{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T00:22:53Z","timestamp":1793319773919,"version":"4.5.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T00:00:00Z","timestamp":1724889600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Addressing the rising prevalence of pain disorders and limitations of current analgesics, our study explores repurposing antihypertensive drugs for pain management, inspired by the link between hypertension and pain. We leverage a drug-target Mendelian Randomization (MR) approach to explore their dual benefits and establish causal connections.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A comprehensive compilation of antihypertensive drug classes was undertaken through British National Formulary, with their target genes identified using the DrugBank database. Relevant single nucleotide polymorphisms (SNPs) associated with these targets were selected from published genomic studies on systolic blood pressure (SBP) as genetic instruments. These SNPs were validated through MR against acute coronary artery disease (CAD) to ensure genes not linked to CAD were excluded from acting as proxies for antihypertensive drugs. An MR analysis of 29 pain-related outcomes was conducted using the FinnGen R10 database employing the selected and validated genetic instruments. We utilized the Inverse Variance Weighted (IVW) method for primary analysis, applying Bonferroni correction to control type I error. IVW\u2019s multiplicative random effects (MRE) addressed heterogeneity, and MR-PRESSO managed pleiotropy, ensuring accurate causal inference.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our analysis differentiates strong and suggestive evidence in linking antihypertensive drugs to pain disorder risks. Strong evidence was found for adrenergic neuron blockers increasing migraine without aura risk, loop diuretics reducing panniculitis, and vasodilator antihypertensives lowering limb pain risk. Suggestive evidence suggests alpha-adrenoceptor blockers might increase migraine risk, while beta-adrenoceptor blockers could lower radiculopathy risk. Adrenergic neuron blockers also show a potential protective effect against coxarthrosis (hip osteoarthritis) and increased femgenpain risk (pain and other conditions related to female genital organs and menstrual cycle). Additionally, suggestive links were found between vasodilator antihypertensives and reduced radiculopathy risk, and both alpha-adrenoceptor blockers and renin inhibitors possibly decreasing dorsalgianas risk (unspecified dorsalgia). These findings highlight the intricate effects of antihypertensive drugs on pain disorders, underlining the need for further research.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The findings indicate that antihypertensive medications may exert varied effects on pain management, suggesting a repurposing potential for treating specific pain disorders. The results advocate for further research to confirm these associations and to explore underlying mechanisms, to optimize pain management practices.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2024.1448319","type":"journal-article","created":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T05:07:30Z","timestamp":1724908050000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Repurposing antihypertensive drugs for pain disorders: a drug-target mendelian randomization study"],"prefix":"10.3389","volume":"15","author":[{"given":"Kai","family":"Du","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-Yu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Ming","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,8,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"143","DOI":"10.4193\/Rhino12.187","article-title":"A Randomized Controlled Trial comparing the efficacy of low-dose amitriptyline, amitriptyline with pindolol and surrogate placebo in the treatment of chronic tension-type facial pain","volume":"51","author":"Agius","year":"2013","journal-title":"Rhinology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1097\/BRS.0000000000004485","article-title":"Association between hypercholesterolemia and neck pain in a cross-sectional population-based study","volume":"48","author":"Ahorukomeye","year":"2023","journal-title":"Spine"},{"key":"B3","doi-asserted-by":"publisher","first-page":"13","DOI":"10.5505\/agri.2013.29484","article-title":"Pretreatment with a very low dose of intravenous esmolol reduces propofol injection pain","volume":"25","author":"Akg\u00fcn Salman","year":"2013","journal-title":"Agri"},{"key":"B4","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1016\/j.joca.2021.04.020","article-title":"Epidemiology of osteoarthritis","volume":"30","author":"Allen","year":"2022","journal-title":"Osteoarthr. Cartil."