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

Abstract

Editor’s Perspective 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−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.

Resting-state brain functional connectivity in patients with chronic pain who responded to subanesthetic-dose ketamine

“…Becerra reported that ketamine coma therapy recovered the altered brain functional network of patients with chronic pain, and the recovered state had paralleled as default networks of healthy volunteers 32 . Rachael reported that patients with refractory neuropathic pain who was treated with ketamine (0.5 to 2 mg/kg/h; mean dose 1.1 mg/kg/h) for 6 hour/day for 5 consecutive days 33 . They reported that approximately 50% of patients had a reduction in NRS of 30% or greater at 1 month after intravenous ketamine infusion, and the relationship between temporal summation of pain and pain relief is mediated by default mode network–descending antinociceptive pathway dynamic functional connectivity.…”

Pharmacokinetic and pharmacodynamic considerations for NMDA-receptor antagonist ketamine in the treatment of chronic neuropathic pain: an update of the most recent literature

“…Of all mentioned NMDAR antagonists, ketamine is possibly most efficacious in reducing windup and temporal summation [12]. In a recent study in patients with refractory NP, temporal summation measured just before treatment was a predictor of the efficacy of ketamine [13].…”

Exposure in vivo Induced Changes in Neural Circuitry for Pain-Related Fear: A Longitudinal fMRI Study in Chronic Low Back Pain

“…Further, results of clinical studies in chronic pain investigating treatment-induced functional brain changes show some overlap with neural changes related to pain-related fear and experimental fear extinction (e.g., implicating the amygdala, mPFC, and PAG) (Baliki et al, 2008; Becerra et al, 2014; Erpelding et al, 2014; Simons et al, 2014). The majority of treatment studies focused on intrinsic brain activity, i.e., in rest and without a specific task (Napadow et al, 2012; Harris et al, 2013; Bosma et al, 2018). The effects of EXP specifically have also only been investigated using resting-state fMRI (Zhu et al, 2018), showing that patients with post-traumatic stress disorder showed enhanced post-treatment resting-state functional connectivity between the amygdala, orbitofrontal cortex, hippocampus and the medial PFC.…”