Brain Dynamics and Temporal Summation of Pain Predicts Neuropathic Pain Relief from Ketamine Infusion

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 2mg . kg(-1). h(-1); mean dose 1.1 mg .kg(-1) . h(-1)) for 6h/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 (rho = -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 (rho = 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.