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

Fifty-five participants with mild TBI were enrolled in this study. Eleven participants dropped out of this study before completing the last study visit at 4 months. These 11 participants were no-shows for the last follow-up visit and/or did not return calls and emails of research staff to schedule the follow-up visit. Thus, 44 participants completed the study and will be the focus herein. Mild TBI participants had to have a mild TBI diagnosis according to the criteria recommended by the World Health Organization Task Force [19]: 1) a Glasgow Coma Scale score between 13 and 15 when examined at the emergency center, 2) no abnormal findings on a computed tomography scan of the brain to exclude secondary disorders such as hematoma, cerebral vein thrombosis, cerebral hemorrhage, or epilepsy, and 3) the presence of one or more of the following: confusion or disorientation, post-traumatic amnesia for less than 24 h, or a loss of consciousness for less than 30 min. The mild TBI could not be due to drugs, alcohol, medications, caused by other injuries or treatments for other injuries, caused by other problems (i.e. coexisting medical conditions, psychological trauma), or a penetrating craniocerebral injury. Exclusion criteria included: 1) chronic cardiovascular disease or uncontrolled hypertension, 2) metabolic disease, 3) neurological disease, 4) serious psychiatric conditions or hospitalization within the preceding year for psychiatric illness, 5) chronic headaches before the head injury, 6) current involvement in litigation, 7) chronic use of narcotics, and 8) fracture or polytrauma at the time of head injury. A subset of these participants were included in the data analysis of Carey et al., which compared mild TBI participants 1–2 weeks post injury to matched control participants [13].

The Indiana University and St. Vincent Indianapolis Hospital Human Subject Review Boards approved this study. In this prospective, observational study, participants completed three laboratory visits. The first visit occurred within 2 weeks post injury while visits 2 and 3 occurred approximately 1-month and 4-months post injury, respectively. During visit 1, participants reviewed and signed a written informed consent form approved by the IRB. To verify participants met inclusion/exclusion criteria, participants completed a health history questionnaire supplemented by interview. During each visit, participants completed the same questionnaires and quantitative sensory tests (QST). These assessments are described below. All participants were asked to refrain from pain-relief medication and consuming caffeine on the day of testing before their session.

Descriptive statistics were calculated for all the outcome variables. The Chi-square test was conducted to determine whether differences in sex existed between the PPTH and no-PPTH groups. Independent-t tests examined group differences between BMI and age. First, we sought to determine differences in the primary outcome measures in mild TBI patients who developed PPTH’s compared to mild TBI patients who did not develop PPTH’s at 1-week, 1-month, and 4 months post injury. Shapiro-Wilk’s test of normality indicated that the TS variables were not normally distributed. Thus, Mann-Whitney U tests were conducted to determine if TS at the hand and forehead differed between the PPTH and No-PPTH groups at each time point. We conducted 2(Group) × 3(Time) mixed model ANOVAs with repeated measures on time on CPM score, PPT-Head, PCS score, CES-D score, and HA-intensity score. Due to difficulties with the algometer for one participant visit, the no-PPTH group had data for one participant missing in the analysis for PPT-Head. Because the Chi-square test indicated that sex differed between groups, sex was considered as a covariate in each analysis. Tukey’s post hoc tests were used for significant main effects or interactions. The p-value for significance was set at p < 0.05.

Secondly, we used multiple logistic regression to identify baseline (1–2 week) predictors of the presence of PPTH at 4 months post injury (0 = no-PPTH group, 1 = PPTH group). Due to the large number of potential predictors, the initial choice of the independent variables for the model was based on the results of the Chi-square tests and ANOVAs discussed above. Because sex was a potential confounding variable, sex was added into the model first. Other primary outcome variables with p < 0.10 were retained in the final model. The goodness of fit of the final multivariate model was evaluated by Hosmer–Lemeshow (H–L) test, with p > 0.05 representing the acceptable result. The p-value for significance was set at p < 0.05.

