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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.

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).)

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.

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.

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: 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.

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.

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.

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: Cervicogenic headache (CEH) is caused by a structural abnormality in the cervical spine. Available treatments for CEH include medical therapy, local botulinum toxin injection, cervical epidural corticosteroid injection, and surgery. The objective of this study was to investigate the safety and efficacy of a continuous epidural block of the cervical vertebra., Methods: Medical records were retrospectively analyzed for 37 patients diagnosed with CEH treated by a continuous epidural block of the cervical vertebra with lidocaine, dexamethasone, and saline (5 ml/min) for 3 - 4 weeks and triamcinolone acetonide 5 mg once weekly for 3 - 4 weeks. Pain was measured via the visual analogue scale (VAS) in combination with quality of life assessment. Outcome measures were patient-reported days with mild or moderate pain, occurrence of severe pain, and the daily oral dosages of non-steroidal anti-inflammatory drug use (NSAID)., Results: In the 3 months immediately preceding placement of the epidural catheter, the mean number of days with mild or moderate pain was 22.0 +/- 4.3. The mean occurrence of severe pain was (3.20 +/- 0.75) times and the mean oral dosage of NSAID was (1267 +/- 325) mg. During the first 6 months after epidural administration of lidocaine and corticosteroids, the mean number of days with mild or moderate pain, the mean occurrence of severe pain, and the mean daily oral dosages of NSAIDs were significantly decreased compared to 3-month period immediately preceding treatment (P < 0.01). By 12 months post-treatment, no significant difference in these three outcome measures was noted., Conclusions: Continuous epidural block of the cervical vertebra for patients with CEH is effective for at least six months. Further research is needed to elucidate mechanisms of action and to prolong this effect.

Background: Cervicogenic headache descriptors include its unilateral nature, "signs and symptoms linking it to the neck," and trauma of the neck. Since the pain often occurs over the C2 or C3 nerve root, we used a modification of the deep cervical block technique for treatment of this refractory type headache., Objective: To determine the efficacy of a modified deep cervical block for treatment of cervicogenic headache., Design: Prospective case study., Methods: Thirty-nine patients referred to our pain clinic participated in this study. All patients had undergone extensive screening/diagnostic testing. The blocks were performed unilaterally, without inducing a risk of invading the neural foramen, and repeat injection of the contra-lateral side occurred at >1 week after initial injection. Patients were followed for a 6-month period using a pain diary and questionnaire. Pain was assessed pre- and post-injection and 3 and 6 months post treatments., Results: The mean treatment period was 59 +/- 61 days. The mean values for pre- and post-injection series pain scores (0-10 pain scale) were 9.54 +/- 1.53 and 6.75 +/- 3.23 respectively (p <0.001). Thirty-three percent (33%) of the patients reported pain scores of < or = 4 on the 0-10 pain scale after their last treatment. Effectiveness of the therapy following the injection procedure was rated to be 42% effective for all first injections and 40% effective for last injections (p =NS). Six months evaluations showed that return of moderate to severe pain took 6.62 +/- 8.1 weeks. At the 3 and 6 months follow up evaluations, mean pain scores had returned to 8.41 +/- 2.96 and 8.83 +/- 2.78, respectively. Ten patients (24%) had pain scores < or = 4 at the 3-month evaluation while 7 of the patients (18%) had pain scores < or = 4 at the 6-month evaluation., Conclusions: These results showed that for some patients this series of blocks provided effective pain relief for 3 months post treatment but by 6 months the pain had returned to pre-treatment levels. This block technique significantly diminished pain after the initial as well as the last treatment. These clinically significant changes in pain relief suggest that more aggressive selective therapy targeting these nerve routes might provide longer lasting relief.

Unlabelled: The differential diagnosis of headache is often challenging, with significant clinical and socioeconomic consequences of incomplete or inaccurate diagnosis. Overlapping symptoms contribute to the diagnostic challenge. Four female patients, ages 26 to 69 with standing diagnoses of migraine, were evaluated and treated for complaints of chronic, severe headaches. All had obtained limited relief from migraine therapies. On physical examination, all had occipital nerve tenderness or positive Tinel sign over the occipital nerve. All responded well to occipital nerve blocks with local anesthetic, achieving complete or substantial pain relief lasting up to 2 months. We conclude that accurate diagnosis of occipital neuralgia or cervicogenic headache as contributing factors can lead to substantial headache relief through occipital nerve blocks in patients with coexisting or misdiagnosed migraine., Perspective: The pathophysiology of many types of chronic headaches is not well understood. Mixed mechanisms such as neurovascular, neuropathic, myofascial, and cervicogenic may all contribute. Our four patients with chronic headaches responded well to occipital nerve blocks. The neuroanatomical relationship between the trigeminocervical nucleus and occipital nerve may serve as the basis of efficacy for these blocks.