Abstract: We included 66 studies with 7840 participants in the review, though most analyses were based on data from fewer participants. In total there are 17 studies awaiting classification. No studies were at a low risk of bias. We noted substantial statistical and clinical heterogeneity between trials. Most of the studies reported the primary outcome pain as assessed by verbal response from participants in an awake state but some trials reported withdrawal of the injected limb as a proxy for pain after induction of anaesthesia in response to rocuronium administration. Few studies reported adverse events and no study reported heart rate and blood pressure changes after administration of rocuronium. Lidocaine was the most commonly studied intervention drug, used in 29 trials with 2256 participants. The risk ratio (RR) of pain on injection if given lidocaine compared to placebo was 0.23 (95% confidence interval (CI) 0.17 to 0.31; I² = 65%, low quality of evidence). The RR of pain on injection if fentanyl and remifentanil were given compared to placebo was 0.42 (95% CI 0.26 to 0.70; I² = 79%, low quality of evidence) and (RR 0.10, 95% CI 0.04 to 0.26; I² = 74%, low quality of evidence), respectively. Pain on injection of intervention drugs was reported with the use of lidocaine and acetaminophen in one study. Cough was reported with the use of fentanyl (one study), remifentanil (five studies, low quality evidence) and alfentanil (one study). Breath holding and chest tightness were reported with the use of remifentanil in two studies (very low quality evidence) and one study (very low quality evidence), respectively. The overall rate of complications was low. The evidence to suggest that the most commonly investigated pharmacological interventions reduce pain on injection of rocuronium is of low quality due to risk of bias and inconsistency. There is low or very low quality evidence for adverse events, due to risk of bias, inconsistency and imprecision of effect. We did not compare the various interventions with one another and so cannot comment on the superiority of one intervention over another. Complications were reported more often with use of opioids.

Plain-language summary: We included trials up to July 2013 in our review. We re-ran the searches in February 2015. In total there are 17 studies awaiting classification. We included 66 studies with 7840 participants, both male and female, and including children and adults. Most of these participants were undergoing various planned surgical procedures in hospitals in several countries including Korea, Turkey and India. The trials compared an intervention aiming to reduce pain on injection with a placebo to ascertain whether any intervention was effective at reducing pain. The outcome was assessed by recording the level of pain reported by patients when injected with rocuronium bromide. The most studied treatments were injection of the local anaesthetic lidocaine, or the painkillers fentanyl or remifentanil, into the vein before injecting rocuronium. These treatments may reduce the pain associated with injecting rocuronium, but the evidence is of low quality. Some interventions, for example using painkillers such as fentanyl, may increase cough, chest tightness and breath holding. These are recognized side effects of these drugs. The low quality of the evidence for the assessment of changes in the level of pain was due to inadequate reporting of study design and variation in the study results. In addition to these limitations, for some adverse event outcomes we did not have enough information to be certain about the average effect. Further research is needed with high quality, well designed studies to determine whether pain on injection of rocuronium bromide can be reduced by using an appropriate intervention.