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The Impact of Triptan and Doxycycline on Neuroinflammatory Biomarkers in Acute Migraine: Study Protocol of a Randomized Controlled Trial Study Protocol

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The Impact of Triptan and Doxycycline on Neuroinflammatory Biomarkers in Acute Migraine: Study Protocol of a Randomized Controlled Trial Study Protocol iMedPub Journals INTERNATIONAL ARCHIVES OF MEDICINE 2015 http://journals.imed.pub SECTION: NEUROLOGY Vol. 8 No. 13 ISSN: 1755-7682 doi: 10.3823/1612 The impact of triptan and doxycycline on neuroinflammatory biomarkers in acute migraine: study protocol of a randomized controlled trial STUDY PROTOCOL Shaheen E Lakhan, MD, Abstract PhD, MEd, MS1 Background: Increased inflammatory cytokines and matrix meta- 1 Neurological Institute, Cleveland Clinic, lloproteinases (MMPs) have been recently implicated in migraine. In- Euclid Ave, S100C, Cleveland OH . flammation may be a key player in the pathophysiology of migraine by altering blood-brain barrier (BBB) function. As an inflammation induced MMP, MMP-9 is involved in both BBB disruption and neuro- Contact information: pathic pain, and is largely derived by neutrophil degranulation during neutrophil-BBB interaction. The tetracycline group of antibiotics may Shaheen E Lakhan, MD, PhD, MEd, MS. Neurological Institute, Cleveland Clinic, suppress MMP production and neutrophil degranulation. 9500 Euclid Ave, S100C, Cleveland OH 44195. Methods/Design: We hypothesize that migraine is a primary neu- Tel: (216) 444-2200 roinflammatory disorder. We will address this theory by measuring serum biomarkers in healthy controls and after one of three abortive slakhan @gnif.org therapy strategies for acute migraine attacks and inter-ictally. We intend to investigate known neuroinflammatory biomarkers with a focus on BBB breakdown during acute migraine attacks and assess marker responses to conventional treatment (triptans), novel MMP targeted therapy (doxycycline), or a combination of triptan and do- xycycline. We will measure the effects of the interventions on neu- roinflammatory markers for acute migraine attacks, clinical outcomes (headache relief and recurrence) for acute migraine attacks, inter- ictal neuroinflammatory load per serum biomarkers in migraineurs versus healthy controls, and neuroinflammatory markers correlation with headache duration and peak headache intensity during acute migraine attacks. © Under License of Creative Commons Attribution 3.0 License This article is available at: www.intarchmed.com and www.medbrary.com 1 INTERNATIONAL ARCHIVES OF MEDICINE 2015 SECTION: NEUROLOGY Vol. 8 No. 13 ISSN: 1755-7682 doi: 10.3823/1612 Discussion: To our knowledge, this trial will be the first systematic study on the use of a MMP inhibitor in episodic migraine. Our pilot project data will supplement future projects investigating novel the- rapeutic strategies such as MMP inhibitors in both migraine acute treatment and prevention. Trial Registration: ClinicalTrials.gov NCT01653522, registered 07/23/2012. Background MMP-9 were significantly higher than controls [19- Migraine is a common neurovascular disorder that 22]. MMP-9 potentiates chemokines for leukocyte- affects over 30 million Americans. There is signi- endothelial cell interaction leading to an inflam- ficant economic impact secondary to headache- mation cascade at the brain vasculature. The inflam- related disability [1]. Current theories of migraine mation may be a reason for migraine patients being pathophysiology include cortical spreading depres- at a higher risk of stroke [8]. Utilizing anti-inflam- sion (CSD) and neurogenic inflammation [2]. More matory and -MMP effect, doxycycline coupled with recently, a compromised BBB as a result of neuro- interferon beta-1a reduced multiple sclerosis lesions genic inflammation has been implicated in migraine in humans [23] and minocycline prevented hemo- pathophysiology [3]. rrhagic transformation in acute ischemic strokes in The BBB protects the brain against compounds a rate model treated with IV tPA [24]. However, and pathogens in the blood stream and maintains the origin of MMP-9 in migraine patients remains central nervous system homeostatsis. This neuro- unknown, as does the effect of acute migraine vascular interface is composed of endothelial tight treatment targeting MMP-9. junctions, basal lamina, and astrocyte endfeet in the Compounds such as triptans and magnesium brain parenchyma. It is hypothesized that vascular may not cross an intact BBB, however, their utility inflammation is a common final pathway for migrai- in migraine may be in the setting of BBB disruption. ne with or without aura [4-8]. A few studies have Moreover, glucocorticoids, commonly used in acute indicated that inflammatory cytokines are elevated migraine treatment, are known to stabilize the BBB. in migraine patients intra- and inter-ictally [9-13]. In a migraine animal model, MMP-9 was downre- CSD may create BBB permeability in migraine me- gulated with methyl-prednisolone [25]. diated by MMPs and other inflammatory molecules. Interestingly, Todd Rozen of the Geisinger Medi- MMPs and tissue inhibitors of MMPs (TIMPs) are cal Group has written on doxycycline use as an anti- involved in the remodeling of extracellular matrix via inflammatory drug for primary