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Post-traumatic headache (PTH) is a common and debilitating consequence of traumatic brain injury (TBI), often resembling migraine and tension-type headaches. Despite its prevalence, the optimal treatment for PTH remains unclear, with current strategies largely extrapolated from other headache disorders. This review evaluates the use of onabotulinumtoxin A (ONA) and anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) in the treatment of PTH. A comprehensive literature search was conducted on PubMed, including studies published up to September 2024, focusing on the efficacy, safety, and mechanisms of onabotulinumtoxin A and anti-CGRP mAbs in PTH. Both clinical trials and observational studies were reviewed. ONA, widely recognized for its efficacy in chronic migraine, has shown limited benefits in PTH with only one trial involving abobotulinumtoxin A in a cohort of 40 subjects. A phase 2 trial with fremanezumab, an anti-CGRP monoclonal antibody, failed to demonstrate significant efficacy in PTH, raising questions about the utility of targeting CGRP in this condition. ONA may offer advantages over anti-CGRP mAbs, not only in terms of its broader mechanism of action but also in cost-effectiveness and higher patient adherence. Both ONA and anti-CGRP mAbs are potential options for the management of PTH, but the current evidence is insufficient to establish clear guidelines. The negative results from the fremanezumab trial suggest that CGRP inhibition may not be sufficient for treating PTH, whereas onabotulinumtoxin A's ability to target multiple pain pathways may make it a more promising candidate.

Objective: Our primary outcome was to determine the feasibility of patients with post-traumatic headache (PTH) keeping a daily headache diary and using sumatriptan as directed. Secondary outcomes include determining if sumatriptan is effective in aborting PTH and whether headache resolution is dependent on PTH phenotype., Background: PTH is prevalent and persistent after traumatic brain injury, yet there have been few studies evaluating the effects of pharmacological treatments in individuals with PTH., Methods: This is a single-arm, prospective, non-randomized phase 2 clinical trial registered at Clinicaltrials.gov (NCT01854385) and conducted from 2013 to 2017. Data analysis was completed in 2022. Of the 299 participants screened, 40 were enrolled in the study. Participants kept a headache diary documenting headache characteristics and severity. Headache characteristics were used to determine PTH phenotypes of migraine-like, probable migraine-like, or non-migraine-like. Participants reported whether sumatriptan was used for their headache, their response to the medication, if a second dose was taken, and their response to the second dose., Results: A total of 15 participants out of the 40 enrolled (mean [SD] age, 41.9 [14.2] years, and 53% [21/40] male), met the criteria for the use of sumatriptan, and completed all assessments. Average headache diary compliance rate for the final month of the study was 80% (372/465). While sumatriptan was used for only 19% (122/654) of all reported headaches, 72% (88/122) of those headaches resolved within 2 h of taking the medication. Resolution of headaches with sumatriptan was not significantly different among headache phenotypes (migraine-like: 22/38 [58%], probable migraine-like: 24/29 [83%], non-migraine-like: 6/15 [40%]; p = 0.154)., Conclusions: A daily headache diary is feasible for tracking headache symptoms. Preliminary results also suggest that sumatriptan, a migraine-specific medication, may be beneficial for the treatment of PTH of different clinical phenotypes. Future studies, such as a phase 3 clinical trial with a larger sample size, are needed to better understand the efficacy of sumatriptan in the treatment of PTH., (© 2024 American Headache Society.)

Objective: Despite the high prevalence, mild traumatic brain injury (mTBI)-induced chronic headache and cognitive deficits are poorly understood and lack effective treatments. Low-dose interleukin-2 (LD-IL-2) treatment soon after mTBI or overexpressing IL-2 in brain astrocytes prior to injury protects mice from developing post-traumatic headache (PTH)-related behaviors and cognitive decline. The present study addresses a clinically relevant knowledge gap: whether LD-IL-2 treatment long after the initial injury is still effective for chronic PTH and cognitive deficits., Methods: mTBI was induced by a noninvasive closed-head weight drop method. LD-IL-2 was administered 4-6 weeks post-mTBI to assess its effects on chronic PTH-related facial mechanical hypersensitivity as well as mTBI-induced impairment in novel object recognition and object location tests. Endogenous regulatory T (Treg) cells were depleted to investigate the mechanism of action of LD-IL-2., Results: Delayed LD-IL-2 treatment abolished chronic PTH-related behaviors. It also completely reversed mTBI-induced cognitive impairment in both male and female mice. Treg cell depletion not only prolonged PTH-related behaviors but also abolished the effects of LD-IL-2. Interestingly, LD-IL-2 treatment significantly increased the number of Treg cells in dura but not in brain tissues., Interpretation: These results suggest that the beneficial effects of LD-IL-2 treatment are mediated through the expansion of meningeal Treg cells. Collectively, our study identifies Treg as a cellular target and LD-IL-2 as a promising therapy for both chronic PTH and mTBI-induced cognitive impairment for both males and females, with a wide therapeutic time window and the potential of reducing polypharmacy in mTBI treatment. ANN NEUROL 2024;96:508-525., (© 2024 American Neurological Association.)

Background: Posttraumatic headache (PTH) is a common and debilitating symptom following repetitive mild traumatic brain injury (rmTBI), and it mainly resembles a migraine-like phenotype. While modulation of the endocannabinoid system (ECS) is effective in treating TBI and various types of pain including migraine, the role of augmentation of endocannabinoids in treating PTH has not been investigated., Methods: Repetitive mild TBI was induced in male C57BL/6J mice using the non-invasive close-head impact model of engineered rotational acceleration (CHIMERA). Periorbital allodynia was assessed using von Frey filaments and determined by the "Up-Down" method. Immunofluorescence staining was employed to investigate glial cell activation and calcitonin gene-related peptide (CGRP) expression in the trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC) of the rmTBI mice. Levels of 2-arachidonoyl glycerol (2-AG), anandamide (AEA), and arachidonic acid (AA) in the TG, medulla (including TNC), and periaqueductal gray (PAG) were measured by mass spectrometry. The therapeutic effect of endocannabinoid modulation on PTH was also assessed., Results: The rmTBI mice exhibited significantly increased cephalic pain hypersensitivity compared to the sham controls. MJN110, a potent and selective inhibitor of the 2-AG hydrolytic enzyme monoacylglycerol lipase (MAGL), dose-dependently attenuated periorbital allodynia in the rmTBI animals. Administration of CGRP at 0.01 mg/kg reinstated periorbital allodynia in the rmTBI animals on days 33 and 45 post-injury but had no effect in the sham and MJN110 treatment groups. Activation of glial cells along with increased production of CGRP in the TG and TNC at 7 and 14 days post-rmTBI were attenuated by MJN110 treatment. The anti-inflammatory and anti-nociceptive effects of MJN110 were partially mediated by cannabinoid receptor activation, and the pain-suppressive effect of MJN110 was completely blocked by co-administration of DO34, an inhibitor of 2-AG synthase. The levels of 2-AG in TG, TNC and PAG were decreased in TBI animals, significantly elevated and further reduced by the selective inhibitors of 2-AG hydrolytic and synthetic enzymes, respectively., Conclusion: Enhancing endogenous levels of 2-AG appears to be an effective strategy for the treatment of PTH by attenuating pain initiation and transmission in the trigeminal pathway and facilitating descending pain inhibitory modulation., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Large conductance  calcium-activated potassium (BK Ca ) channels have been implicated in the neurobiological underpinnings of migraine. Considering the clinical similarities between migraine and persistent post-traumatic headache (PPTH), we aimed to examine whether MaxiPost (a BK Ca channel opener) could induce migraine-like headache in persons with PPTH., Methods: This is a randomized double-blind, placebo-controlled, two-way crossover study from September 2023 to December 2023. Eligible participants were adults with PPTH after mild traumatic brain injury who reported having no personal history of migraine. The randomized participants received a single dose of either MaxiPost (0.05 mg/min) or placebo (isotonic saline) that was infused intravenously over 20 minutes. The two experiment sessions were scheduled at least one week apart to avoid potential carryover effects. The primary endpoint was the induction of migraine-like headache after MaxiPost as compared to placebo within 12 hours of drug administration. The secondary endpoint was the area under the curve (AUC) values for headache intensity scores between MaxiPost and placebo over the same 12-hour observation period., Results: Twenty-one adult participants (comprising 14 females and 7 males) with PPTH were enrolled and completed both experiment sessions. The proportion of participants who developed migraine-like headache was 11 (52%) of 21 participants after MaxiPost infusion, in contrast to four (19%) participants following placebo (P = .02). Furthermore, the median headache intensity scores, represented by AUC values, were higher following MaxiPost than after placebo (P < .001)., Conclusions: Our results indicate that BK Ca channel opening can elicit migraine-like headache in persons with PPTH. Thus, pharmacologic blockade of BK Ca channels might present a novel avenue for drug discovery. Additional investigations are nonetheless needed to confirm these insights and explore the therapeutic prospects of BK Ca channel blockers in managing PPTH., Gov Identifier: NCT05378074., (© 2024. The Author(s).)

