The Prevention of Pain from Injection of Rocuronium by Ondansetron, Lidocaine, Tramadol, and Fentanyl

Abstract

We compared the efficacy of ondansetron, lidocaine, tramadol, and fentanyl in minimizing pain caused by the injection of rocuronium in 250 patients. After tourniquet application on the forearm, the patients were given saline (3 mL) (Group 1, n = 50), ondansetron (4 mg) (Group 2, n = 50), lidocaine (30 mg) (Group 3, n = 50), tramadol (50 mg) (Group 4, n = 50), or fentanyl (100 μg) (Group 5, n = 50) diluted into a 3-mL solution. The occlusion was released after 20 s and rocuronium was injected over 10–15 s. The patients were observed and asked immediately if they had pain in the arm, and the response was assessed. Reactions such as discomfort and pain, withdrawal of the hand, and so on after the administration of rocuronium were recorded as side effects for 24 h. Ten patients in Group 1, 28 patients in Group 2, 37 patients in Group 3, 30 patients in Group 4, and 15 patients in Group 5 reported no pain. Light pain was seen in 11 patients in Group 1, 14 patients in Group 2, 11 patients in Group 3, 12 patients in Group 4, and 20 patients in Group 5. Moderate pain was seen in 15 patients in Group 1, 6 patients in Group 2, 2 patients in Group 3, 8 patients in Group 4, and 10 patients in Group 5. Severe pain was seen in 14 patients in Group 1, 2 patients in Group 2, 0 patients in Group 3, 0 patients in Group 4, and 5 patients in Group 5. Correlation determined with log-linear analysis found in Group 1 pain score 0 (P < 0.001), Group 1 pain score 1 (P < 0.001), and Group 3 pain score 0 (P < 0.001). We conclude that ondansetron, lidocaine, tramadol, and fentanyl decrease the level of rocuronium injection pain. Among these drugs, lidocaine is the most effective, whereas fentanyl is the least effective.

Pain on injection of rocuronium is common, occurring in 50%–80% of patients ⁽¹⁾. We recently observed in some patients the occurrence of sudden flexion, lasting 10–20 s, of the wrist and arm into which rocuronium was infused. Although this compound is considered to be tolerated well during injection, severe burning can occur after IV injection ^(2,3). ¹

Ondansetron is an antiemetic drug that, upon the demonstration of its local anesthetic property, began to be used in the prevention of injection pain of propofol ^(4–6). Ye et al. ⁽⁵⁾ have demonstrated that ondansetron blocks sodium channels in the neurons of the rat brain and might serve as a prototype molecule for developing a novel series of local anesthetics. Several studies have tried to determine the concentration of lidocaine and fentanyl that most efficiently diminishes or eliminates pain from propofol and rocuronium injection ^(3,7–9). ¹ Tramadol is a synthetic analgesic that can be used to treat moderate and severe pain ⁽¹⁰⁾. Pang et al. ⁽¹¹⁾ observed a local anesthetic effect with intradermal injection of tramadol and lidocaine, and Tsai et al. ⁽¹²⁾ demonstrated a local anesthetic-type effect by possible neural conduction blockage of tramadol on sciatic nerves of rats. Fentanyl showed a local analgesic effect in reducing the pain on propofol injection, but the mechanisms of action are unknown ^(13,14). We compared the efficacy of ondansetron, lidocaine, tramadol, and fentanyl in minimizing the pain caused by injection of rocuronium.

Methods

Our hospital ethics committee approved the protocol, and written, informed consent was obtained from the patients. The study was conducted on 250 patients from ASA physical status I–II groups who were to undergo various elective hysteroscopy or arthroscopy operations. Patients with opioid and local anesthetic allergies, Parkinson’s disease, or weak, thin dorsal veins were excluded from the study.

The patients were randomly assigned to five groups. The study was designed to be randomized and double-blinded. A randomization list was generated, and identical syringes containing each drug were prepared by personnel blinded to the study, according to the list. No premedication was given. The patients were then taken into the operating room, the backs of both hands were catheterized with 20-gauge catheters, and the mean arterial pressure, Spo₂, and heart rate were monitored. With the aim of keeping the drug within the vein, the forearm was squeezed with a tourniquet up to 70 mm Hg; the patients were administered saline (3 mL) (Group 1, n = 50), ondansetron 4 mg (Group 2, n = 50), lidocaine 30 mg (Group 3, n = 50), tramadol 50 mg (Group 4, n = 50), or fentanyl 100 μg (Group 5, n = 50), diluted into 3 mL of saline IV at ambient operating room temperature (20°C–22°C). The occlusion was released after 20 s and a tracheal intubating dose of 0.6 mg/kg of rocuronium at room temperature was injected over 10–15 s. The patients were observed and asked immediately if they had pain in the arm, and the response was assessed. Reactions such as discomfort and pain, tears in the eye, withdrawal of the hand, and so on after the administration of the rocuronium were recorded as side effects ⁽¹⁵⁾ (Table 1). Thirty seconds after the administration of rocuronium, 5 mg/kg of thiopental was administered IV. For the crystalloid infusion and other medication, the IV catheter opened in the alternate hand was used. Via orotracheal intubation, anesthesia was continued during 50% N₂O/oxygen and isoflurane anesthesia. Within the first 24 h after the operation, the injection site was checked for any complications, such as pain, swelling, or allergic reactions, by an anesthesiologist who did not know which drug was administered.

Table 1: Assessment of Pain During Injection of Rocuronium

In the statistical analysis, one-way analysis of variance was used for the demographic data. The global association between the rows and columns was determined by log-linear analysis. For pain scores, the appropriate χ² test was used for paired comparison of groups. P < 0.05 was taken as a significant value.

