Pain from the injection of some anesthetics such as propofol is a common side effect (1) in anesthetic practice. Aminosteroidal nondepolarizing muscle relaxants such as rocuronium also cause pain on injection. There are several reports of burning pain from injection of rocuronium that can be severe and distressing (2–4).
Indeed, pain from rocuronium injection was reported to occur in 50%–80% of patients (4–7). We have observed in our practice that IV injection of rocuronium was often associated with a localized withdrawal response even after loss of consciousness during induction of anesthesia. Consequently, the withdrawal movements observed in anesthetized patients had been attributable to pain from injection of rocuronium (5,6).
Pain from injection of rocuronium can be attenuated or abolished by clinical treatments similar to those used for the prevention pain on injection of propofol (8), such as previous administration of an IV local anesthetic (6,7) or opioid (9,10).
The aim of this study was to compare the efficacy of pretreatment with IV fentanyl and IV lidocaine, without tourniquet, for the prevention of withdrawal response from rocuronium injection.
This prospective, randomized, placebo-controlled, double-blind study was performed after approval from our institutional ethics committee. After obtaining informed consent, 90 patients aged between 18 and 65 yr, ASA physical status I or II, undergoing elective surgical procedures requiring general anesthesia and positive pressure ventilation were randomly allocated to 1 of 3 groups. Patients in group F received 2 mL IV fentanyl 50 μg/mL (100 μg), group L received 2 mL of preservative-free lidocaine 2% (40 mg), and group P received 2 mL of normal saline (placebo).
Patients with chronic pain syndromes, neurological deficits, thrombophlebitis, difficult venous access, and clinical conditions that contraindicated the administration of any of the drugs used in the study were excluded. Patients who had received an analgesic within the previous 24 h were also excluded.
All patients were premedicated with oral midazolam 7.5 mg 30–60 min before arrival in the operating room (OR). On arrival in the OR, an 18-gauge IV cannula was inserted into the vein of the dorsum of the hand or cephalic vein of the forearm ensuring free flow by gravity using lactated Ringer’s solution as IV fluid.
The investigator prepared all study drugs in identical syringes and labeled them with removable stickers. The syringes were kept at room temperature. The appropriate syringe was selected by another anesthesiologist according to the patient group allocation by using a computer-generated randomized number in a sealed envelope and the syringe label was removed. All drugs were administered through the injection port of the IV cannula with a free flow of IV fluid. The test drug was given by the investigator who was blinded to the study at baseline (0 s). After 120 s, anesthesia was induced using sodium thiopental 2.5% titrated until loss of consciousness, as assessed by standard clinical criteria (no verbal response and loss of eyelash reflex as the end-point). This was followed immediately by the administration of 0.6 mg/kg of 1% rocuronium injected over 10–15 s. Patient response was graded by the investigator according to the following scale: 1 = no response, 2 = movement at the wrist only, 3 = movement/withdrawal involving arm only (elbow/shoulder), and 4 = generalized response: movement/withdrawal in more than one extremity, cough, or breath holding. The anesthesia was continued with an appropriate technique at the discretion of the attending anesthesiologist.
Based on an estimated incidence of 80%, a power analysis indicated that a sample size of 30 in each group was sufficient to have 80% power (Type II error β = 0.2) of detecting a 50% difference in incidence of pain among the 3 groups at 95% significance level (type I error α = 0.05). Patient characteristics were analyzed using one-way analysis of variance. χ2 or Fisher’s exact tests were used for other statistical analysis. Statistical significance was defined as P ≤ 0.05.
There was no significant difference in demographic characteristics among the 3 groups (Table 1). The incidence of withdrawal response after rocuronium injection (grade 2 or more) was 57%, 30%, and 7% in the placebo, lidocaine and fentanyl groups, respectively (Table 2). The incidence of withdrawal response in the two treatment groups (fentanyl and lidocaine) was less frequent compared with the placebo group; this was statistically significant (P < 0.05). Additionally, the incidence of withdrawal response in the fentanyl group was significantly less than in the lidocaine group (P < 0.05). We found no significant difference in incidence of withdrawal response between injections using the vein of the dorsum of the hand and the cephalic vein of the forearm (Table 3).
Pain on IV injection of some anesthetic drugs, such as propofol and rocuronium, is an undesirable side effect in clinical practice (1). Peripheral veins are innervated with polymodal nociceptors (11) which mediate the response to the injection of certain anesthetics that cause pain. Recently, Blunk et al. (12) concluded that the algogenic effect of aminosteroidal neuromuscular blocking drugs could be attributed to a direct activation of C-nociceptors.
