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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.)

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.

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.)

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.