Final Report:  Endogenous Modulation and Central Sensitization in New Daily Persistent Headache (NDPH) in Children

Summary

New daily persistent headache (NDPH) is the most intractable, most disabling, and least understood chronic headache subtype. It is particularly distressing when present in children and adolescents, often resulting in delay in diagnosis, multiple ineffective toxic treatment trials, and disruption of developmentally important familial, social, and academic experiences.

With the support of the Migraine Research Foundation and concerned families, we proposed a comprehensive study of pediatric NDPH, hoping to provide unique insights into the mechanisms of this chronic disease and, ultimately, suggest possible modulatory treatments. At the time of study closure, we did not discern a significant biomarker for the NDPH phenotype using offset analgesia or serum cytokine levels. In the imaging subset, resting-state functional connectivity for pain modulatory regions in the brain showed significant differences between NDPH patients and age-matched/sex-matched patients with persistent post-traumatic headache, as well as with a matched fMRI data set. Only 4 of the 25 patients with NDPH who used low-dose naltrexone for 3 months reported > 50% efficacy in pain reduction.

We sought to enroll a sample of 110 patients with NDPH and 50 age and sex matched healthy controls from the greater Boston area over a 3 year period. By the onset of COVID-19 precautions in March, 2020, 41 patients and 4 controls were entered into the database, with no subjects in a recovered state. Per protocol, three visits to the clinic were required and non-regional patients generally did not enroll. Participating patients did complete all visits. Thirteen patients had fMRI imaging. We gathered saliva samples for possible future cytokine RNA analysis. Enrollment was halted due to COVID-19 in-person patient restrictions and the prior enrollment difficulties.

Hypotheis vs. Findings

Primary Aims

Aim 1.1: Psychophysical Characterization of NDPH: To define differences in altered modulatory systems using offset analgesia as well as detailed clinical descriptors as part of a clinical evaluation in well characterized NDPH pediatric patients in the symptomatic and recovered state. We hypothesized that there would be significant differences and psychophysical parameters of offset analgesia between the symptomatic and recovered state. Specifically, there would be less pain inhibition as measured by the OA paradigm in the symptomatic patients. 

Findings: We were unable to enroll and have no patients in recovered state in a sample of 41 subjects. Preliminary results present a decrease in self-reported pain rating, further analysis will be conducted. We will also work to summarize the cumulated clinical descriptors on this patient population.

Aim 1.2: Treatment Effects in NDPH: To define the effects of naltrexone on patients with NDPH using offset analgesia. At present, we have 25 patients who have taken the study medication, low-dose naltrexone.  We hypothesized that there would be significant differences in offset analgesia in the pre vs. post treatment groups.

Findings: Preliminary results present no significant difference using offset analgesia in comparison to healthy controls. We will report on the current number of patients on their self-reported positive and negative effects of low-dose naltrexone. Further analysis of the whole aggregated data will examine the full spectrum of offset analgesic response in this patient population and the results will be compared with a control group in another OA study. We have a total of 35 subjects who have participated in offset analgesia, with 23 who have completed the test at all three visits.

Secondary Aims

Aim 2.1:  Laboratory Markers of Disease Persistence: To define the potential of pain-related inflammatory markers in predicting disease persistence.  Specifically, a cytokine panel consisting of Interleukin 1 Beta, Interleukin 6, Interleukin 8, and Tumor Necrosis Factor will be collected for evaluation. We hypothesized that Inflammatory Markers would also define differences in responders vs. non-responders.

Findings: In our sample of 41 patients, preliminary analysis shows no significant difference in laboratory markers for inflammation.

Aim 2.2: Brain Markers of Disease Resilience: To evaluate brain markers of disease state through an evaluation of resting state endogenous modulatory systems (viz., cingulate -> PAG connectivity). We hypothesized that specific functional brain connectivity would define significant differences in modulatory systems (viz., Anterior Cingulate -> PAG Connectivity) in responders vs. non-responders.

Findings: Currently the study has 13 participants who have completed the resting state imaging and show a difference in connectivity in comparison with post-traumatic headache population and healthy controls. We have collaborated with an imaging group to summarize the significance of this finding.

Unanswered Questions

Do patients with NDPH have discernable pathophysiologic differences, as defined by our current physiological and laboratory measures, from patients with other chronic pain disorders or uncomplicated chronic migraine?

Are the resting state fMRI findings robust in a larger patient sample, and do they clearly differentiate these patients from those with other chronic pain disorders and chronic migraine?

Is low- dose naltrexone, a putative antagonist of glial inflammation, effective at a higher dose or for particular patients qualified by history, physical exam, and psychological profiles?

Is our offset analgesia paradigm sensitive enough to detect central sensitization changes in patients with chronic headache, or should testing (strength of stimulus, site) be adjusted?

What This Means To You

In our daily clinical practice we see pediatric patients with severe and chronic disabling headache pain whose lives are complicated by school absence, decreased physical activity and socialization, disordered sleep, anxiety, depression, and family stress. We provide multidisciplinary care based on ongoing analyses of pain processing, based on current data available. We need a greater understanding of the complex nervous system changes in pediatric patients with chronic headache to effect meaningful change, advance a nascent field, and to answer the questions of our burdened families.