Du Kai, Li Ao, Zhang Chen-Yu, Li Shu-Ming, Chen Ping
Graduate School, Beijing University of Chinese Medicine, Beijing, China.
Department of Pain Medicine, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China.
Front Pharmacol. 2024 Aug 29;15:1448319. doi: 10.3389/fphar.2024.1448319. eCollection 2024.
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.
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's multiplicative random effects (MRE) addressed heterogeneity, and MR-PRESSO managed pleiotropy, ensuring accurate causal inference.
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.
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.
鉴于疼痛性疾病的患病率不断上升以及当前镇痛药存在局限性，我们的研究受高血压与疼痛之间联系的启发，探索将抗高血压药物重新用于疼痛管理。我们采用药物 - 靶点孟德尔随机化（MR）方法来探索其双重益处并建立因果关系。
通过《英国国家处方集》全面汇编抗高血压药物类别，并使用DrugBank数据库确定其靶基因。从已发表的关于收缩压（SBP）的基因组研究中选择与这些靶点相关的单核苷酸多态性（SNP）作为遗传工具。通过针对急性冠状动脉疾病（CAD）的MR验证这些SNP，以确保与CAD无关的基因不会作为抗高血压药物的替代物。使用FinnGen R10数据库，采用选定并经验证的遗传工具对29个与疼痛相关的结局进行MR分析。我们采用逆方差加权（IVW）方法进行主要分析，并应用Bonferroni校正来控制I型错误。IVW的乘性随机效应（MRE）解决了异质性问题，MR - PRESSO处理了多效性问题，以确保准确的因果推断。
我们的分析区分了将抗高血压药物与疼痛性疾病风险联系起来的有力证据和提示性证据。发现有力证据表明肾上腺素能神经元阻滞剂会增加无先兆偏头痛风险，袢利尿剂会降低脂膜炎风险，血管扩张剂类抗高血压药物会降低肢体疼痛风险。提示性证据表明α - 肾上腺素能受体阻滞剂可能会增加偏头痛风险，而β - 肾上腺素能受体阻滞剂可能会降低神经根病风险。肾上腺素能神经元阻滞剂还显示出对髋关节炎（髋骨关节炎）的潜在保护作用，并增加女性生殖器官疼痛风险（与女性生殖器官和月经周期相关的疼痛及其他病症）。此外，发现血管扩张剂类抗高血压药物与降低神经根病风险之间存在提示性联系，α - 肾上腺素能受体阻滞剂和肾素抑制剂都可能降低背痛风险（未明确的背痛）。这些发现突出了抗高血压药物对疼痛性疾病的复杂影响，强调了进一步研究的必要性。
研究结果表明，抗高血压药物可能对疼痛管理产生不同影响，提示其在治疗特定疼痛性疾病方面具有重新利用的潜力。结果主张进一步研究以确认这些关联并探索潜在机制，从而优化疼痛管理实践。
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