},{"key":"B5","doi-asserted-by":"publisher","first-page":"a041302","DOI":"10.1101\/cshperspect.a041302","article-title":"Mendelian randomization","volume":"12","author":"Birney","year":"2022","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression","volume":"44","author":"Bowden","year":"2015","journal-title":"Int. J. Epidemiol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1497","DOI":"10.1093\/ije\/dyt179","article-title":"Calculating statistical power in Mendelian randomization studies","volume":"42","author":"Brion","year":"2013","journal-title":"Int. J. Epidemiol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1093\/ije\/dyr036","article-title":"Avoiding bias from weak instruments in Mendelian randomization studies","volume":"40","author":"Burgess","year":"2011","journal-title":"Int. J. Epidemiol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"2006","DOI":"10.1016\/S0140-6736(20)32340-0","article-title":"Global estimates of the need for rehabilitation based on the global burden of disease study 2019: a systematic analysis for the global burden of disease study 2019","volume":"396","author":"Cieza","year":"2020","journal-title":"Lancet"},{"key":"B10","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1016\/s0006-3223(98)00043-2","article-title":"Multiple correlations and Bonferroni\u2019s correction","volume":"44","author":"Curtin","year":"1998","journal-title":"Biol. Psychiatry"},{"key":"B11","doi-asserted-by":"publisher","first-page":"959","DOI":"10.3906\/sag-1311-79","article-title":"Effects of pretreatment with esmolol and lidocaine on injection pain and rocuronium-induced withdrawal response","volume":"45","author":"Ergil","year":"2015","journal-title":"Turk J. Med. Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1412","DOI":"10.1038\/s41588-018-0205-x","article-title":"Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits","volume":"50","author":"Evangelou","year":"2018","journal-title":"Nat. Genet."},{"key":"B13","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1097\/00004872-199102000-00013","article-title":"The antihypertensive effect of calcitonin gene-related peptide in rats with norepinephrine- and angiotensin II-induced hypertension","volume":"9","author":"Fujioka","year":"1991","journal-title":"J. Hypertens."},{"key":"B14","doi-asserted-by":"publisher","first-page":"2926","DOI":"10.1002\/sim.6522","article-title":"Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome","volume":"34","author":"Greco M","year":"2015","journal-title":"Stat. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1007\/s00540-015-2041-9","article-title":"Beta-adrenergic antagonists during general anesthesia reduced postoperative pain: a systematic review and a meta-analysis of randomized controlled trials","volume":"29","author":"H\u00e4rk\u00e4nen","year":"2015","journal-title":"J. Anesth."},{"key":"B16","doi-asserted-by":"publisher","first-page":"e1007081","DOI":"10.1371\/journal.pgen.1007081","article-title":"Orienting the causal relationship between imprecisely measured traits using GWAS summary data","volume":"13","author":"Hemani","year":"2017","journal-title":"PLoS Genet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"e067670","DOI":"10.1136\/bmj-2021-067670","article-title":"Management of chronic migraine","volume":"379","author":"Hovaguimian","year":"2022","journal-title":"BMJ"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e0130733","DOI":"10.1371\/journal.pone.0130733","article-title":"A comparative effectiveness meta-analysis of drugs for the prophylaxis of migraine headache","volume":"10","author":"Jackson","year":"2015","journal-title":"PLoS One"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e0212785","DOI":"10.1371\/journal.pone.0212785","article-title":"Beta-blockers for the prevention of headache in adults, a systematic review and meta-analysis","volume":"14","author":"Jackson","year":"2019","journal-title":"PLoS One"},{"key":"B20","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1016\/j.ejvs.2009.02.006","article-title":"Atherosclerosis and disc degeneration\/low-back pain \u2013 a systematic review","volume":"37","author":"Kauppila","year":"2009","journal-title":"Eur. J. Vasc. Endovascular Surg."},{"key":"B21","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1161\/01.res.67.3.733","article-title":"Age-related decrease of calcitonin gene-related peptide-containing vasodilator innervation in the mesenteric resistance vessel of the spontaneously hypertensive rat","volume":"67","author":"Kawasaki","year":"1990","journal-title":"Circ. Res."