Background: Phosphodiesterase 3 (PDE-3) inhibition have been implicated in the neurobiologic underpinnings of migraine. Considering the clinical similarities between migraine and persistent post-traumatic headache (PPTH), we aimed to ascertain whether PDE-3 inhibition can elicit migraine-like headache in persons with PPTH., Methods: We tested cilostazol, which inhibits PDE-3, in a randomized, double-blind, placebo-controlled, two-way crossover study involving persons with PPTH attributed to mild traumatic brain injury. The randomized participants were allocated to receive oral administration of either 200-mg cilostazol or placebo (calcium tablet) on two separate experiment days. The primary end point was the incidence of migraine-like headache during a 12-hour observation window post-ingestion. The secondary endpoint was the area under the curve (AUC) for reported headache intensity scores during the same observation window., Results: Twenty-one persons underwent randomization and completed both experiment days. The mean participants' age was 41.4 years, and most (n = 17) were females. During the 12-hour observation window, 14 (67%) of 21 participants developed migraine-like headache post-cilostazol, in contrast to three (14%) participants after placebo (P =.003). The headache intensity scores were higher post-cilostazol than after placebo (P <.001)., Conclusions: Our results provide novel evidence showing that PDE-3 inhibition can elicit migraine-like headache in persons with PPTH. Given that PDE-3 inhibition increases intracellular cAMP levels, our findings allude to the potential therapeutic value of targeting cAMP-dependent signaling pathways in the management of PPTH. Further investigations are imperative to substantiate these insights and delineate the importance of cAMP-dependent signaling pathways in the neurobiologic mechanisms underlying PPTH., Gov Identifier: NCT05595993., (© 2024. The Author(s).)

Pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38), known for its role in migraine pathogenesis, has been identified as a novel drug target. Given the clinical parallels between post-traumatic headache (PTH) and migraine, we explored the possible role of PACAP-38 in the pathogenesis of PTH. To this end, we conducted a randomized, double-blind, placebo-controlled, two-way crossover trial involving adult participants diagnosed with persistent PTH resulting from mild traumatic brain injury. Participants were randomly assigned to receive a 20-min continuous intravenous infusion of either PACAP-38 (10 pmol/kg/min) or placebo (isotonic saline) on two separate experimental days, with a 1-week washout period in between. The primary outcome was the difference in incidence of migraine-like headache between PACAP-38 and placebo during a 12-h observational period post-infusion. The secondary outcome was the difference in the area under the curve (AUC) for baseline-corrected median headache intensity scores during the same 12-h observational period. Of 49 individuals assessed for eligibility, 21 were enrolled and completed the trial. The participants had a mean age of 35.2 years, and 16 (76%) were female. Most [19 of 21 (90%)] had a migraine-like phenotype. During the 12-h observational period, 20 of 21 (95%) participants developed migraine-like headache after intravenous infusion of PACAP-38, compared with two (10%) participants after placebo (P < 0.001). Furthermore, the baseline-corrected AUC values for median headache intensity scores during the 12-h observational period was higher after PACAP-38 than placebo (P < 0.001). These compelling results demonstrate that PACAP-38 is potent inducer of migraine-like headache in people with persistent PTH. Thus, targeting PACAP-38 signalling might be a promising avenue for the treatment of PTH., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Purpose of Review: We evaluate evidence-based treatments for posttraumatic headache (PTH), a secondary headache disorder resulting from traumatic brain injury (TBI), comprising nearly 4% of all symptomatic headache disorders. Utilizing recent publications, we aim to inform clinicians of current treatment methods., Recent Findings: There is limited research on PTH treatment. A randomized controlled trial (RCT) of metoclopramide with diphenhydramine for acute PTH found that the treatment group (N = 81) experienced more significant pain improvement than placebo by 1.4 points. For persistent PTH, an open-label study of erenumab (N = 89) found that 28% of participants reported ≥ 50% reduction in moderate-to-severe headache days, but an RCT of fremanezumab showed a non-significant reduction in moderate-to-severe headache days. A randomized crossover study of 40 patients with persistent PTH found that onabotulinum toxin-A decreased cumulative number of headaches/week by 43.3% in the treatment group and increased by 35.1% among placebos. In a study of military veterans with severe posttraumatic stress disorder and persistent/delayed onset PTH (N = 193), patients who received Cognitive Behavioral Therapy reported significant improvements in headache-related disability compared to usual care (aggregate mean HIT-6, -3.4). A transcranial magnetic stimulation (N = 24) study found that 58% of participants with mild TBI-related headache experienced a 50% reduction in headache frequency. New studies indicate promise in improving clinically important outcomes of PTH. However, more research is necessary to determine the optimal treatment and whether combining pharmacologic and nonpharmacologic treatment versus a single modality is more effective., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Persistent headache attributed to traumatic injury to the head is divided into two subtypes, one attributed to moderate or severe traumatic injury and another attributed to mild traumatic injury (i.e., concussion). The latter is much more prevalent, in part because more than 90% of cases with traumatic brain injury are classified as mild. The pathophysiology of persistent post-traumatic headache is poorly understood and the underlying mechanisms are likely multifactorial. There is currently no approved treatment specifically for persistent post-traumatic headache, and management strategies rely on medications used for migraine or tension-type headache. Therefore, high-quality trials are urgently needed to support clinical decision-making and optimize management strategies. International guidelines can facilitate appropriate trial design and ensure the acquisition of high-quality data evaluating the efficacy, tolerability, and safety of available and novel pharmacological therapies for the preventive treatment of persistent post-traumatic headache., Methods: The development of this guideline was based on a literature review of available studies in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, along with a review of previously published guidelines for controlled trials of preventive treatment for episodic and chronic migraine. The identified literature was critically appraised, and due to the scarcity of scientific evidence, recommendations were primarily based on the consensus of experts in the field., Objective: To provide guidelines for designing state-of-the-art controlled clinical trials aimed at evaluating the effectiveness of preventive treatments for persistent post-traumatic headache attributed to mild traumatic brain injury.

Objective: To investigate whether levcromakalim (a K ATP channel opener) induces migraine-like headache in people with persistent post-traumatic headache who had no known history of migraine., Methods: In a randomized, double-blind, placebo-controlled, 2-way crossover trial, participants were randomly assigned to receive a 20-minute continuous intravenous infusion of levcromakalim (50 µg/mL) or placebo (isotonic saline) on two separate experimental days with a 1-week wash-out period in between. The primary endpoint was the difference in incidence of migraine-like headache between levcromakalim and placebo during a 12-hour observational period after infusion start. The secondary endpoint was the difference in area under the curve for baseline-corrected median headache intensity scores between levcromakalim and placebo during the 12-hour observational period., Results: A total of 21 participants with persistent post-traumatic headache were randomized and completed the trial. During the 12-hour observational period, 12 (57%) of 21 participants reported experiencing migraine-like headache following the levcromakalim infusion, compared with three after placebo ( P  = 0.013). Moreover, the baseline-corrected median headache intensity scores were higher following the levcromakalim infusion than after placebo ( P  = 0.003)., Conclusion: Our findings suggest that K ATP channels play an important role in the pathogenesis of migraine-like headache in people with persistent post-traumatic headache. This implies that K ATP channel blockers might represent a promising avenue for drug development. Further research is warranted to explore the potential therapeutic benefits of K ATP channel blockers in managing post-traumatic headache. Trial Registration : ClinicalTrials.gov Identifier: NCT05243953., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DWD. reports the following competing interests. Consulting: Amgen, Atria, CapiThera Ltd., Cerecin, Ceruvia Lifesciences LLC, CoolTech, Ctrl M, Allergan, AbbVie, Biohaven, GlaxoSmithKline, Lundbeck, Eli Lilly, Novartis, Impel, Satsuma, Theranica, WL Gore, Genentech, Nocira, Perfood, Praxis, AYYA Biosciences, Revance, Pfizer. Honoraria: American Academy of Neurology, Headache Cooperative of the Pacific, Canadian Headache Society, MF Med Ed Research, Biopharm Communications, CEA Group Holding Company (Clinical Education Alliance LLC), Teva (speaking), Amgen (speaking), Eli Lilly (speaking), Lundbeck (speaking), Pfizer (speaking), Vector Psychometric Group, Clinical Care Solutions, CME Outfitters, Curry Rockefeller Group, DeepBench, Global Access Meetings, KLJ Associates, Academy for Continued Healthcare Learning, Majallin LLC, Medlogix Communications, Medica Communications LLC, MJH Lifesciences, Miller Medical Communications, WebMD Health/Medscape, Wolters Kluwer, Oxford University Press, Cambridge University Press. Non-profit board membership: American Brain Foundation, American Migraine Foundation, ONE Neurology, Precon Health Foundation, International Headache Society Global Patient Advocacy Coalition, Atria Health Collaborative, Arizona Brain Injury Alliance, Domestic Violence HOPE Foundation/Panfila. Research support: Department of Defense, National Institutes of Health, Henry Jackson Foundation, Sperling Foundation, American Migraine Foundation, Henry Jackson Foundation, Patient Centered Outcomes Research Institute (PCORI). Stock options/shareholder/patents/board of directors: Aural analytics (options), Axon Therapeutics (shares/board), ExSano (options), Palion (options), Man and Science, Healint (options), Theranica (options), Second Opinion/Mobile Health (options), Epien (options), Nocira (options), Matterhorn (shares), Ontologics (shares), King-Devick Technologies (options/board), EigenLyfe (shares), AYYA Biosciences (options), Cephalgia Group (shares/board), Atria Health (options/employee). Patent 17189376.1-1466:vTitle: Onabotulinum Toxin Dosage Regimen for Chronic Migraine Prophylaxis (Non-royalty bearing). Patent application submitted: Synaquell® (Precon Health). In addition, R.B. has received honoraria, acted as a consultant or advisory board member for Alder, Allergan, Amgen, Autonomic Technologies, Avanir, Biohaven, CGRP Diagnostics, Dr. Reddy's Laboratories, ElectroCore, Eli Lilly, GlaxoSmithKline, Merck, Pernix, Teva, and Trigemina. RB also reports receiving CME fees from Healthlogix, Medlogix, and WebMD/Medscape, and holds patents for several products, including (9061025, 11732265.1, 10806890, US2021-0015908, WO21007165, US2021-0128724, WO21005497). RB is a reviewer for the National Institute of Neurological Disorders and Stroke (NINDS) and holds stock options in Allay Lamp and Percept, outside of the submitted work. HA reports personal fees from Teva, outside of the submitted work. HMA reports personal fees from Pfizer, outside of the submitted work. The remaining authors declare no competing interests.

