During anesthesia induction period, injection pain/withdrawal response from rocuronium occurred frequently. This meta-analysis included 9 RCTs involving 819 patients, and the observable endpoints were the incidence of total and different severities of rocuronium-induced injection pain/withdrawal response. The results indicated that AAs were effective in preventing, especially for moderate and severe RAIPWR, though not as effective as lidocaine. Our secondary outcome, pain generated by preventative medicines themselves was reported in 3 RCTs [10,13-14], and the result suggested the injection pain induced by AAs occurred less than that of lidocaine.
Previous studies revealed AAs were capable of alleviating injection pain from propofol [19,20], and some studies were designed to identify the prophylactic effect of AAs on rocuronium-induced injection pain/withdrawal response under the assumption that the mechanisms of injection pain generated by propofol and rocuronium were the same. However, no conclusion has been reached on the benefit to date. Our study identified the preventive effect of AAs on RAIPWR, and compared it with lidocaine, the most widely applied pharmacological method to prevent injection pain induced by rocuronium , in advantages and disadvantages simultaneously, and the results indicated AAs might be more desirable for pretreatment due to less injection pain when administrated intravenously.
AAs were widely used to treat inflammatory disease for decades and with the emergence of concept of preemptive analgesia and multimodal analgesia, AAs had been a crucial part in pain management [22,23]. As a result, when applied to prevent RAIPWR, AAs could also play a role in alleviating postoperative pain.
The mechanism of RAIPWR is still unrevealed. Arndt and Klement  reported that peripheral veins were invested with polymodal nociceptors, which released endogenous pain mediators such as prostaglandins after being stimulated by unphysiological osmolarity or pH of drug solution. Rocuronium has a PH of 4.0, and dilution could reduce injection pain , which may explain the injection pain of it . Blunk and Seifert  demonstrated the dolorific effect of rocuronium may be on account for direct activation of C-nociceptors nerve endings with release of calcitonin prostaglandin (PG) E2 and gene-related peptide (CGRP). In animal experiments, Baek and his colleagues  found that rocuronium was able to suppress nitric oxide production and enhance prostaglandin E2 synthesis in calf pulmonary artery endothelial cells, inducing inflammation and pain. Antipyretic analgesics, containing nonsteroidal anti-inflammatory drugs (NSAIDs) and the most widely used analgesic in the world, acetaminophen, are cyclooxygenase (COX) enzyme blockers which may exert their analgesic effects via inhibiting the synthesis of prostaglandins peripherally and preventing the release of PGE2 together with activating medullary and cortical regions involved in the descending inhibitory pain cascade centrally.
Injecting lidocaine was reported the best intervention to prevent RAIPWR , and we found AAs also took effect. Though were not so effective as lidocaine, the injection pain caused by preventive medicine itself occurred less when AAs were acting as pretreatments in our review, namely, AAs may be more acceptable and suitable for patients regarding the side effect of prophylactic itself.
Limitations of our review. Firstly, our study recruited literatures published in only Chinese and English, which may lead to bias caused by the publication language. Secondly, the injection sites, dosage, injection speed of drugs and other details of pretreatment varied among enrolled studies, which may influence the results. However, all RCTs illustrated the details of the intervention: prophylactic or placebo was injected 2 to 5 minutes before intravenous rocuronium, and after assessment finished, other anesthetics (such as opioids and propofol) for induction were administrated, guaranteeing that the injection pain or withdrawal movement was merely caused by rocuronium, and the prophylactic effect, if any, was the result of pretreatment. Thirdly, some of studies included didn’t depict details of random sequence generation [11,15-17,] and allocation concealment [15-16,18], and 3 of them didn’t mention the blind method [15-16,18], all of above may lead to high risk of bias, so the power of this review was confined. We discovered Uzun’s study  was the main source of heterogeneity when carried out sensitive analysis, so we rechecked this study, and found that methodology it abided by resembled to others but they enrolled patients who underwent elective orthopedic, gastrointestinal, and gynecological procedures while other studies recruited all kinds of elective surgeries. Given the impossible task of conducting subgroup analysis stratified by operation types, and the results were homogeneous when excluded the particular study or not, we didn’t do further analysis.