},{"key":"B22","volume-title":"Translational pain research: from mouse to man","author":"L.,","year":"2010"},{"key":"B23","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1038\/s41586-022-05473-8","article-title":"FinnGen provides genetic insights from a well-phenotyped isolated population","volume":"613","author":"Kurki","year":"2023","journal-title":"Nature"},{"key":"B24","doi-asserted-by":"publisher","first-page":"2009","DOI":"10.1111\/jch.14362","article-title":"The effects of different antihypertensive drugs on pain and joint space width of knee osteoarthritis \u2013 a comparative study with data from Osteoarthritis Initiative","volume":"23","author":"Li","year":"2021","journal-title":"J. Clin. Hypertens."},{"key":"B25","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/s11906-016-0636-7","article-title":"Loop diuretics in the treatment of hypertension","volume":"18","author":"Malha","year":"2016","journal-title":"Curr. Hypertens. Rep."},{"key":"B26","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1007\/s10072-008-0884-7","article-title":"Migraine with and without aura: a single entity?","volume":"29","author":"Manzoni","year":"2008","journal-title":"Neurol. Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1111\/j.1529-8019.2010.01333.x","article-title":"Infection and panniculitis","volume":"23","author":"Morrison","year":"2010","journal-title":"Dermatol. Ther."},{"key":"B28","doi-asserted-by":"publisher","first-page":"e032050","DOI":"10.1136\/bmjopen-2019-032050","article-title":"Do \u03b2-adrenoreceptor blocking drugs associate with reduced risk of symptomatic osteoarthritis and total joint replacement in the general population? A primary care-based, prospective cohort study using the Clinical Practice Research Datalink","volume":"9","author":"Nakafero","year":"2019","journal-title":"BMJ Open"},{"key":"B29","doi-asserted-by":"publisher","first-page":"5686","DOI":"10.1093\/rheumatology\/keab234","article-title":"\u03b2-blocker prescription is associated with lower cumulative risk of knee osteoarthritis and knee pain consultations in primary care: a propensity score-matched cohort study","volume":"60","author":"Nakafero","year":"2021","journal-title":"Rheumatol. Oxf."},{"key":"B30","doi-asserted-by":"publisher","first-page":"2173","DOI":"10.1111\/bph.13789","article-title":"Calcium channel modulation as a target in chronic pain control","volume":"175","author":"Patel","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1976","DOI":"10.1097\/j.pain.0000000000001939","article-title":"The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises","volume":"161","author":"Raja","year":"2020","journal-title":"Pain"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1152\/physrev.00034.2013","article-title":"Calcitonin gene-related peptide: physiology and pathophysiology","volume":"94","author":"Russell","year":"2014","journal-title":"Physiol. Rev."},{"key":"B33","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1007\/s12017-007-8018-6","article-title":"The sympathetic nervous system and pain","volume":"10","author":"Schlereth","year":"2008","journal-title":"Neuromol Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1002\/gepi.22295","article-title":"A comparison of robust Mendelian randomization methods using summary data","volume":"44","author":"Slob","year":"2020","journal-title":"Genet. Epidemiol."},{"key":"B35","doi-asserted-by":"crossref","first-page":"E395","DOI":"10.36076\/ppj\/2019.22.E395","article-title":"Beta-blocker use is associated with a reduction in opioid use 30 Days after total knee arthroplasty","volume":"22","author":"Starr","year":"2019","journal-title":"Pain Physician"},{"key":"B36","first-page":"0","article-title":"The sympathetic nervous system and pain","volume-title":"The oxford handbook of the neurobiology of pain","author":"Strong","year":"2020"},{"key":"B37","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1016\/s0006-8993(97)01277-8","article-title":"Alpha 2-adrenergic receptor activation inhibits calcitonin gene-related peptide expression in cultured dorsal root ganglia neurons","volume":"782","author":"Supowit","year":"1998","journal-title":"Brain Res."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.1016\/j.spinee.2023.04.001","article-title":"Evidence of causal effects of blood pressure on back pain and back pain on type II diabetes provided by a bidirectional Mendelian randomization study","volume":"23","author":"Suri","year":"2023","journal-title":"Spine J."