Effect of ondansetron pretreatment on pain after rocuronium and propofol injection: a randomised, double-blind controlled comparison with lidocaine
Dr M. S. ReddyE-mail: firstname.lastname@example.org
In a randomised, controlled, double-blinded trial to study the effect of ondansetron pretreatment on the pain produced after intravenous injection of rocuronium and propofol in comparison with lidocaine, 60 patients were randomly assigned to one of three groups. Group 1 received 5 ml of intravenous 0.9% sodium chloride solution pretreatment, group 2 received ondansetron 4 mg (2 mg.ml−1 solution) diluted into a 5-ml solution, and group 3 received 50 mg lidocaine (5 ml 1% solution); this was followed 1 min later by rocuronium and propofol. Pain was reduced significantly in the ondansetron and lidocaine groups (p < 0.0001) compared with placebo, and significantly better with lidocaine than with ondansetron (p = 0.02). We conclude that ondansetron is effective in relieving the pain of rocuronium but is not as effective as lidocaine.
Ondansetron, a 5-HT3 antagonist, is commonly used prophylactically in our institution to reduce postoperative nausea and vomiting (PONV). Recently, Ye and colleagues  reported that ondansetron blocks sodium channels in rat brain neurones. They also demonstrated that ondansetron was 15 times more potent than lidocaine as a local anaesthetic when injected under the skin.
Propofol is an intravenous anaesthetic with a fast onset which produces good recovery. Its main disadvantage is that of pain during intravenous injection . Many methods have been shown to alleviate the pain of injection, including the use of a local anaesthetic .
Rocuronium is an aminosteroidal neuromuscular blocking drug of rapid onset and intermediate duration of action. Intubation conditions have been reported to be almost as good as succinylcholine at doses of 0.6 mg.kg−1 after 90 s . Using the ‘timing principle’, with rocuronium being given before the induction agent, Sieber et al.  reported similar intubating conditions to succinylcholine at 45 s and 1 min after induction of anaesthesia. The use of rocuronium in the awake patient, however, is associated with considerable discomfort and pain during injection . The use of lidocaine to reduce the discomfort of rocuronium injection has been reported in children and adolescents  and recently in adults by Cheong & Wong .
The use of ondansetron was recently shown to reduce the pain of injection after propofol . In this study, no comparison was made with lidocaine, a drug commonly used to reduce the pain of propofol injection. As ondansetron is commonly used in our institution to reduce PONV, we designed this double-blind, placebo-controlled study to determine the efficacy of ondansetron compared with lidocaine in reducing the pain of both rocuronium and propofol injection during induction of anaesthesia.
After institutional ethics committee approval, informed consent was obtained from 60 ASA I and II patients undergoing elective orthopaedic and gastrointestinal procedures under general anaesthesia. All subjects received midazolam 7.5 mg orally as premedication, 1 h before induction of anaesthesia. Patients were monitored during induction of anaesthesia with ECG, pulse oximetry and non-invasive blood pressure. A 20-G cannula was inserted into the dorsum of the left hand and an intravenous dextrose–saline infusion started. An independent blinded anaesthetist then asked the patient to evaluate the pain score at the infusion site, graded as 0−3 in accordance with the scale advocated by McCrirrick & Hunter (Table 1). The pain score was assessed as 0 for no pain, 1 for mild pain, 2 for moderate pain and 3 for severe pain.
Table 1. Assessment of pain 
|0||None||Negative response to questioning.|
|1||Mild||Pain reported in response to questioning only without any behavioural signs|
|2||Moderate||Pain reported in response to questioning and accompanied by a behavioural |
sign or pain reported spontaneously without questioning
|3||Severe||Strong vocal response or response accompanied by facial grimacing, arm withdrawal, or tears|
Subjects were randomly allocated to one of three groups by the drawing of lots. Group 1 received 5 ml 0.9% sodium chloride solution intravenously as the control, group 2 ondansetron 4 mg (2 mg.ml−1) diluted with water into a 5-ml solution and group 3 received 50 mg lidocaine (5 ml 1% solution) intravenously. All syringes of test solution were prepared by another investigator and covered so that the investigator who assessed the patient's response was unaware of the nature of the solution. An elastic tourniquet, 2.2 cm in width, which is normally used in our hospital to assist intravenous cannulation, was applied to the mid left forearm sufficient to block the intravenous infusion and the test solution was then administered over 10 s. One minute after the administration of the test solution, the tourniquet was removed and an intubating dose of rocuronium 0.6 mg.kg−1 at room temperature was injected over 5–10 s followed by propofol 2.5 mg.kg−1 given over 10 s. The blinded independent anaesthetist asked the subjects to assess the pain of injection after the test solution, after rocuronium and after propofol. Tracheal intubation was carried out 90 s after the end of the propofol injection and the intubating conditions noted by the independent anaesthetist. Intubating conditions were graded on five variables: jaw relaxation, laryngoscopy, vocal cord movements, coughing and limb movements (Table 2) based on the four-point scoring system devised by Helbo Hansen and colleagues . Intubating conditions were judged acceptable when all five scores were ≤ 2. If any of the five scores were 3 or 4, intubating conditions were judged unacceptable. Anaesthesia was then maintained with sevoflurane supplemented with fentanyl and morphine.
