02-26 Impact factor: 4.881