Results

No significant differences were found in terms of demographic criteria (Table 2). When group and pain variables were investigated with log-linear analysis, important correlations between groups and pain scores were determined (likelihood ratio, χ² = 71.128, P = 0.000). This correlation was found in Group 1 pain score 0 (z = −4.75, P < 0.001), Group 1 pain score 1 (z = −2.47, P < 0.001), and Group 3 pain score 0 (z = 3.09, P < 0.001). This was the result of differences in pain intensity. According to our results, the most effective drug was lidocaine.

Table 2: Characteristics of the Patients (mean ± sd)

Paired comparison of groups for pain scores is shown in Table 3. Statistically evaluated differences can be seen in Table 3. Ondansetron, lidocaine, tramadol, and fentanyl prevent or decrease the degree of rocuronium injection pain. We found the most effective drug to be lidocaine, whereas the least effective drug was fentanyl. Within the first 24 h after the operation, the injection site was checked for any complications, such as pain, swelling, or allergic reactions, but none was observed.

Table 3: Distribution According to Intensity of Pain

Discussion

Earlier reports described burning pain associated with the administration of rocuronium before the induction of anesthesia ^(1,2,16). ¹ These studies noted a brisk flexion of the elbow and wrist in patients after the induction of anesthesia. The incidence of pain on injection from rocuronium is frequent; reports suggest that 50%–80% of patients experience pain ⁽¹⁾. Mencke et al. ⁽¹⁷⁾ found that the incidence and the degree of withdrawal reactions in response to the injection of rocuronium were more frequent in women than in men. Klement and Arndt ⁽¹⁸⁾ showed that acidic and alkaline solutions elicited pain at pH values of <4 and >11, respectively. Pain latency also decreased with increasing osmolality, acidity, and alkalinity. Rocuronium is supplied as an isotonic solution with a pH of 4. Injection pain is probably caused by the effect of the acidic pH of rocuronium ^(8,19). We also compared different pretreatment drugs, such as ondansetron, lidocaine, tramadol, and fentanyl. Lidocaine was the most effective in reducing pain, whereas fentanyl was the least effective.

Venous retention with a tourniquet is a technique often used for pretreatment of propofol injection pain ^(13,14,16). In our study we also used this technique.

Ondansetron is an antiemetic drug and a commonly used 5-hydroxytryptamine-3 antagonist ⁽⁴⁾. Ye et al. ⁽⁵⁾ have demonstrated that ondansetron blocks sodium channels in neurons of the rat brain and might serve as a prototype molecule for developing a novel series of local anesthetics. Ondansetron can block sodium channels similar to local anesthetics; peripheral 5-hydroxytryptamine-3 receptors are also involved in nociceptive pathways and have demonstrated binding at opioid μ receptors exhibiting agonist activity, thus resulting in a peripheral antinociceptive effect ^(5,20). Ondansetron also attaches to opioid μ receptors with agonist activity and may be effective in preventing injection pain caused by drugs such as propofol ⁽²⁰⁾. Ambesh et al. ⁽⁶⁾ administered 2 mL (4 mg) of ondansetron to successfully prevent injection pain. Reddy et al. ⁽²¹⁾ found that pain from rocuronium and propofol was significantly reduced in the ondansetron (4 mg) and lidocaine (50 mg) groups compared with placebo and that pain was significantly less with lidocaine than with ondansetron. In our study, we used similar doses of ondansetron as Ambesh et al. ⁽⁶⁾ and Reddy et al. ⁽²¹⁾ and found that this method decreased but did not eliminate pain.

Lockey and Coleman ¹ reported marked discomfort in all patients who received 0.6 mg/kg of rocuronium IV immediately after an induction dose of propofol mixed with 20 mg of lidocaine; this discomfort seemed to be unrelated to the discomfort from propofol. Cheong and Wong ⁽⁸⁾ evaluated whether prior administration of lidocaine 10 or 30 mg IV decreased the incidence of injection pain. They found that both lidocaine 10 and 30 mg IV given before the administration of rocuronium significantly reduced the incidence and severity of pain from injection of rocuronium and that the larger dose was more effective. In our study we determined that 30 mg of lidocaine was the most effective in reducing pain.

Tramadol is an analgesic drug with central effects that produces an analgesic effect by preventing the norepinephrine uptake and release without activating all of the opioid receptors ⁽²²⁾. Pang et al. ⁽²²⁾ found that injection of 25 mg of tramadol IM has a local anesthetic effect. Pang et al. ⁽²³⁾ also observed that 50 mg of tramadol IV prevents injection pain from propofol as compared with lidocaine. However, neither drug totally eliminates the pain. In our study, 50 mg of IV tramadol did not completely eliminate injection pain.

Joshi and Whitten ⁽³⁾ found that 2 mg of IV midazolam and 100 μg of fentanyl does prevent the pain associated with the injection of a defasciculating dose of rocuronium (0.06 mg/kg) in an unspecified number of adult patients. Borgeat et al. ⁽²⁴⁾ found that 2 μg/kg of IV fentanyl is effective in reducing rocuronium injection pain. In our study, IV fentanyl 100 μg decreased the pain but was not as effective as ondansetron, lidocaine, or tramadol.

Klement and Arndt ⁽¹⁸⁾ showed that injection of acidic solutions causes pain. The authors noted that after injection of acidic solutions, perivenous edema developed immediately. In our study, we did not see such side effects.

We conclude that ondansetron, lidocaine, tramadol, and fentanyl were effective in decreasing the level of rocuronium injection pain. According to our study, lidocaine was the most effective drug, whereas fentanyl was the least effective, in reducing injection pain.