Posttraumatic headache (PTH) attributed to traumatic brain injury (TBI) is a secondary headache developed within 7 days after head injury, and in a substantial number of patients PTH becomes chronic and lasts for more than 3 months. Current medications are almost entirely relied on the treatment of primary headache such as migraine, due to its migraine-like phenotype and the limited understanding on the PTH pathogenic mechanisms. To this end, increasing preclinical studies have been conducted in the last decade. We focus in this review on the trigeminovascular system from the animal studies since it provides the primary nociceptive sensory afferents innervating the head and face region, and the pathological changes in the trigeminal pathway are thought to play a key role in the development of PTH. In addition to the pathologies, PTH-like behaviors induced by TBI and further exacerbated by nitroglycerin, a general headache inducer through vasodilation are reviewed. We will overview the current pharmacotherapies including calcitonin gene-related peptide (CGRP) monoclonal antibody and sumatriptan in the PTH animal models. Given that modulation of the endocannabinoid (eCB) system has been well-documented in the treatment of migraine and TBI, the therapeutic potential of eCB in PTH will also be discussed.

Objective: Investigation of onabotulinumtoxinA in a murine model of acute and persistent post-traumatic headache., Methods: Mild traumatic brain injury was induced with a weight drop method. Periorbital and hindpaw cutaneous allodynia were measured for 14 days. Mice were then exposed to bright light stress and allodynia was reassessed. OnabotulinumtoxinA (0.5 U) was injected subcutaneously over the cranial sutures at different post-injury time points., Results: After milt traumatic brain injury, mice exhibited periorbital and hindpaw allodynia that lasted for approximately 14 days. Allodynia could be reinstated on days 14-67 by exposure to stress only in previously injured mice. OnabotulinumtoxinA administration at 2 h after mild traumatic brain injury fully blocked both transient acute and stress-induced allodynia up to day 67. When administered 72 h post-mild traumatic brain injury, onabotulinumtoxinA reversed acute allodynia, but only partially prevented stress-induced allodynia. OnabotulinumtoxinA administration at day 12, when initial allodynia was largely resolved, produced incomplete and transient prevention of stress-induced allodynia. The degree of acute allodynia correlated positively with subsequent stress-induced allodynia., Conclusion: Mild traumatic brain injury induced transient headache-like pain followed by long lasting sensitization and persistent vulnerability to a normally innocuous stress stimulus, respectively modeling acute and persistent post-traumatic headache.. Administration of onabotulinumtoxinA following the resolution of acute post-traumatic headache diminished persistent post-traumatic headache but the effects were transient, suggesting that underlying persistent mild traumatic brain injury-induced maladaptations were not reversed. In contrast, early onabotulinumtoxinA administration fully blocked both acute post-traumatic headache as well as the transition to persistent post-traumatic headache suggesting prevention of neural adaptations that promote vulnerability to headache-like pain. Additionally, the degree of acute post-traumatic headache was predictive of risk of persistent post-traumatic headache.

Background: Cervicogenic headache (CGH) can often be difficult to treat, given the overlapping clinical features of other headaches and the varying sources of pain that patients report. While imaging is not useful in diagnosing CGH, anesthetic blockade of the atlanto-occipital joint, lateral atlantoaxial joint, or specific cervical zygapophyseal joints can be used to confirm the diagnosis. When conservative treatment measures, such as physical therapy, fail, interventional techniques, such as intraarticular steroid injections, have been shown in observational studies to provide relief in some patients., Objectives: To determine the efficacy of intraarticular cervical facet steroid injections in the treatment of CGH., Study Design: Systematic review and meta-analysis., Methods: We conducted a comprehensive search of Ovid Medline, Embase, Cochrane Central Register of Controlled Trials , Cumulative Index to Nursing and Allied Health Literature Plus with Full Text, Scopus, and the Web of Science platform, from inception to April 2021, for studies using intraarticular cervical facet injections to treat CGH in adults aged 18 or older. Primary outcomes included mean postinjection pain scores. Outcomes were pooled using a random effects model and reported as mean differences (MD) with 95% confidence intervals (CI)., Results: Three studies with a total of 64 patients met the inclusion criteria. According to data from each of the included studies, intraarticular cervical facet injections were shown to demonstrate improvement in the mean pain score from baseline to postintervention. The overall effect size-pooled MD in the Visual Analog Scale score-was 3.299 (95% CI: 2.045 to 4.552, P < 0.001). Heterogeneity (I2) was 36.11%., Limitations: Small sample size, lack of control group, and varying pain generators and interventional technique between studies contribute to the limitations of the analysis., Conclusions: Our findings suggest that therapeutic intraarticular cervical facet injections may be effective in the treatment of CGH. Because of the heterogeneity among the studies, these results should be interpreted with caution.

Purpose of Review: Post-traumatic headache is a common sequela of injury to the head and/or neck. Here, we review the current approach to pharmacologic management of post-traumatic headache and explore the therapeutic promise of targeting calcitonin gene-related peptide signaling to address unmet treatment needs., Recent Findings: The scarcity of data from controlled trials has left clinicians to rely on mainly expert opinion for the pharmacologic management of post-traumatic headache. The current view is that a phenotype-guided approach should be used, in which patients are treated according to the primary headache phenotype that their clinical features resemble the most (e.g. migraine, tension-type headache). Moreover, incremental advances are being made in the field that aim to identify possible cellular and molecular drivers of headache persistence. Calcitonin gene-related peptide has emerged as a key drug target which, in turn, has prompted novel insights on the potential importance of early initiation of pharmacologic treatment following the onset of post-traumatic headache. This, in turn, might prevent subsequent persistence and chronification of headache., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose of Review: To discuss the treatment of post-traumatic headache (PTH) and how to choose pharmacotherapy based upon known pathophysiology., Recent Findings: Preclinical models of traumatic brain injury are finally revealing some of the mechanisms of PTH, including the significant role that inflammatory neuropeptides like calcitonin gene-related peptide (CGRP) play in the initiation and persistence of symptoms. To effectively treat post-traumatic headache (PTH), one needs to understand the pathophysiology behind the initiation and persistence of symptoms. Recent animal models are starting to elucidate these mechanisms, but effective treatment will also likely rely on the identification of patients who are most at risk for persistent PTH. Trials of early, targeted therapy for at-risk patients will be needed to validate these hypotheses. Additionally, high powered clinical trials are lacking in the field of persistent PTH for medications that are known to be effective in primary headache disorders. Effective treatment for persistent PTH also requires understanding how headache interacts with the complex nature of persistent post-concussion symptoms, as this disease often necessitates a multi-disciplinary approach. Regardless, with the knowledge gained by new PTH models cited in this paper, and an increasing availability of novel headache medications, more effective treatment models are on the horizon.