Since the publication of several reports of severe burning pain on injection of rocuronium (2–4), various mechanisms responsible for pain on injection have been postulated. The mechanism is still unclear. Lockey and Coleman (3) described a marked discomfort in patients when rocuronium was injected entirely separate in timing and quality from that caused by propofol. Because rocuronium bromide is formulated with sodium acetate, sodium chloride, or acetic acid (13) to produce a solution of pH 4, Lockey and Coleman (3) postulated that the low pH is a possible cause of pain. Indeed, Klement and Arndt (14) found that pain on injection of some drugs was likely to be caused by formulations of extremely unphysiological osmolalities or pH values. However, Borgeat and Kwiatkowski (5) speculated that local release of mediators might be implicated because of the short duration of the pain and the marked decrease or absence of pain during a subsequent second administration.
The injection pain can be attenuated by pretreatment with IV lidocaine (6,7,15). Cheong and Wong (7) compared the influence of two doses of lidocaine pretreatment (10 mg and 30 mg, 10 seconds before rocuronium administration) in adult patients and found that both significantly reduced the incidence and severity of the pain on injection of rocuronium and that the larger dose was more effective. In our study, IV lidocaine also produced a statistically significant reduction in the incidence of injection pain compared with placebo (P < 0.05), although the reduction was not as much as was reported in a previous study (7). We found that the incidence of withdrawal reaction was reduced to only 30% despite using a larger dose (40 mg), whereas Cheong and Wong observed a reduction to 7% using lidocaine 30 mg. This was comparable to the reduction by IV fentanyl in our study. One important difference was the timing between the administration of lidocaine and rocuronium (120 seconds in our study versus 10 seconds) (7). A possible explanation for the different findings is that the peripheral analgesic effect of lidocaine may be short and did not last for 2 min in our study. Therefore, lidocaine may be more effective when used immediately before injection of rocuronium.
The application of venous tourniquet is a technique that has been used for pretreatment of rocuronium injection pain (6,15). The venous occlusion technique is suitable for studying the peripheral action of pretreatment drugs with local anesthetic properties such as lidocaine (6,15), ondansetron (15), or tramadol (15) but is not useful for drugs that are postulated to act centrally, such as morphine or fentanyl, as it prevents the delivery of drugs to the effect sites. However, we did not use the tourniquet technique in our study to distinguish between the peripheral and central effects of the pretreatment drugs.
Pretreatment with an opioid such as fentanyl also relieves the injection pain associated with rocuronium (9,10). Joshi and Whitten (9) noted that administration of midazolam 2 mg and fentanyl 100 μg before rocuronium 0.06 mg/kg prevented the pain on injection. However, the duration before rocuronium injection was not specified. Borgeat et al. (10) found a significant decrease in the incidence of spontaneous movements associated with rocuronium injection with previous administration of fentanyl 2 μg/kg for approximately 2 minutes. Indeed, our study found that IV fentanyl given 2 minutes before administration of rocuronium did significantly decrease the incidence of injection pain compared with placebo.
Interestingly, we also found that fentanyl was better than lidocaine for the prevention of pain on injection of rocuronium. On the contrary, Memis et al. (15), who compared the efficacy of ondansetron, lidocaine, tramadol and fentanyl, found that lidocaine was the most effective drug, and fentanyl the least effective, in reducing injection pain. In their study, the test drug was given after tourniquet application on the forearm, which was then released after 20 seconds. In our study, we administered fentanyl 2 minutes before induction followed by injection of rocuronium, confident that there was adequate time for the onset of the analgesic effect, as the effect-site concentration for fentanyl peaks at 3 to 4 minutes (16). This was consistent with the fact that fentanyl has a central analgesic effect in reducing the injection pain associated with rocuronium. Therefore, to prevent injection pain when using opioids such as fentanyl, adequate time should be allowed for the onset of drug effect.
The crux of the matter is the timing of the administration of the pretreatment drug. Pretreatment with opioids is only effective if adequate time is allowed for the onset of analgesia, whereas pretreatment with drugs with local anesthetic property is effective both when it is administered immediately before or with a venous occlusion technique. However, further research to study the effect of timing may be needed. Consequently, clinical treatments for the prevention of injection pain and withdrawal response can only be compared if the postulated mechanisms of action of the drugs were similar.
The combined use of IV fentanyl 2 μg/kg and lidocaine 0.5–1 mg/kg should be recommended, as they may have potential benefits. The administration of fentanyl 2 minutes before (for its central analgesic action) and lidocaine immediately before (for its peripheral analgesic action) rocuronium may not only reduce or abolish pain and withdrawal response on injection of rocuronium but also attenuate hemodynamic effects of laryngoscopy and intubation.
In conclusion, both fentanyl and lidocaine were effective clinical treatments for the prevention of pain and withdrawal response associated with rocuronium injection, and fentanyl was more effective than lidocaine.
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