Pelone Ferruccio, Kwok Bessie, Ahmed Sabahat, Kilic Yakup, Ali Syed Ahsan, Ahmed Nida, Ahmad Mahmood, Bray Jonathan Jh, Shokraneh Farhad, Cassandra Miryan, Celermajer David S, Marijon Eloi, Providencia Rui
Institute of Health Informatics Research, University College London, London, UK.
Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.
EClinicalMedicine. 2024 Sep 4;76:102817. doi: 10.1016/j.eclinm.2024.102817. eCollection 2024 Oct.
Three to 4-weekly intramuscular injections of benzathine penicillin G (BPG) for a prolonged period (e.g., 10 years, until age 40 years, or lifelong) are recommended for preventing group A streptococcal infections that cause recurrent acute rheumatic fever (ARF) and potential progression to rheumatic heart disease (RHD). The duration of treatment, frequency and local pain associated with BPG injections may lead to reduced compliance. Shorter courses of BPG are recommended for the treatment of syphilis and Streptococcal infections. We aimed to assess the effects of local anaesthesia in reducing injection pain in patients who are being treated with BPG.
In this systematic review and meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Conference Proceedings Citation Index-Science and LILACS from database inception up to May 4, 2024, and performed additional searches for grey literature. Randomised controlled trials comparing BPG vs. BPG administered alongside local anaesthetics were included. Randomized controlled trials using BPG, irrespectively of indication, and testing any local anaesthetic agent for pain alleviation were considered eligible. We applied GRADE to assess the quality of evidence. Summary data were extracted from included trials. The primary outcome was injection pain, assessed through mean differences. A random-effects model was utilized to account for study heterogeneity. This study is registered with PROSPERO, CRD42022342437.
Database searches identified a total of 3958 records, and 3 additional records were retrieved from grey literature searches. After removal of duplicates, screening of abstracts and full-text review, eight trials were included, combining a total of 489 patients (151 patients with RHD). Immediate pain level, as reported by patients, was of high intensity in most studies. Low intensity pain was still reported at 24 h. Administration of lidocaine mixed with BPG was associated with a significant reduction in immediate post-injection pain (mean difference -3.84, 95% confidence interval -6.19 to -1.48, P = 0.0001; 4 studies; I = 98%; GRADE: moderate quality), pain at 5 min (mean difference -2.85, 95% CI confidence interval -3.78 to -1.92, P < 0.0001; 1 study; GRADE: moderate quality), and pain at 20 min (mean difference -1.85, 95% confidence interval -2.61 to -1.09, P < 0.0001; 1 study; GRADE: moderate quality) on a 1 to 10 scale. One study assessed lidocaine cream applied to the skin prior to BPG injection and showed no significant reduction in injection pain (mean difference = -0.54, 95% CI confidence interval -1.17 to 0.09, P = 0.13; 1 study; GRADE: low quality). Mepivacaine mixed with BPG in patients with syphilis showed a significant reduction of immediate post-injection pain (mean difference -2.19, 95% CI confidence interval -2.49 to -1.89, P < 0.0001; 1 study; GRADE: moderate quality). Two studies assessed procaine mixed with BPG and reported: lower immediate pain levels or pain assessed at 1 h (mean difference and 95% CI confidence intervals not provided, P = 0.001 and P = 0.008, respectively; 1 study; GRADE: low quality), or less immediate pain and pain at 24 h on the buttock injected with procaine mixed with BPG (mean difference and 95% CI confidence intervals not provided, P < 0.001 for both; 1 study; Grade: low quality). No severe adverse reactions were reported.
In patients receiving intramuscular BPG injections, moderate quality quantitative evidence suggests that BPG injections diluted with lidocaine or mepivacaine may improve post-injection pain scores compared to BPG injections diluted with sterile water. Procaine may also have a benefit, but quality of evidence was lower. Most studies included small patient samples and assessed pain levels at different timepoints. Due to insufficient data we were not able to assess the impact of injection volume, and local anaesthetics' dose on pain intensity and duration of pain relief.
WHO.
为预防由A组链球菌感染引起的复发性急性风湿热（ARF）及可能进展为风湿性心脏病（RHD），推荐长期（例如10年，直至40岁，或终身）每3至4周肌内注射苄星青霉素G（BPG）。BPG注射的疗程、频率及局部疼痛可能导致依从性降低。对于梅毒和链球菌感染的治疗，推荐使用更短疗程的BPG。我们旨在评估局部麻醉在减轻接受BPG治疗患者注射疼痛方面的效果。
在这项系统评价和荟萃分析中，我们检索了Cochrane对照试验中央注册库、MEDLINE、EMBASE、会议论文引文索引 - 科学版和LILACS，检索时间从数据库建立至2024年5月4日，并对灰色文献进行了额外检索。纳入比较BPG与联合局部麻醉药使用的BPG的随机对照试验。使用BPG的随机对照试验，无论其适应证如何，且测试任何局部麻醉药以减轻疼痛的均被视为 eligible。我们应用GRADE来评估证据质量。从纳入的试验中提取汇总数据。主要结局是注射疼痛，通过平均差值进行评估。采用随机效应模型来处理研究的异质性。本研究已在PROSPERO注册，注册号为CRD42022342437。
数据库检索共识别出3958条记录，从灰色文献检索中又获取了3条记录。在去除重复记录、筛选摘要和全文审查后，纳入了8项试验，共计489例患者（151例RHD患者）。在大多数研究中，患者报告的即时疼痛程度为高强度。在24小时时仍有低强度疼痛报告。利多卡因与BPG混合使用与注射后即时疼痛显著减轻相关（平均差值 -3.84，95%置信区间 -6.19至 -1.48，P = 0.0001；4项研究；I² = 98%；GRADE：中等质量），5分钟时疼痛（平均差值 -2.85，95%置信区间 -3.78至 -1.92，P < 0.0001；1项研究；GRADE：中等质量），以及20分钟时疼痛（平均差值 -1.85，95%置信区间 -2.61至 -1.09，P < 0.0001；1项研究；GRADE：中等质量），疼痛程度采用1至10分制。一项研究评估了在BPG注射前应用于皮肤的利多卡因乳膏，结果显示注射疼痛无显著减轻（平均差值 = -0.54，95%置信区间 -1.17至0.09，P = 0.13；1项研究；GRADE：低质量）。在梅毒患者中，甲哌卡因与BPG混合使用显示注射后即时疼痛显著减轻（平均差值 -2.19，95%置信区间 -2.49至 -1.89，P < 0.0001；1项研究；GRADE：中等质量）。两项研究评估了普鲁卡因与BPG混合使用，报告如下：即时疼痛水平较低或在1小时时评估的疼痛（未提供平均差值和95%置信区间，P = 0.001和P = 0.008，分别；1项研究；GRADE：低质量），或在注射了与BPG混合的普鲁卡因的臀部，即时疼痛和24小时时疼痛较轻（未提供平均差值和95%置信区间，两者P < 0.001；1项研究；等级：低质量）。未报告严重不良反应。
在接受肌内注射BPG的患者中，中等质量的定量证据表明，与用无菌水稀释的BPG注射相比，用利多卡因或甲哌卡因稀释的BPG注射可能改善注射后疼痛评分。普鲁卡因可能也有益处，但证据质量较低。大多数研究纳入的患者样本量较小，且在不同时间点评估疼痛水平。由于数据不足，我们无法评估注射体积和局部麻醉药剂量对疼痛强度及疼痛缓解持续时间的影响。
世界卫生组织。