Objectives: The pathogeneses of chronic tension-type headache (CTTH) and cervicogenic headache (CEH) are not well established. Peripheral activation or sensitization of myofascial nociceptors is suggested as a potential mechanism and injections of botulinum toxin (BONTA) have thus been used in the treatment for both headache conditions. BONTA inhibits the release of acetylcholine at the neuromuscular junction and inhibits contraction of skeletal muscles. If the pain is precipitated by increased tone in cervical muscles, local injections of BONTA could represent a prophylactic measure. However, the treatment is still controversial, and a thorough assessment of the current evidence is required. This review aims to assess the evidence of BONTA injection as a prophylactic treatment for CTTH and CEH by reviewing and examining the quality of placebo-controlled, randomized trials., Methods: Data sources: we searched in the following databases: PubMed (including Medline), Embase, Cochrane Central register of Controlled Trials, Cinahl, Amed, SCOPUS and Google Scholar including other repository sources. Both MeSH and free keywords were used in conducting the systematic search in the databases. The search covered publications from the root of the databases to November 2020., Study Eligibility Criteria: The review included RCTs, comparing single treatment of BONTA with placebo on patients with CTTH or CEH above 18 years of age, by measuring pain severity/relief or headache frequency., Data Extraction: The following data were extracted: year of publication, country, setting, trial design, number of participants, injection procedure, BONTA dosages, and clinical outcome measures., Study Appraisal: To assess validity and quality, and risk of bias, the Oxford Pain Validity Scale, Modified Jadad Scale, last version of Cochrane Collaboration's tool for assessing risk of bias (RoB 2), and the CONSORT 2010 Checklist were used. The trials were assessed, and quality scored independently by two of the reviewers. A quantitative synthesis and meta-analyses of headache frequency and intensity were performed., Results: We extracted 16 trials, 12 on prophylactic BONTA treatment for CTTH and four on CEH. Of these 12 trials (8 on CTTH and 4 on CEH) were included in the quantitative synthesis. A majority of the trials found no significant difference on the primary outcome measure when BONTA treatment was compared with placebo. Three "positive" trials, reporting significant difference in favor of BONTA treatment, but two of these were hampered by low validity and quality scores and high risk of bias., Conclusions: There is no clear clinical evidence supporting prophylactic treatment with BONTA for CTTH or CEH., (© 2021 Sissel Breivold Roland et al., published by De Gruyter, Berlin/Boston.)

Objective: To determine whether IV metoclopramide 20 mg + diphenhydramine 25 mg (M + D) was more efficacious than IV placebo for acute moderate or severe posttraumatic headache in the emergency room., Methods: We conducted this randomized, double-blind, placebo-controlled, parallel-group study in 2 urban emergency departments (EDs). Participants who experienced head trauma and presented to our EDs within 10 days with a headache fulfilling criteria for acute posttraumatic headache were included. We randomized participants in a 1:1 ratio to M + D or placebo. Participants, caregivers, and outcome assessors were blinded to assignment. The primary outcome was improvement in pain on a scale of 0 to 10 between baseline and 1 hour after treatment., Results: This study was completed between August 2017 and March 2020. We screened 414 patients for participation and randomized 160: 81 to M + D and 79 to placebo. Baseline characteristics were comparable between the groups. All enrolled participants provided primary outcome data. Patients receiving placebo reported mean improvement of 3.8 (SD 2.6), while those receiving M + D improved by 5.2 (SD 2.3), for a difference favoring metoclopramide of 1.4 (95% confidence interval [CI] 0.7-2.2, p < 0.01). Adverse events were reported by 35 of 81 (43%) patients who received metoclopramide and 22 of 79 (28%) of patients who received placebo (95% CI 1-30 for difference of 15%, p = 0.04)., Conclusion: M + D was more efficacious than placebo with regard to relief of posttraumatic headache in the ED., Trial Registration Information: ClinicalTrials.gov Identifier: NCT03220958., Classification of Evidence: This study provides Class I evidence that for patients with acute moderate or severe posttraumatic headache, IV M + D significantly improved pain compared to placebo., (© 2021 American Academy of Neurology.)

Introduction: Botulinum toxin type A (BoNT/A) is an approved treatment for chronic migraine and has been shown to be effective in reducing number, days, and severity of headache in other headache disorders. Whether botulinum toxin is a safe and effective treatment specifically for post-traumatic headache (PTH), however, is unknown. This study sought to determine whether treatment with BoNT/A improved symptoms of PTH in military veterans., Materials and Methods: Forty subjects with PTH were randomized to receive treatment of either BoNT/A or a saline placebo. Sixteen weeks post-treatment or at return to baseline headache severity, subjects were crossed over to receive treatment with the other medication than previously treated with in the first session. Subjects recorded number of headaches, number of headache days, and headache pain severity in daily diaries. Outcome measures included change in the weekly number of headaches, number of headache days per week, and headache pain severity compared to baseline, and the change in number of headaches and number of headaches days at baseline compared to the rating scores averaged across weeks 6-11., Results: The number of headaches per week significantly decreased by 2.24 (43.3%) with BoNT/A treatment (P < .001) and significantly increased by 1.28 (35.1%) with placebo (P = .02) at the end of the 16 weeks and the difference between groups was also significant (P < .001). The number of headache days per week also significantly decreased by 2.24 (44.4%) at the end of 16 weeks with BoNT/A treatment (P < .001), was not significantly changed with placebo, and the difference between the two groups was significant (P < .001). Both the change in number of headaches and number of headache days averaged across weeks 6-11 compared to baseline were significantly decreased in the BoNT/A group (1.6 and 1.4, respectively) compared to a significant increase of 0.3 in number of weekly headaches and a nonsignificant decrease of 0.1 in number of headache days for the placebo group (P = .048 and P = .005, respectively). Headache pain severity was significantly reduced by 0.06 with botulinum toxin treatment (P = .02) and was not significantly increased by 0.04 in the placebo group with a significant difference between groups (P = .006)., Conclusions: Treatment with BoNT/A clinically and significantly improved the frequency and pain severity of PTH compared to placebo in military veterans. Limitations of the study include subject dropout, adherence to documenting variables daily in the dairy, and only one treatment of BoNT/A. Strengths include the cross-over study design, which demonstrated that BoNT/A was effective regardless of treatment order. This dataset is the first prospective study to evaluate BoNT/A as an intervention for symptoms of PTH and provides evidence that larger-scale and multiple treatment studies evaluating BoNT/A for this headache type are warranted., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2020. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Aim: Determine the role of calcitonin-gene related peptide in promoting post-traumatic headache and dysregulation of central pain modulation induced by mild traumatic brain injury in mice., Methods: Mild traumatic brain injury was induced in lightly anesthetized male C57BL/6J mice by a weight drop onto a closed and unfixed skull, which allowed free head rotation after the impact. We first determined possible alterations in the diffuse noxious inhibitory controls, a measure of net descending pain inhibition called conditioned pain modulation in humans at day 2 following mild traumatic brain injury. Diffuse noxious inhibitory control was assessed as the latency to a thermally induced tail-flick that served as the test stimulus in the presence of right forepaw capsaicin injection that provided the conditioning stimulus. Post-traumatic headache-like behaviors were assessed by the development of cutaneous allodynia in the periorbital and hindpaw regions after mild traumatic brain injury. We then determined if intraperitoneal fremanezumab, an anti-calcitonin-gene related peptide monoclonal antibody or vehicle administered 2 h after sham or mild traumatic brain injury induction could alter cutaneous allodynia or diffuse noxious inhibitory control responses on day 2 post mild traumatic brain injury., Results: In naïve and sham mice, capsaicin injection into the forepaw elevated the latency to tail-flick, reflecting the antinociceptive diffuse noxious inhibitory control response. Periorbital and hindpaw cutaneous allodynia, as well as a loss of diffuse noxious inhibitory control, was observed in mice 2 days after mild traumatic brain injury. Systemic treatment with fremanezumab blocked mild traumatic brain injury-induced cutaneous allodynia and prevented the loss of diffuse noxious inhibitory controls in mice subjected to a mild traumatic brain injury., Interpretation: Sequestration of calcitonin-gene related peptide in the initial stages following mild traumatic brain injury blocked the acute allodynia that may reflect mild traumatic brain injury-related post-traumatic headache and, additionally, prevented the loss of net descending inhibition within central pain modulation pathways. As loss of conditioned pain modulation has been linked to multiple persistent pain conditions, dysregulation of descending modulatory pathways may contribute to the persistence of post-traumatic headache. Additionally, evaluation of the conditioned pain modulation/diffuse noxious inhibitory controls response may serve as a biomarker of vulnerability for chronic/persistent pain. These findings suggest that early anti-calcitonin-gene related peptide intervention has the potential to be effective both for the treatment of mild traumatic brain injury-induced post-traumatic headache, as well as inhibiting mechanisms that may promote post-traumatic headache persistence.