headache disorders, chemokines and cellular adhesion molecules. An al- especially new daily persistent headache. However, teration of MMP expression may lead to the break- he only published one abstract on his open label down of the BBB, demyelination, cytokine produc- use [26], no peer-reviewed paper, and referred to it tion and an inflammatory response, deposition of in a recent review [27]. amyloid proteins, and tumor invasion and metas- tasis [14-18]. In migraine, post-headache levels of 2 This article is available at: www.intarchmed.com and www.medbrary.com INTERNATIONAL ARCHIVES OF MEDICINE 2015 SECTION: NEUROLOGY Vol. 8 No. 13 ISSN: 1755-7682 doi: 10.3823/1612 Methods There will be three treatment arms: 1. Oral triptan (as prescribed) Objectives 2. Doxycycline (one dose of 200mg by mouth) Primary endpoint: Determine the effects of oral trip- 3. Triptan (as prescribed) + Doxycycline (one tan, doxycycline, and triptan + doxycycline on neu- dose of 200mg by mouth) roinflammatory markers for acute migraine attacks. There will be one non-treatment arm of “con- Secondary endpoints: trol” subjects who do not have migraines, will not 1. Compare the effects of oral triptan, doxy- complete a diary, and will have one set of pain free cycline, and triptan + doxycycline on clinical bloodwork drawn. outcomes (headache relief and recurrence) Subjects will be randomly assigned to one of the for acute migraine attacks. three treatment groups until there are about 10 2. Determine if inter-ictal neuroinflammatory subjects in each group. Venous blood during an load per serum biomarkers is greater in mi- inter-ictal period will be drawn at least seven days graineurs than healthy controls. after the most recent migraine attack. Subjects will 3. Determine if the levels of neuroinflammatory be telephoned three days after this bloodwork to markers correlate with headache duration document that they have not experienced a migrai- and peak headache intensity during acute ne since the bloodwork was obtained. The subjects migraine attacks. will be instructed to maintain a headache diary con- taining the following details: (A) date/time of mi- Design graine onset, (B) migraine pain intensity based on a This is a single site, randomized, 4 arm open-label four-point scale (0= no pain, 1= mild pain, 2= mo- pilot study of levels of neuroinflammatory markers derate pain, 3= severe pain); (C) date/time migraine in adult episodic migraineurs and healthy controls treatment medication was taken including medica- without migraine. We will recruit participants at a tion name and total dose taken; (D) date/time of major 1,300-bed tertiary teaching hospital, the Cle- migraine resolution and (E) date/time of start and veland Clinic. time of stop for any adverse drug reactions and any We will recruit two groups of patients to partici- treatments for those adverse reactions. pate in this study: (1) generally healthy adult episo- The “active” subjects will be instructed to self- dic migraine patients of the Headache Center (the administer oral medication during a migraine attack “Actives”) or (2) healthy controls who are patients when the pain level is of moderate to severe inten- (the “Controls”). The “actives” will have migraine sity. Venous blood will be collected at a designed with or without aura that fulfill the 2nd Edition of lab at a six hour timepoint starting from the time The International Headache Classification (ICHD-II) migraine treatment is taken. criteria for episodic migraine. Migraine recruits (“ac- Both the “active” subjects and the “controls” tives”) will also have an active prescription for an will also have an inter-ictal (or pain free time for oral triptan medication to abort acute migraines. the controls) venous blood obtained at a designed The “actives”/migraineurs will not be on a tetracy- lab. (The “controls”/healthy volunteers will be sub- cline group or other anti-inflammatory medication jects without a headache disorder who are age for the preceding three months. Informed consent and gender matched to the “active” migraineurs will be obtained from all subjects prior to research in the treatment arms.) Both sets of labs will be enrollment and subsequent research bloodwork, delivered to the processing lab within one hour of diary use, and medication use. being drawn, for handling and storage. Specifically © Under License of Creative Commons Attribution 3.0 License 3 INTERNATIONAL ARCHIVES OF MEDICINE 2015 SECTION: NEUROLOGY Vol. 8 No. 13 ISSN: 1755-7682 doi: 10.3823/1612 the specimens will be centrifuged, pipetted into ali- 1. subject is 18 years or older at screening quots, labeled, and those sera will be kept at -80˚C 2. subject has been diagnosed with episodic until further processing is performed. Serum levels migraine by the ICHD-II criteria of MMP-9 (active enzyme), hs-CRP, TNF-alpha, IL-1 3. subject is not pregnant or nursing and IL-6 will be measured by ELISA. Once these 4. subject has not taken a medication in the te- study assays are completed and documented, the tracycline group or anti-inflammatory medi- remaining specimens, if any, will be stored 1 year cation within the prior 3 months to screening maximally and maybe used for other institutionally A healthy subject (“control”) will be eligible to approved studies related to migraine.
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