},{"key":"B39","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1097\/FPC.0b013e328337f9ab","article-title":"Effect of catechol-O-methyltransferase polymorphism on response to propranolol therapy in chronic musculoskeletal pain: a randomized, double-blind, placebo-controlled, crossover pilot study","volume":"20","author":"Tchivileva","year":"2010","journal-title":"Pharmacogenetics Genomics"},{"key":"B40","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1111\/j.1526-4610.2008.01298.x","article-title":"Verapamil for cluster headache. Clinical pharmacology and possible mode of action","volume":"49","author":"Tfelt-Hansen","year":"2009","journal-title":"Headache J. Head Face Pain"},{"key":"B41","unstructured":"The genetic architecture of pain intensity in a sample of 598,339 U.S. veterans\n            ToikumoS.\n            Vickers-SmithR.\n            JinwalaZ.\n            XuH.\n            SainiD.\n            HartwellE.\n          2023"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1076","DOI":"10.1002\/acr.23091","article-title":"Association of beta-blocker use with less prevalent joint pain and lower opioid requirement in people with osteoarthritis","volume":"69","author":"Valdes","year":"2017","journal-title":"Arthritis Care Res. Hob."},{"key":"B43","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1161\/CIRCRESAHA.117.312086","article-title":"Identification of 64 novel genetic loci provides an expanded view on the genetic architecture of coronary artery disease","volume":"122","author":"van der Harst","year":"2018","journal-title":"Circ. Res."},{"key":"B44","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1038\/s41588-018-0099-7","article-title":"Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases","volume":"50","author":"Verbanck","year":"2018","journal-title":"Nat. Genet."},{"key":"B45","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1186\/s10194-023-01575-4","article-title":"Migraine symptoms, healthcare resources utilization and disease burden in a large Polish migraine cohort: results from 'Migraine in Poland'-a nationwide cross-sectional survey","volume":"24","author":"Waliszewska-Pros\u00f3\u0142","year":"2023","journal-title":"J. Headache Pain"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1320","DOI":"10.1111\/liv.15566","article-title":"Association between antihypertensive drugs and hepatocellular carcinoma: a trans-ancestry and drug-target Mendelian randomization study","volume":"43","author":"Wang","year":"2023","journal-title":"Liver Int."},{"key":"B47","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1186\/s12916-018-1151-2","article-title":"Musculoskeletal conditions may increase the risk of chronic disease: a systematic review and meta-analysis of cohort studies","volume":"16","author":"Williams","year":"2018","journal-title":"BMC Med."},{"key":"B48","doi-asserted-by":"publisher","first-page":"e1003897","DOI":"10.1371\/journal.pmed.1003897","article-title":"Genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers: a mendelian randomization analysis","volume":"19","author":"Yarmolinsky","year":"2022","journal-title":"PLoS Med."},{"key":"B49","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/j.jclinane.2007.02.011","article-title":"Esmolol pretreatment reduces the frequency and severity of pain on injection of rocuronium","volume":"19","author":"Yavascaoglu","year":"2007","journal-title":"J. Clin. Anesth."},{"key":"B50","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.joca.2019.08.008","article-title":"Lack of evidence that beta blocker use reduces knee pain, areas of joint pain, or analgesic use among individuals with symptomatic knee osteoarthritis","volume":"28","author":"Zhou","year":"2020","journal-title":"Osteoarthr. Cartil."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1740","DOI":"10.1097\/j.pain.0000000000002557","article-title":"A global study of pain prevalence across 52 countries: examining the role of country-level contextual factors","volume":"163","author":"Zimmer","year":"2022","journal-title":"Pain"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1448319\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T05:07:35Z","timestamp":1724908055000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1448319\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,29]]},"references-count":51,"alternative-id":["10.3389\/fphar.2024.1448319"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2024.1448319","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,29]]},"article-number":"1448319"}}