Background: Herbal medicines are empirically used to treat cervicogenic dizziness. However, till date there have been no systematic review to evaluate the efficacy and safety of these medicines. Therefore, this study protocol describes the methods for evaluating the efficacy and safety of herbal medicine for cervicogenic dizziness., Methods and Analysis: The following electronic academic databases will be searched up to December 2019 without language or publication status restrictions: Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), and the Cochrane Central Register of Controlled Trials (CENTRAL), together with Korean, Chinese, and Japanese databases. Any randomized controlled trials related to herbal medicine for cervicogenic dizziness will be included. The functional outcomes and the vertebrobasilar artery hemodynamic states will be evaluated as primary outcomes. The total effective rate, hematological conditions, and adverse events will be assessed as secondary outcomes. Study selection, data extraction, quality assessment of studies, and qualitative evaluation of clinical evidence will be performed by 2 independent reviewers. The methodological quality of the included studies will be evaluated using a revised Cochrane risk-of-bias tool for randomized trials. The strength of evidence from the included data will be evaluated using the Grading of Recommendations Assessment, Development, and Evaluation approach. Data synthesis will be performed as either a fixed-effects or a random-effects model using Review Manager software version 5.3. The results will be reported as a risk ratio for dichotomous outcomes and as a mean difference or standardized mean difference for continuous outcomes., Ethics and Dissemination: No ethical approval is required since the individual clinical information of the patient is not used. The findings of this systematic review will be disseminated through the peer-reviewed publications or conference presentations., Review Registry Unique Identifying Number: reviewregistry1036., Competing Interests: The authors declare no conflicts of interest regarding the publication of this article., (Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Calcitonin gene-related peptide (CGRP) has recently been implicated in the pathogenesis of post-traumatic headache (PTH), which raises the prospect for therapeutic use of monoclonal antibodies targeting CGRP or its receptor. Therefore, we decided to assess the efficacy, tolerability, and safety of erenumab for prevention of persistent PTH attributed to mild traumatic brain injury., Methods: A single-center, non-randomized, single-arm, open-label study of erenumab for adults aged 18-65 years with persistent PTH. Patients were assigned to receive 140-mg erenumab monthly by two subcutaneous 1-mL injections, given every 4 weeks for 12 weeks. The primary outcome measure was the mean change in number of monthly headache days of moderate to severe intensity from baseline (4-week pretreatment period) to week 9 through 12. Tolerability and safety endpoints were adverse events (i.e. number and type)., Results: Eighty-nine of 100 patients completed the open-label trial. At baseline, the mean monthly number of headache days of moderate to severe intensity was 15.7. By week 9 through 12, the number was reduced by 2.8 days. The most common adverse events were constipation (n = 30) and injection-site reactions (n = 15). Of 100 patients who received at least one dose of erenumab, two patients discontinued the treatment regimen due to adverse events., Conclusions: Among patients with persistent PTH, erenumab resulted in a lower frequency of moderate to severe headache days in this 12-week open-label trial. In addition, erenumab was well-tolerated as discontinuations due to adverse events were low. Placebo-controlled randomized clinical trials are needed to adequately evaluate the efficacy and safety of erenumab in patients with persistent PTH., Trial Registration: ClinicalTrials.Gov, NCT03974360. Registered on April 17, 2019 - Retrospectively registered.

Background and aims Cervicogenic headache (CEH) is a debilitating condition and analgesics have limited effect. Percutaneous cryoneurolysis is thus still in use although the clinical evidence is lacking. We present a randomized, controlled study to assess the clinical efficacy of cryoneurolysis compared with a corticosteroid combined with a local anaesthetic. Methods In a university-based outpatient pain clinic we performed a randomized, double blinded, comparative study with an 18-week follow-up. After positive diagnostic test blocks 52 eligible patients were randomly allocated in a ratio of 3:2, 31 participants to occipital cryoneurolysis and 21 participants to injections of 1 mL methylprednisolone 40 mg/mL (Depo-Medrol®) combined with 1 mL bupivacaine 5 mg/mL. Results We observed a significant pain reduction of more than 50% in both treatment groups, slightly improved neck function and reduced number of opioid consumers. After 6-7-weeks, however, pain intensity increased gradually, but did not reach baseline within 18 weeks. Although cryoneurolysis provided a more prolonged effect, the group differences did not reach statistical significance. Health related quality of life and psychological distress improved minimally. A large number reported minor and transient side effects, but we found no significant group differences. After 18 weeks, 29% rated the headache as much improved, and 12 (24%) somewhat improved, but a large proportion (78%) reported need for further intervention/treatment. Conclusions Cryoneurolysis provided substantial, but temporary pain relief, and the effect was not significantly different from injections of a corticosteroid combined with a local anaesthetic. Participants were selected by a single test block, and the neurolytic procedure was guided by anatomical landmarks and nerve stimulation. A stricter patient selection and an ultrasound-guided technique might have improved the results. Cryoneurolysis provides temporary pain relief not significantly superior to corticosteroid injection, and the results question the value of occipital cryoneurolysis for a chronic pain condition like CEH. Implications Occipital cryoneurolysis may be considered when non-invasive treatments appear insufficient, but only for patients who have responded substantially to test blocks. A risk of local scar and neuroma formation by repeated cryoneurolysis, leading to neuropathic pain has been discussed by other researchers.

Background: Acute and persistent post-traumatic headache are often debilitating consequences of traumatic brain injury. Underlying physiological mechanisms of post-traumatic headache and its persistence remain unknown, and there are currently no approved therapies for these conditions. Post-traumatic headache often presents with a migraine-like phenotype. As calcitonin-gene related peptide promotes migraine headache, we explored the efficacy and timing of intervention with an anti- calcitonin-gene related peptide monoclonal antibody in novel preclinical models of acute post-traumatic headache and persistent post-traumatic headache following a mild traumatic brain injury event in mice., Methods: Male, C57Bl/6 J mice received a sham procedure or mild traumatic brain injury resulting from a weight drop that allowed free head rotation while under minimal anesthesia. Periorbital and hindpaw tactile stimulation were used to assess mild traumatic brain injury-induced cutaneous allodynia. Two weeks after the injury, mice were challenged with stress, a common aggravator of migraine and post-traumatic headache, by exposure to bright lights (i.e. bright light stress) and cutaneous allodynia was measured hourly for 5 hours. A murine anti- calcitonin-gene related peptide monoclonal antibody was administered after mild traumatic brain injury at different time points to allow evaluation of the consequences of either early and sustained calcitonin-gene related peptide sequestration or late administration only prior to bright light stress., Results: Mice with mild traumatic brain injury, but not a sham procedure, exhibited both periorbital and hindpaw cutaneous allodynia that resolved by post-injury day 13. Following resolution of injury-induced cutaneous allodynia, exposure to bright light stress re-instated periorbital and hindpaw cutaneous allodynia in injured, but not sham mice. Repeated administration of anti-calcitonin-gene related peptide monoclonal antibody at 2 hours, 7 and 14 days post mild traumatic brain injury significantly attenuated the expression of cutaneous allodynia when evaluated over the 14-day post injury time course and also prevented bright light stress-induced cutaneous allodynia in injured mice. Administration of anti-calcitonin-gene related peptide monoclonal antibody only at 2 hours and 7 days after mild traumatic brain injury blocked injury-induced cutaneous allodynia and partially prevented bright light stress-induced cutaneous allodynia. A single administration of anti-calcitonin-gene related peptide monoclonal antibody after the resolution of the peak injury-induced cutaneous allodynia, but prior to bright light stress challenge, did not prevent bright light stress-induced cutaneous allodynia., Conclusions: We used a clinically relevant mild traumatic brain injury event in mice along with a provocative stimulus as novel models of acute post-traumatic headache and persistent post-traumatic headache. Following mild traumatic brain injury, mice demonstrated transient periorbital and hindpaw cutaneous allodynia suggestive of post-traumatic headache-related pain and establishment of central sensitization. Following resolution of injury-induced cutaneous allodynia, exposure to bright light stress re-established cutaneous allodynia, suggestive of persistent post-traumatic headache-related pain. Continuous early sequestration of calcitonin-gene related peptide prevented both acute post-traumatic headache and persistent post-traumatic headache. In contrast, delayed anti-calcitonin-gene related peptide monoclonal antibody treatment following establishment of central sensitization was ineffective in preventing persistent post-traumatic headache. These observations suggest that mechanisms involving calcitonin-gene related peptide underlie the expression of acute post-traumatic headache, and drive the development of central sensitization, increasing vulnerability to headache triggers and promoting persistent post-traumatic headache. Early and continuous calcitonin-gene related peptide blockade following mild traumatic brain injury may represent a viable treatment option for post-traumatic headache and for the prevention of post-traumatic headache persistence., Abbreviations: CA Cutaneous allodynia CGRP Calcitonin gene-related peptide mTBI Mild traumatic brain injury PTH Post-traumatic headache APTH Acute post-traumatic headache PPTH Persistent post-traumatic headache.

