The major finding of this study was that 1) ketorolac with venous occlusion, significantly reduced the incidence of rocuronium-induced withdrawal movements, from 74.3% in the placebo group to 40% in the ketorolac group, which was similar to the 34.3% after lidocaine and 2) the combination of lidocaine and ketorolac was more efficacious in decreasing the incidence of withdrawal movements during the injection of rocuronium than either treatment alone (8.6% versus 40% or 34.3%).
The mechanism of rocuronium-induced pain remains obscure, although various theories have been postulated. These include direct activation of nociceptors by the low pH or nonphysiological osmolality, or activation via the local release of endogenous mediators such as kinin [1
]. However, Borgeat and Kwiatkowski [14
] showed that patients, who received normal saline adjusted to pH 4.0, reported no pain. Tuncali et al. [15
] showed that undiluted (10 mg/ml) rocuronium caused significant pain on injection compared to diluted preparations (1 or 0.5 mg/ml), although the osmolality of both preparations did not differ significantly. These results render causes associated with pH or osmolality unlikely. Instead, an enzymatic cascade, possibly the local kinin cascade triggered by kininogen, is suspected of being the likely mechanism. According to Borgeat and Kwiatkowski [14
], the nature of the pain with rocuronium (eg, immediate, short-duration pain with a marked decrease in severity with repeated administration) probably reflects a direct irritant effect on the kinin cascade. These characteristics of rocuronium injection pain are similar to the characteristics of pain induced by the intravenous injection of propofol. Therefore, mediators that are related to the pain induced by propofol injections may also be involved in the pain associated with rocuronium injection [14
]. Huang et al. [12
] demonstrated that pretreatment with 10 mg ketorolac with venous occlusion for 2 min reduced the propofol injection pain. They compared the retention time under venous occlusion and commented that sufficiently long venous occlusion (120 s, but not 30 or 60 s) played a significant role in reducing this pain. Therefore, we used the same dose of ketorolac and venous occlusion to hold the ketorolac within the vein for 2 min, allowing time to inhibit the kinin cascade peripherally. We drew a similar conclusion: ketorolac pretreatment alleviated withdrawal movements during rocuronium injection. Therefore, the reduction in withdrawal movements that we observed could also be the result of a local peripheral action via inhibition of the kinin cascade through the cyclooxygenase pathway. Indeed, experimental data suggest that ketorolac produces analgesia, mainly peripherally, by reducing sensitizing prostaglandins [17
], although some NSAIDs also have a central action [19
Ketorolac improved the tourniquet tolerance and quality of postoperative analgesia when it was combined with lidocaine as intravenous regional anesthesia [20
]. Studies indicate that 20 mg of ketorolac is effective in intravenous regional anesthesia without adverse effects, implying that a larger dose may increase the risk of local complications [21
]. We used 10 mg of ketorolac with the venous occlusion technique and no localized complications, such as pain, edema, wheal, inflammation, or hematoma were observed at the injection site within 24 hours, postoperatively.
Based on our literature search, ours appears be the first investigation of the efficacy of ketorolac alone or in combination with lidocaine as pretreatment for reducing pain on injecting rocuronium. Although lidocaine pretreatment has positive results and is widely used for reducing rocuronium injection pain, it is contraindicated in patients with lidocaine allergy [23
]. Based on our results, ketorolac could be a useful alternative pretreatment for patients allergic to lidocaine. In other cases, the lidocaine/ketorolac combination could be a more effective pretreatment option.
In conclusion, ketorolac pretreatment had an effect comparable to that of lidocaine in attenuating rocuronium-induced withdrawal movements and the lidocaine/ketorolac combination pretreatment, compared with lidocaine or ketorolac alone, effectively reduced withdrawal movements during rocuronium injection.