Means ± standard deviations and p-values for participant characteristics are presented in Table 1. The PPTH group contained significantly more females than the No-PPTH group, but no differences existed in age or BMI between groups. Reported causes of head injury included: falls, motor vehicle crashes, hit by object on head, hit by car/truck, hit head on wall, snow board accident, and bike accidents. Nineteen mild TBI participants reported loss of consciousness for under 30 min following head injury. Thirty-nine of 42 mild TBI participants reported headaches at visit 1, whereas 21 participants reported headaches at visit 3 (PPTH group). During visit 1, 36 participants reported taking medications for their headaches including triptans [1], NSAIDS [21], acetaminophen [17], opiates (6: short-term use only, as chronic use is an exclusion), and medicine that treats muscle spasms [4]. At 1-month post injury, 28 participants reported taking medications for their headaches including triptans [2], NSAIDS [22], acetaminophen [10], opiates (2, short-term use only, as chronic use is an exclusion), medicine that treats muscle spasms [2], and anti-anxiety [1] and antidepressant [1] medicine. At 4-months post injury, 20 participants reported taking medications for their headaches including triptans [2], NSAIDS [14], acetaminophen [6], medicine that treats muscle spasms [1], and anti-anxiety [2] and antidepressant [1] medicine. All participants reported taking medicine for abortive purposes only (i.e. only using medications when a headache was present). However, these medications were not taken on the day of testing, before the session took place.

Table 2 presents the means and standard errors (SE) of all primary outcome variables across time for the PPTH group and no-PPTH group. Data presented in the text represent mean ± SE.

The final model for the multiple logistic regression included sex, headache pain intensity at 1-week, and CPM score at 1-week as independent variables. The overall model was statistically significant, p < .001. The inferential goodness-of-fit test was the Hosmer-Lemeshow test that yielded an insignificant result (p = .340), indicating that the model fit the data well. The results for the individual predictors are provided in Table 3. Headache pain intensity and CPM score were significant predictors, with greater headache pain intensity and lower CPM score predicting a higher likelihood of having PPTH at 4 months post-injury.

Preclinical and human studies suggest that mild TBI is characterized by diminished pain inhibitory capacity in the early stages following injury [12‐14]. For example, a recent rodent study indicated that mild TBI may cause profound disruption of descending noxious inhibitory controls (DNIC). DNIC is the corresponding test in animals to CPM in humans [22]. The mechanism for diminished pain inhibition following mild TBI is unknown; however, it could be associated with TBI-induced damage to the ascending spinothalamic/ thalamocortical tracts in the brain [29]. Furthermore, prior research suggests that brain regions involved in the major descending pain inhibitory tracts, such as the brain stem, are particularly susceptible to damage following TBI [30]. This TBI-induced damage may diminish the descending inhibitory control that is elicited by ascending nociceptive information [31]. Importantly, our findings provide novel evidence that mild TBI patients developing persistent PTH exhibit significantly diminished pain inhibitory capacity following injury compared to those who do not develop persistent PTH. Furthermore, we showed that this diminished endogenous pain inhibitory control within 2 weeks post-injury places mild TBI patients at an increased risk for developing persistent PTH’s at 4 months post injury. These results are in line with Defrin et al., 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 [15]. Overall, our findings add to the accumulating body of research suggesting that individuals with impaired engagement of descending pain inhibitory pathways are at an increased risk for developing chronic pain [11, 32].

We also hypothesized that sensitization of the head/neck area, as measured by quantitative sensory tests, at 1–2 weeks post injury would play a role in persistent PTH’s. Prior research indicates that central sensitization is characteristic of many chronic pain conditions [9, 33, 34] and may be a risk factor for the development of intense and chronic pain [35]. Furthermore, our prior study had demonstrated greater pressure pain hyperalgesia of the head in the mild TBI patients compared to controls at 1–2 weeks post injury, with greater pressure pain hyperalgesia associated with headache pain within the mild TBI group [13]. Rodent studies have also revealed sustained sensitization to mechanical stimuli in the head area and distal sites in mice following mild TBI [12, 36]. However, our hypothesis was not supported. Pressure pain sensitivity and temporal summation of pain did not predict persistent PTH’s and were not significantly facilitated in the PPTH group compared to the no-PPTH group. These results are in contrast to a cross-sectional human study on primary headaches demonstrating the presence of sensitization of the head as measured by both PPT’s and temporal summation of pain in patients with chronic migraine and tension-type headaches compared to controls [9]. It is possible that longer maintenance of headaches facilitate greater central sensitization, rather than central sensitization being a contributing causal factor to persistent PTH. Perhaps with a longer maintenance of PTH, the sensitization measures would significantly differ between those with and without PTH’s in the chronic phase. However, larger studies with longer follow-up are needed to test this hypothesis.