Background: Post-traumatic headache (PTH) is associated with considerable disability and reduced health-related quality of life. Despite the very high prevalence of PTH, there are no evidence-based guidelines for PTH treatment. Thus, we found it timely to provide a systematic review of the current literature on acute and preventive pharmacological treatment of PTH using PubMed and Embase databases., Findings: Included studies involved acute and preventive pharmacological treatment of headache attributed to traumatic injury to the head in adherence to the International Classification of Headache Disorders (ICHD) criteria. Of 1424 potentially relevant articles identified, 63 were retrieved for detailed evaluation and seven studies (one prospective and six retrospective) met the inclusion criteria. None of the seven included studies were randomized clinical trials (RCTs) or used a placebo-controlled study design., Conclusion: We found that there is a lack of high-quality evidence-based studies on the pharmacological treatment of PTH. Future studies are highly needed and must emphasize open-label studies with rigorous methodology or RCTs with a placebo-controlled design.

Traumatic brain injury causes significant morbidity in youth, and headache is the most common postconcussive symptom. No established guidelines exist for pediatric post-traumatic headache management. We aimed to characterize common clinical practices of child neurologists. Of 95 practitioners who completed our survey, most evaluate <50 pediatric concussion patients per year, and 38.9% of practitioners consistently use International Classification of Headache Disorders criteria to diagnose post-traumatic headache. Most recommend nonsteroidal anti-inflammatory drugs as abortive therapy, though timing after injury and frequency of use varies, as does the time when providers begin prophylactic medications. Amitriptyline, topiramate, and vitamins/supplements are most commonly used for prophylaxis. Approach to rest and return to activities varies; one-third recommend rest for 1 to 3 days and then progressive return, consistent with current best practice. With no established guidelines for pediatric post-traumatic headache management, it is not surprising that practices vary considerably. Further studies are needed to define the best, evidence-based management for pediatric post-traumatic headache.

Objective: There is a lack of definitive pediatric literature on effective pharmacotherapy for persistent post-concussion headache symptoms. This study assessed whether acute metoclopramide treatment in the Emergency Department (ED) was associated with a reduction in persistent headache in children at 1- and 4-weeks post-concussion., Methods: Children aged 8-17years with acute concussion presenting to 9-Canadian Pediatric EDs were enrolled in a prospective cohort study, from August 2013-June 2015. Primary and secondary outcomes were persistent headache at 1- and 4-week post-injury respectively. Headache persistence was based on the one and four-week headache scores minus recalled pre-injury score using the Post-Concussion Symptom Inventory. The association between metoclopramide and headache persistence at 1- and 4-weeks were examined using unadjusted and adjusted regression and 1:4 propensity score matching model., Results: Baseline assessments were completed in 2095 participants; 65 (3.1%) received metoclopramide within 48-hours of injury. At 1- and 4-weeks, 54% (963/1808) and 26% (456/1780) of participants had persistent headache relative to baseline respectively. In unadjusted analysis, no association between metoclopramide and headache persistence at 1-week was found [treated vs. untreated: 1-week (53% vs. 53%; relative risk (RR)=1.0 (95%CI: 0.8, 1.3); 4-weeks (27.3% vs. 25.6%; RR=1.0 (95% CI: 0.9, 1.2)]. Metoclopramide was not associated with lower headache risk on propensity score matching [treated vs. untreated: 1-week, n=220 (52% vs. 59.4%; RR=0.8 (95%CI: 0.6, 1.2) and 4-weeks, n=225 (27.1% vs. 32.8%; RR=0.9 (95%CI: 0.8, 1.1)]., Conclusion: Metoclopramide administration was not associated with a reduction in headache persistence in children seeking ED care due to a concussion. Further research is necessary to determine which pharmacotherapies may be effective for acute and persistent post-concussive headache., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Posttraumatic headache (PTHA) is defined as headache that develops within 7 days after a head trauma or injury. Reported rates of PTHA range from 30% to 90% among patients who meet criteria for traumatic brain injury. Approximately 20% of PTHAs persist at 1 year after the inciting injury, and nearly 25% of patients report headaches 4 years after the trauma. Confounding variables for prognosis include return to play decisions, injury biomechanics, pain coping resources, medication overuse headache, and mental conditions. Evaluation requires identification of emergent signs or symptoms of postconcussion syndrome. Pre-existing factors, including disordered sleep or mood changes, may delay recovery or alter treatment choices. Pharmacotherapy is based on the primary headache disorder that most resembles the posttraumatic headache of the individual patient. The management strategy should be tailored to patient symptoms, comorbid or pre-existing conditions, and other considerations, including the potential adverse effects of specific drugs., (Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.)

Concussion, now most often referred to as mild traumatic brain injury in recent literature, is common in pediatrics, and headache is often the most common complaint post-injury. Although most children and adolescents recover within 1-2 weeks, some develop frequent and debilitating headaches that can last for months or longer. Most clinicians would agree on the importance of managing both acute and persistent posttraumatic headaches appropriately to speed recovery, minimize disability, maximize function, and improve quality of life, but there are no well-established guidelines to instruct physicians in doing so. As this continues to be a developing field, there is much we still need to learn about concussion and the appropriate strategies to prevent and treat these injuries and their sequelae. This review is intended to help providers understand the current evidence, and sometimes the lack thereof, and ultimately to lead to improved care for children with headaches after mild traumatic brain injury.

Background: Headache is a frequent complaint among the 1.4 million patients who present to US emergency departments (ED) annually following trauma to the head. There are no evidence-based treatments of acute post-traumatic headache., Methods: This was an ED-based, prospective study of intravenous (IV) metoclopramide 20mg+diphenhydramine 25mg for acute post-traumatic headache. Patients who presented to our EDs with a moderate or severe headache meeting international criteria were enrolled and followed by telephone 2 and 7days later. The primary outcome was "sustained headache relief" (headache level less than "moderate" in the ED, no additional headache medication, and no relapse to headache worse than "mild").We also gathered data on associated symptomotology using the validated Post Concussion Symptom Scale (PCSS)., Results: 21 patients were enrolled. Twelve of 20 (60%) patients with available follow-up data reported sustained headache relief. All but one of the 21 enrolled patients (95%) reported improvement of headache to no worse than mild. Seven of 19 (37%) patients with available data reported moderate or severe headache during the 48h after ED discharge. One week later, 5/19 patients reported experiencing headaches "frequently" or "always". The mean Post Concussion Symptom Score improved from 47.5 (SD 29.4) before treatment to 10.9 (SD 14.8) at the time of ED discharge and 11.4 (SD 21.4) at one week after treatment., Conclusion: IV metoclopramide 20mg+diphenhydramine 25mg is an effective and well-tolerated medication regimen for patients presenting to the ED with acute post-traumatic headache, though 1/3 of patients report headache relapse after ED discharge and 1/4 of patients report persistent headaches one week later., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective . The aim of this study was to compare the efficacy of ultrasound-guided deep cervical plexus block with fluoroscopy-guided deep cervical plexus block for patients with cervicogenic headache (CeH). Methods . A total of 56 patients with CeH were recruited and randomly assigned to either the ultrasound-guided (US) or the fluoroscopy-guided (FL) injection group. A mixture of 2-4 mL 1% lidocaine and 7 mg betamethasone was injected along C 2 and/or C 3 transverse process. The measurement of pain was evaluated by patients' ratings of a 10-point numerical pain scale (NPS) before and 2 wks, 12 wks, and 24 wks after treatments. Results . The blocking procedures were well tolerated. The pain intensity, as measured by NPS, significantly decreased at 2 wks after injection treatment in both US and FL groups, respectively, compared with that of baseline ( P < 0.05). The blocking procedures had continued, and comparable pain relieving effects appeared at 12 wks and 24 wks after treatment in both US and FL groups. There were no significant differences observed in the NPS before and 2 wks, 12 wks, and 24 wks after treatment between US and FL groups. Conclusions . The US-guided approach showed similar satisfactory effect as the FL-guided block. Ultrasonography can be an alternative method for its convenience and efficacy in deep cervical plexus block for CeH patients without radiation exposure., Competing Interests: All named authors declare that they have no conflict of interests.

Context: Pediatric concussions are common, and emphasis on correct diagnosis and management is stressed in consensus guidelines. Medications may have a role in management of concussion, but no consensus exists regarding appropriate pharmacologic therapy., Evidence Acquisition: Nonsystematic review., Study Design: Clinical review., Level of Evidence: Level 4., Results: There is limited evidence for hypertonic saline to improve posttraumatic headache in the emergency department setting. There is essentially no evidence for the use of any other medication in management of pediatric sport-related concussion., Conclusion: Further research is necessary to determine whether there is benefit to the use of any pharmacotherapy in the management of pediatric-aged athletes with concussions.

