The role of deficient pain modulatory systems in the development of persistent post-traumatic headaches following mild traumatic brain injury: an exploratory longitudinal study

DOI: https://doi.org/10.1186/s10194- 020- 01207- 1

Abstract-Summary The primary purpose of this prospective pilot study was to evaluate whether early pain modulatory profiles (sensitization and endogenous pain inhibitory capacity) and psychological factors after mild TBI predict the development of persistent PTH in mild TBI patients.

Participants completed the following outcome measures during each session: conditioned pain modulation to measure endogenous pain inhibitory capacity, tem- poral summation of pain and pressure pain thresholds of the head to measure sensi- tization of the head, Pain Catastrophizing Scale, Center for Epidemiological Studies—Depression Scale, and a standardized headache survey.

The results revealed that mild TBI patients developing persistent PTH exhibited significantly diminished pain inhibitory capacity, and greater depression and pain catastrophizing following injury compared to those who do not develop persis- tent PTH.

Logistic regression indicated that headache pain intensity at 1–2 weeks and pain inhibitory capacity on the conditioned pain modulation test at 1–2 weeks predicted persistent PTH classification at 4 months post injury.

The results suggested that persistent PTH is characterized by dysfunctional alter- ations in endogenous pain modulatory function and psychological processes in the early stages following mild TBI, which likely exacerbate risk for the mainte- nance of PTH.

Extended: Future studies with larger sample sizes should still explore the possi- bility of both common and different underlying neurophysiological mechanisms underlying persistent PTH of different phenotypes.

Background A cross-sectional human study demonstrated that mild TBI patients with chronic PTH (>1 year post injury) exhibit diminished pain inhibitory capacity compared to control groups [179], with the magnitude of headache pain intensity correlating negatively with magnitude of pain inhibition.

We sought to determine differences in pain sensitization and pain inhibitory capacity on quantitative sensory tests in mild TBI patients who develop persistent

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Post-concussion Syndrome

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PTH compared to mild TBI patients who do not develop persistent PTH across 4 months post injury.

We evaluated whether early pain modulatory (sensitization and endogenous pain inhibitory capacity) profiles and psychological factors after mild TBI predicted the development of persistent PTH’s in mild TBI patients.

We hypothesized that sensitization of the head, deficient pain inhibitory capacity, and increased pain catastrophizing at 1–2 weeks post injury would predict the development of persistent posttraumatic headaches following mild TBI at 4 months post injury.

Methods Several quantitative sensory tests in human experimental studies have been used to identify the presence of central sensitization including temporal summation of pain and generalized pressure hyperalgesia [180].

For the CPM test, pressure pain thresholds (test stimulus) on the left arm were measured before and immediately following the submersion of the right hand in a cold water bath (conditioning stimulus).

Diagnostic criteria of PPTH attributed to mild head injury according to the ICHD-3 includes [56]: (A) Headache fulfilling criteria C and D; (B) Head injury fulfilling both of the following: one associated with none of the following: (a) loss of consciousness for >30 min, (b) Glasgow Coma Scale (GCS) score <13, (c) post- traumatic amnesia lasting >24 h, (d) altered level of awareness for >24 h, (e) imag- ing evidence of a traumatic head injury such as skull fracture, intracranial hemorrhage and/or brain contusion; two associated with one or more of the follow- ing symptoms and/or signs: (a) transient confusion, disorientation or impaired con- sciousness, (b) loss of memory for events immediately before or after the head injury, (c) two or more of the following symptoms suggestive of mild traumatic brain injury: (i) nausea.

Results The mixed model ANOVA on headache pain intensity revealed a significant effect of time (p < 0.001) and group (p < 0.001), which was superseded by a significant time by group interaction (p < 0.001).

The follow-up tests indicated that headache pain intensity significantly decreased

from 1 to 2 weeks to 1 month to 4 months post injury in the no-PPTH group.

For CPM score, the ANOVA revealed a significant main effect of group (p = 0.001), with the no-PPTH group (M = 29.5 ± 3.6) exhibiting greater pain inhi- bition on the CPM test compared to the PPTH group (M = 11.9 ± 3.6).

The main effect of time (p < 0.001) was also significant, with pain catastrophiz- ing significantly greater at 1-week post injury (19.9 ± 1.6) compared to 1-month (14.9 ± 1.7) and 4 months post injury (12.3 ± 1.6).

Discussion Our findings provide novel evidence that mild TBI patients developing persistent PTH exhibit significantly diminished pain inhibitory capacity following injury com- pared to those who do not develop persistent PTH.

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5 Future Directions

We showed that this diminished endogenous pain inhibitory control within 2 weeks post-injury places mild TBI patients at an increased risk for developing per- sistent PTH’s at 4 months post injury.

These results are in line with Defrin and others, who demonstrated cross- sectionally that mild TBI patients at least 1 year post-injury with chronic PTH’s had diminished pain inhibitory capacity on the CPM test compared to mild TBI patients without headaches and mild TBI free individuals [179].

We provided evidence that mild TBI patients who develop persistent PTH’s report higher pain catastrophizing and depression at 1-week, 1-month, and 4-months post-injury compared to those who do not develop persistent PTH’s.

Conclusions No specific pharmacological therapy currently exists for persistent PTH [See Guglielmette and others for a Review of PPTH treatments: [181]].

Evidenced-based approaches to persistent PTH prevention and management are greatly needed in which mechanisms and other factors contributing to headache pain are identified to guide treatment.

The current study provides the first longitudinal human evidence for the contri- bution of deficient endogenous pain inhibition in the transition from acute to persis- tent PTH.

Once potential treatment targets are identified, such as deficient pain inhibition, a second step will be to test the efficacy of mechanistic based treatments (e.g., phar- macological agents aimed at increasing inhibitory tone) to prevent or manage per- sistent PTHs.

Acknowledgement A machine generated summary based on the work of Naugle, Kelly M.; Carey, Christopher; Evans, Eric; Saxe, Jonathan; Overman, Ryan; White, Fletcher A. 2020 in The Journal of Headache and Pain.

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