Mild TBI is often accompanied by psychological distress [37], including high levels anxiety, depression, and pain catastrophizing [13]. In general, a substantial amount of evidence supports the importance of these psychological factors in shaping pain-related experiences. However, no prior research has longitudinally evaluated pain catastrophizing and posttraumatic headaches following mild TBI. 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. These findings are in accordance with prior research showing an increased co-occurrence of depression and PTH’s over time [38]. Additionally, Chaput and colleagues demonstrated cross-sectionally that pain catastrophizing was associated with adverse mild TBI outcomes at 8 weeks post mild TBI, including headache pain [17]. Notably, while depression and pain catastrophizing were elevated in the PPTH group, our findings indicated that these psychological processes at 1–2 weeks post injury did not increase the risk for the development of persistent PTH’s. One alternative explanation is that perhaps these psychological factors contribute to the intensity of headaches experienced vs. the maintenance of headaches over time. Indeed, non-TBI injury-related research has shown that pain catastrophizing at baseline predicts pain severity over 12-months following non-catastrophic injuries [39]. A second possibility is that PTH’s contribute to increased depression and pain catastrophizing versus these psychological factors increasing the risk for persistent PTH’s. In the current study, average depression scores in the PPTH group at each time point were higher than the recommended cut-off score for identifying risk of clinical depression. Importantly, past research has independently linked depression, headaches, and mild TBI to psychosocial impairment [40] and negative outcomes, such as suicidal ideation and behavior [41‐43]. Thus, future research should elucidate how these three variables interactively influence the risk of suicidal behavior and ideation. Furthermore, future research should consider known personality (i.e., affective temperament [43]) and environmental/behavioral (e.g., childhood maltreatment [43]) risk-factors in identifying mild TBI patients at highest risk for these negative psychological outcomes (i.e., depression, suicide).

While not the primary focus of the current study, we also evaluated other potential variables as predictors of persistent PTH. Notably, headache pain intensity at 1–2 weeks post injury increased the risk for persistent PTH, such that every 1-point increase in headache pain nearly doubled the risk for being in the PPTH group. Additionally, the PPTH group reported significantly greater headache pain in the early phase following injury compared to the no-PPTH group. However, the no-PPTH group averaged over a 4 on a 0–10 NRS scale at 1–2 weeks, indicating moderate headache pain still existed in the early phase post injury in those not developing chronic headaches. Other research has also shown the importance of acute pain in the development of chronic pain. For example, a large prospective observational study of PTH following mild and moderate TBI found that having a headache during the emergency department visit for the head injury (all participants recruited from the ED) was a risk factor for persistent PTH [44]. Research investigating the chronification of pain following fracture injuries also demonstrates that acute pain in the first weeks following injury is an important predictor of chronic pain [45‐47].

We also found a greater percentage of females in the PPTH group compared to the no-PPTH group. However, sex was not a significant predictor in the regression model. Research examining sex as a risk factor for persistent PTH has shown mixed results. A recent preclinical study found that traumatic head injury leads to an enhanced and prolonged cephalic hyperalgesic response in female compared to male rats [48]. Along these lines, some clinical research indicates that more women experience post-concussion symptoms (e.g., headaches) and complications following mild TBI compared to men [49, 50]. Additionally, Yilmaz and colleagues identified being a female as a significant risk factor for the presence of PTH 3-months after mild and moderate TBI [44]. In contrast, Mollayeva et al. found no sex differences in the frequency of head/neck and bodily pain for several months following mild TBI [51]. Given the contrasting results, further research is needed to elucidate the contribution of sex to persistent PTH susceptibility.

A few limitations of this study should be noted. First, all participants were recruited from the Emergency Department and we excluded patients with fracture or polytrauma. Thus, we do not know whether the current study’s results would generalize to mild TBI patients not seen at the ED or those with multiple injuries at the time of head injury. Secondly, we only followed participants for 4 months. Predictors of PTH’s at a longer duration post injury (i.e., 12 months) could be different from those found in this study. Third, at the four-month assessment, headaches were assessed retrospectively with an interview versus using a headache diary. Additionally, while we consulted with a neurologist on PTH classification, the neurologist did not personally conduct the headache interviews. Finally, no single defining, clinical characteristic exists for post-traumatic headache [52]. Prospective studies of post-traumatic headaches indicate migraine followed by tension-type headaches are the most common headache types in mild TBI patients [5]. Neuroimaging and electroencephalography studies suggest different and overlapping pathophysiological mechanisms underlying migraine and PTH [53]. As in the current study, very few PTH studies investigate the possibility of differential risk factors for PTH’s of various clinical presentations (i.e., migraine vs. tension-type, vs. mixed). Importantly, prior research has shown that central sensitization and deficient pain inhibition exists in migraine and tension-type headache patients, suggesting a common role for abnormal pain modulation in the chronification of different types of headache [9, 20]. However, future studies with larger sample sizes should still explore the possibility of both common and different underlying neurophysiological mechanisms underlying persistent PTH of different phenotypes.