Aim: To evaluate the results of using cytoflavin in the treatment of chronic post-traumatic headache and analyze possible mechanisms for implementation of therapeutic effects of the drug., Material and Methods: The study included 76 patients (23 men and 53 women) aged 29 - 57 years (mean age - 38.2 ± 8.3). All patients received standard basic therapy with simple or combination analgesics. In addition to standard treatment, 36 patients received cytoflavin in the dosage of two tablets twice a day for 30 days. Results and сonclusion. At the beginning, at the end and 25 days after the completion of treatment, the intensity and frequency of headache as well as the severity of asthenic and depressive symptoms were analyzed. As a result of treatment in the cytoflavin group, there was a significant regression of asthenic and depressive symptoms, which was consistent with the previous studies. Positive changes in the indicators analyzed were correlated with the decrease in the frequency of cephalalgia. Since cytoflavin has no analgesic properties, the results are indirect evidence for the significance of psychopathological factors in the pathogenesis of chronic post-traumatic headache.

Concussion and mild traumatic brain injury (TBI) are common pediatric injuries. Headaches are one of the most common and disabling complaints following concussion in the acute phase and are pervasive in those who have prolonged symptoms following concussion. The body of evidence regarding the epidemiology of and risk factors for pediatric concussion and post-traumatic headache is growing rapidly, but there still is a distinct lack of strong scientific evidence to support the best treatment strategies for post-traumatic headaches in either children or adults. In this article, we will review the current evidence regarding the epidemiology of acute and chronic headaches following concussion in the pediatric population, as well as current recommendations for the management of acute and chronic pediatric post-traumatic headaches.

Objectives: The primary objective was to evaluate the effects of pregabalin relative to placebo in patients with chronic unilateral cervicogenic headache. Primary and secondary end points: To assess the change from baseline in the frequency of cervicogenic headache days per 28-day period between placebo and treatment group. To assess the change from baseline in the intensity of headache, and health outcome measures., Study Design: This was a double-blind, randomized, placebo-controlled, parallel-group study, evaluating the efficacy and safety of pregabalin in patients with cervicogenic headache., Procedures: The study consisted of two phases. A baseline of -28 days and a double-blind placebo-controlled phase: with an escalation and maintenance phase, during which patients remained at their highest dose until the end of the study, at Day 86., Results: Forty one patients were randomized, predominantly females, with a mean age of 52 years old. At screening, both groups had, on average, 26 headache-days per month. By the final phase of the study, the number of headache days dropped to 16 per month for the pregabalin group while remaining stable for the placebo group (p=0.037). No serious adverse events were reported during the study., Conclusion: In this study, primary objectives were achieved with a statistically significant change of ten days in frequency of headache days; with minor side effects that were well tolerated.

Cervicogenic headache (CGH) is defined as referred pain from various cervical structures innervated by the upper three cervical spinal nerves. Such structures are potential pain generators, and include the atlanto-occipital joint, atlantoaxial joint, C2-3 zygapophysial joint, C2-3 intervertebral disc, cervical myofascial trigger points, as well as the cervical spinal nerves. Various interventional techniques, including cervical epidural steroid injection (CESI), have been proposed to treat this disorder. And while steroids administered by cervical epidural injection have been used in clinical practice to provide anti-inflammatory and analgesic effects that may alleviate pain in patients with CGH, the use of CESI in the diagnosis and treatment of CGH remains controversial. This article describes the neuroanatomy, neurophysiology, and classification of CGH as well as a review of the available literature describing CESI as treatment for this debilitating condition.

Background: The causes of persistent headache following concussion are poorly understood. The objective of this study is to explore analgesic overuse as a potential cause of chronic post-traumatic headache among adolescents referred to a headache clinic following concussion., Methods: A retrospective chart review was conducted of all adolescent concussion patients referred to our pediatric headache clinic over the 16-month period between August 1, 2011, and November 30, 2012. Those patients with chronic post-traumatic headaches of 3-12 months' duration who also met International Headache Society criteria for probable medication-overuse headache were identified. Demographic data, concussion symptoms, and headache features were characterized from the initial evaluation and from follow-up visits., Results: Of 104 adolescent concussion patients referred during the study period, 77 had chronic post-traumatic headache of 3-12 months' duration. Fifty-four of 77 (70.1%) met criteria for probable medication-overuse headache. Only simple analgesics were overused. Thirty-seven patients (68.5%) had resolution of headaches or improvements to preconcussion headache patterns after discontinuing analgesics; seven (13%) had no change in headaches or worsening of headaches after discontinuing analgesics and 10 (18.5%) did not discontinue analgesics or were lost to follow-up., Conclusion: Excessive use of analgesics postconcussion may contribute to chronic post-traumatic headaches in some adolescents. Management of patients with chronic post-traumatic headache should include analgesic detoxification when medication overuse is suspected., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To describe patient self-report of headache treatment in the first year following mild traumatic brain injury (TBI)., Background: An understanding of appropriate management of symptoms after mild TBI is crucial for improving acute care and long-term outcomes. This is particularly true for post-traumatic headaches as recent studies suggest that headaches after mild TBI are common with multiple phenotypes. In addition, symptoms such as headache after mild TBI are often managed by primary care providers without specialty training, and often in medically underserved areas. Outside of previous opinion papers, few studies have guided the treatment or examined the effectiveness of the interventions for post-traumatic headache., Methods: One hundred sixty-seven participants admitted to a level 1 trauma hospital with mild TBI who were prospectively enrolled and reported new or worse headache at 3, 6, or 12 months after injury., Results: Participants were primarily male (75%), white (75%), injured in vehicle crashes (62%), and had completed high school (83%). The majority of headaches met International Classification of Headache Disorders-2nd edition criteria for migraine/probable migraine, followed by tension-type headache. Despite the diverse nature of headaches, more than 70% of those with headache at each time period used acetaminophen or a nonsteroidal anti-inflammatory drug for headache control. Only 8% of those with the migraine/probable migraine phenotype used triptans. Of those individuals who used medication, 26% of those with migraine/probable migraine phenotype and 70% of those with tension headache phenotype endorsed complete relief (vs partial or no relief) because of medication use. The majority of individuals with tension headache reported never taking medication., Conclusions: Headaches after mild TBI are frequent and are not optimally treated. Results suggest that many individuals with mild TBI may be self-treating their headaches by utilizing over-the-counter pain relief medications. These medications, however, are only providing effective treatment for a minority of this population. Further research must be conducted to develop evidence-guided treatment and educate providers.

Headache patients frequently contact physiotherapists and manual therapists. In case of elderly patients with unilateral headache, neck and facial pain clinical practice guidelines recommend further referral for medical investigation to exclude red flags. The present patient was seen in a multidisciplinary headache clinic. He was referred by the neurologist (headache specialist) for physiotherapeutic assessment after screening for red flags, including giant cell arteritis (GCA). After first assessment, GCA was considered unlikely, since the sedimentation rate, as a marker for inflammation, was only slightly elevated. The purpose of the referral was to exclude cervicogenic headache (CEH) and to explore physical treatment as a therapeutic option. Physiotherapeutic assessment consisted of a history taking on CEH signs (Sjaastad criteria, 1998), followed by cervical spine assessment including tests for neck mobility, joint pain, and endurance of the short neck flexors. The patient's history revealed no specific signs of CEH and cervical spine assessment was negative. In consultation with the neurologist, the diagnosis of CEH was abandoned. Since palpation of the temporal artery proved to be painful, laboratory examination and biopsy of the temporal artery were thereafter performed, this time revealing GCA. Appropriate treatment (high dose steroids) was initiated promptly, with a good clinical evolution. The presented case shows the potential of a multidisciplinary collaboration in the clinical diagnostic work-up of patients with head and neck pain., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: To observe the therapeutic effect of cervical paravertebral block plus acupuncture treatment for cervicogenic headache., Methods: Sixty cases of cervicogenic headache were randomly and equally divided into cervical paravertebral block (control) group and acupuncture plus cervical paravertebral block (acupuncture) group. Paravertebral block was performed by injection of 5 mL of 0.3% lidocaine solution containing triamcinolone (10 mg) into the 2nd cervical paravertebral tissue from the cross point between the posterior border of the sternomastoid muscle and the angle of jaw, once every week for three weeks. Manual acupuncture stimulation was applied to Baihui (GV 20), unilateral Fengchi (GB 20) and Jiaosun (SJ 20), once daily for 3 weeks. The patients' headache severity was assessed by visual analogue scale (VAS) and their cervical vertebral activity assessed by range of motion (ROM) before and after the treatment., Results: Compared with pre-treatment in the same one group, the scores of both VAS and ROM at time points of one, two and three weeks after the treatment were significantly decreased in the control and acupuncture groups (P < 0.05), suggesting a marked improvement of both headache and cervical motion after the treatment. Comparison between the two groups showed that the VAS and ROM scores of the acupuncture group were evidently lower than those of the control group at each time point after the treatment (P < 0.05), displaying a better therapeutic effect of acupuncture plus paravertebral block for cervicogenic headache., Conclusion: Acupuncture combined with cervical paravertebral block is effective in relieving cervicogenic headache and improving cervical vertebral activity in cervicogenic headache patients, and can strengthen the therapeutic effect of simple paravertebral block.