Table 2. Intubating conditions 
|Jaw relaxation||Complete||Slight tone||Stiff||Rigid|
Pain scores are displayed as median (range). Non-parametric data of pain scores and intubating conditions were analysed by the Kruskal–Wallis test. A p-value of < 0.05 was considered statistically significant.
All 60 patients completed the study. There were no major differences between the three groups in terms of age, body weight, gender distribution and ASA classification (Table 3).
Table 3. Baseline data. Mean (SD)
|Age; years||33.5 (13.5)||39.8 (14.2)||41.4 (18.3)|
|Weight; kg||63.5 (13.0)||64.0 (13.2)||62.3 (10.2)|
The median (range) pain score after venous cannulation, after test solution of sodium chloride (placebo), ondansetron and lidocaine, after rocuronium and after propofol is shown in Table 4. With placebo, one patient complained of mild pain after injection. The main differences in the pain scores were seen after the rocuronium injection. After rocuronium in the placebo group, the median pain score was 2.0 (1–3), significantly higher than those receiving ondansetron and lidocaine (p < 0.0001), with five patients having severe pain, 13 having moderate pain and two having mild pain (Table 5). With ondansetron pretreatment, the median pain score after rocuronium was 1.0 (0–2) and this was comparable with lidocaine pretreatment with the median pain score after rocuronium being 0 (0–2). No patients receiving lidocaine or ondansetron had severe pain. After propofol injection, the median pain scores (range) after placebo, ondansetron and lidocaine were 1 (0–2), 1 (0–2) and 0 (0–2), respectively. These were not significantly different. None of the patients was affected by rocuronium-induced paralysis at the time when the pain of the propofol injection was assessed. There were no significant differences in the intubation scores in the three groups.
Table 4. Pain score. Median (range)
|After cannulation||0 (0–0)||0 (0–0)||0 (0–0)|
|After test solution||0 (0–1)||0 (0–0)||0 (0–0)|
|After rocuronium||2 (1–3)||1 (0–2)*||0 (0–2)†‡|
|After propofol||1 (0–2)||1 (0–2)§||0 (0–2)¶**|
Table 5. Number of subjects with no, mild, moderate and severe pain after placebo, ondansetron and lidocaine pretreatment
This study demonstrates that ondansetron significantly reduces the pain of injection of rocuronium during induction of anaesthesia compared with placebo, but is not as effective as lidocaine.
In animal experiments, ondansetron has previously been shown to reduce nociceptive responses of dorsal horn neurones when administered intrathecally by altering the 5-HT3 nociceptive receptors . Ye et al.  found that, in rats, ondansetron was 15 times more potent than lidocaine as a local anaesthetic when injected under the skin in equal amounts, with 0.1% ondansetron producing an effect similar to that of 1.5% lidocaine.
Local anaesthetics contain hydrophilic and hydrophobic structures separated by an intermediate amide or ester linkage. The hydrophilic group is a tertiary or secondary amine and the hydrophobic group an aromatic moiety. Although ondansetron does not possess this aromatic moiety, it has been shown to block sodium channels . Recently, ondansetron has been shown to bind to opioid µ-receptors in humans and exhibit agonist activity . These properties, together with the observation that 5-HT3 receptors are involved in the nociceptive pathways, has been postulated to explain the antinociceptive properties of ondansetron.
Pain after rocuronium injection is well reported. Moorthy & Dierdorf  observed that patients who received rocuronium before the loss of consciousness after induction of anaesthesia complained of severe burning pain in the arm and forearm. Borgeat & Kwiatkowski  found that eight of 10 awake patients who received 10 mg rocuronium reported a strong burning pain during the injection with brisk flexion of the elbow and wrist. The pain was not associated with any erythema or any changes in the skin. There were no complaints of residual pain and no induration of the veins.
The exact mechanism of the causation of pain after rocuronium is not well established. Rocuronium is supplied in a sterile, non-pyrogenic isotonic solution with a pH of 4 . The pH of 4 is achieved using acetic acid or sodium hydroxide. Although the relatively low pH may have been a cause of pain, as demonstrated by Klement & Arndt , the lack of perivenous oedema and thrombophlebitis postinjection argues against this. Borgeat & Kwiatkowski  found that patients receiving normal saline buffered to pH 4 did not complain of pain. Interestingly, vecuronium has a pH of 4 but has not been associated with pain on injection. Another mechanism of causation of pain after rocuronium may be the release of local mediators such as histamine and kinins. The lack of erythema and warmth in the surrounding tissue after injection, however, makes histamine release unlikely. The immediate onset of pain with rocuronium probably reflects a direct irritant effect and not an indirect effect on the kinin cascade. Kininogen cascade activation has been postulated to explain propofol injection pain .
Rocuronium may be given as a precurarisation , timing or priming technique , or as a variation of the timing principle  before induction of anaesthesia. When given in awake patients before induction of anaesthesia all our patients complained of pain, with 18 patients of a total of 20 complaining of moderate to severe pain. Cheong & Wong , in their study of the effect of 10 and 30 mg of lidocaine pretreatment for rocuronium pain, noted that 30 mg lidocaine reduced the incidence of pain to 7% from 76.7% and 10 mg of lidocaine to 37%. They proposed a dose of 50 mg lidocaine to reduce the pain totally. In our study we used a dose of 50 mg lidocaine, but despite this, two patients still had moderate pain and five mild pain.
In conclusion, we demonstrated that ondansetron is effective in relieving the pain of rocuronium but is not as effective as lidocaine.