Aim: Post-traumatic headaches (PTHs) following mild traumatic brain injury (mTBI) are common; however, few studies have examined the characteristics of PTHs or their response to treatment. The aims of this study were (1) to describe the clinical characteristics of PTH in a prospective cohort of children presenting to a paediatric emergency department with mTBI, and (2) to evaluate the response of PTH to treatment., Method: The emergency department cohort was obtained from a prospective longitudinal cohort study of symptoms following mTBI (n=670; 385 males, 285 females) and a comparison group of children with extracranial injury (n=120; 61 males, 59 females). A retrospective chart review of a separate cohort of children from a brain injury clinic (the treatment cohort) treated for PTH was performed (n=44; 29 females, 15 males; mean age 14 y 1 mo, SD 3 y 1 mo). The median time since injury was 6.9 months (range 1-29 mo). The mean follow-up interval after treatment started was 5.5 weeks (SD 4.3 wks)., Results: Among the emergency department cohort (n=39; 20 males, 19 females; mean age 11 y 1 mo, SD 4 y 3 mo) 11% of children were symptomatic with PTHs at a mean of 15.8 days (SD 11.6d) post injury. Three months post injury, 7.8% of children complained of headaches; of those, 56% had pre-existing headaches and 18% had experienced migraine before the injury. Although headache type varied, 55% met the criteria for migraine. A family or past medical history of migraine was present in 82% of cases. Among the treatment cohort, medications included amitriptyline, flunarizine, topiramate, and melatonin, with an overall response rate of 64%., Conclusion: This is the first prospective cohort study to describe the clinical characteristics of PTHs following mTBI in children. Migraine was the most common headache type seen; other headaches included tension-type, cervicogenic, and occipital neuralgias, and 64% responded to treatment. Referral to a headache specialist should be considered, especially when the features are not typical of one of the primary headache disorders., (© The Authors. Developmental Medicine & Child Neurology © 2013 Mac Keith Press.)

Pharmacotherapy of acute post-traumatic tension headaches consists of analgesics and non-steroidal anti-inflammatory drugs (NSAIDs). Treatment of chronic tension-type head-aches consists mainly of tricyclic antidepressants; local injection of botulinum toxin is one of the comparatively newer therapeutic options. No data on the treatment of post-traumatic headaches with botulinum toxin exist. A 62-year-old woman with a history of major traumatic brain injury five years previously developed chronic tension-type headaches of an oppressive nature. The results of treatment with oral medication were not satisfactory. The patient was treated with local injections of 22 IU Botox® into the frontalis muscle and corrugator supercilii muscle. After only five days, the headaches had improved and after ten days the patient was free of symptoms even when under stress. Sufficiently large-scale clinical studies are now required to better evaluate the effects of botulinum toxin on post-traumatic headaches.

Pediatric traumatic brain injury is a common occurrence, and even an ostensibly mild injury may result in disabling posttraumatic headaches. The headache may result in a number of subsequent unremitting symptoms refractory to many standard headache therapies. Current treatment recommendations are sparse because there is a lack of clinical trial data recommendations and outcomes. From these 2 cases, we report the effectiveness of steroids for severe posttraumatic headache, along with recommended treatment strategies for acute pain management and prevention.

We present a series of four patients with neurological symptoms following head injury. In each case neuroimaging was normal, but careful examination demonstrated altered sensation over the distribution of the supraorbital nerve. We discuss traumatic supraorbital neuralgia and how it differs from the more commonly reported idiopathic form.

Background: The trigeminocervical system is integral in cervicogenic headache. Cervicogenic headache frequently coexists with complaints of dizziness, tinnitus, nausea, imbalance, hearing complaints, and ear/eye pain. Controversy exists as to whether this constellation of symptoms may be cervically mediated., Objectives: To determine whether a wider spectrum of cervically mediated symptoms exist, and to investigate a potential role of greater occipital nerve blocks (GON) and trigger point injections (TPI) in these patients., Methods: Retrospective review of GON/TPI performed in a tertiary otoneurology/headache clinic from May 2006 to March 2007 for suspected cervically mediated symptoms. Data included chief complaint, secondary symptoms, response to injection, pre-GON/TPI posterior vertex sensation changes to pinprick, cervical spine examination, and response to vibration of cervical and suboccipital musculature., Results: Total number of 147 patients were included. Chief complaints in decreasing frequency: dizziness (93%), tinnitus (4%), headache (3%), and ear discomfort (0.7%). Overall symptoms in decreasing frequency: dizziness (97%), headache (88%), neck pain (63%), tinnitus (23%), and ear discomfort (22%). Improvements after GON/TPI: neck range of motion (71%), headache (57%), neck pain (52%), ear discomfort (47%), dizziness (46%), and tinnitus (30%). Dizziness responders had neck position asymmetries (84%), reproducible dizziness by cervical and suboccipital musculature vibration (75%), and preinjection posterior vertex sensory changes (60%)., Conclusions: A wider spectrum of cervically mediated symptoms may exist by influence of trigeminocervical and vestibular circuitry through cervical afferent neuromodulation. Certain examination findings may help to predict benefit from GON/TPI.

Background: he effectiveness of medical therapies for chronic post-traumatic headaches (PTHs) attributable to mild head trauma in military troops has not been established., Objective: To determine the treatment outcomes of acute and prophylactic medical therapies prescribed for chronic PTHs after mild head trauma in US Army soldiers., Methods: A retrospective cohort study was conducted with 100 soldiers undergoing treatment for chronic PTH at a single US Army neurology clinic. Headache frequency and Migraine Disability Assessment (MIDAS) scores were determined at the initial clinic visit and then again by phone 3 months after starting headache prophylactic medication. Response rates of headache abortive medications were also determined. Treatment outcomes were compared between subjects with blast-related PTH and non-blast PTH., Results: Ninety-nine of 100 subjects were male. Seventy-seven of 100 subjects had blast PTH and 23/100 subjects had non-blast PTH. Headache characteristics were similar for blast PTH and non-blast PTH with 96% and 95%, respectively, resembling migraine. Headache frequency among all PTH subjects decreased from 17.1 days/month at baseline to 14.5 days/month at follow-up (P = .009). Headache frequency decreased by 41% among non-blast PTH compared to 9% among blast PTH. Fifty-seven percent of non-blast PTH subjects had a 50% or greater decline in headache frequency compared to 29% of blast PTH subjects (P =.023). A significant decline in headache frequency occurred in subjects treated with topiramate (n = 29, -23%, P = .02) but not among those treated with a low-dose tricyclic antidepressant (n = 48, -12%, P = .23). Seventy percent of PTH subjects who used a triptan class medication experienced reliable headache relief within 2 hours compared to 42% of subjects using other headache abortive medications (P = .01). Triptan medications were effective for both blast PTH and non-blast PTH (66% response rate vs 86% response rate, respectively; P = .20). Headache-related disability, as measured by mean MIDAS scores, declined by 57% among all PTH subjects with no significant difference between blast PTH (-56%) and non-blast PTH (-61%)., Conclusions: Triptan class medications are usually effective for aborting headaches in military troops with chronic PTH attributed to a concussion from a blast injury or non-blast injury. Topiramate appears to be an effective headache prophylactic therapy in military troops with chronic PTH, whereas low doses of tricyclic antidepressants appear to have little efficacy. Chronic PTH triggered by a blast injury may be less responsive to commonly prescribed headache prophylactic medications compared to non-blast PTH. These conclusions require validation by prospective, controlled clinical trials., (© 2011 American Headache Society.)

Aims: Preliminary reports regarding injections in the neck of onabotulinum toxin A have been positive in cervicogenic headache (CeH). The aim was to perform the first methodologically rigorous trial., Methods: A randomised, placebo-controlled, patient-, injector- and evaluator-blinded crossover study included 28 adult patients with a long-standing and treatment-resistant CeH. After a baseline period, injections of either onabotulinum toxin A or placebo were given in fixed sites in the neck muscles on the pain side. Second injections were given after ≥8 weeks. Patients were thereafter followed for another 8 weeks. A detailed headache calendar was filled in, and patients were followed with quality-of-life (QoL) questionnaires, algometry and neck mobility measurements., Results: There was no significant difference between verum and placebo in a mixed linear model analysis (p = 0.084) with regard to the primary end-point, reduction of days with moderate to severe headache. Six patients withdrew from the study before the second injections, but an intention-to-treat (ITT) analysis gave a similar result (p = 0.27). There were no significant differences favouring verum in any of the secondary efficacy measures. Side-effects of onabotulinum toxin A were minor and short-lasting., Conclusion: Onabotulinum toxin A in neck muscles does not seem to be beneficial in CeH.