|Year : 2013 | Volume
| Issue : 2 | Page : 140-143
Nitrous oxide for the prevention of rocuronium injection pain: A randomized, double-blind, controlled clinical trial
Amitesh Pandey, Deban L Singh, Ratan N Singh, Pradip L Singh, Rupendra S Thokchom, Jack Meitei
Department of Anesthesiology, Regional Institute of Medical Sciences, Imphal, Manipur, India
|Date of Web Publication||19-Nov-2013|
Deban L Singh
Department of Anesthesiology, Regional Institute of Medical Sciences, Imphal - 795 004, Manipur
Source of Support: None, Conflict of Interest: None
Background: Pain on injection of rocuronium bromide is a common side-effect in anesthetic practice. This study has been carried out to assess the effect of nitrous oxide on the pain and withdrawal response caused by rocuronium injection. Materials and Methods: A prospective, randomized, double-blind, placebo-controlled study was carried out in the department of Anesthesiology, Regional Institute of Medical Sciences, Imphal to determine the effect of nitrous oxide (N 2 O) on the frequency and severity of pain and withdrawal reactions after injection of rocuronium. 80 (Eighty) ASA physical status I and II patients undergoing general anesthesia for elective surgery were enrolled. The patients were divided into group O and group N and randomized to receive 100% oxygen (O 2 ) or 50% N 2 O in O 2 for 2 minutes followed by a sub-paralyzing dose of rocuronium 0.06 mg/kg. After induction of anesthesia with thiopentone 5 mg/kg, an intubating dose of rocuronium 0.6 mg/kg was given. The patients were observed after injection of rocuronium 0.06 mg/kg, and asked to rate pain in the arm on a 4-point (0-3) verbal rating scale (none, mild, moderate or severe). After the intubating dose of rocuronium, withdrawal reactions were recorded. Results: Thirty-five patients (87.5%) in the group N and 20 patients (50%) in the group O reported no pain (P <0.001). The pain was mild in 5 (12.5%) and 20 (50%) patients in nitrous group and oxygen group, respectively, (P < 0.001). Withdrawal response after an intubating dose of rocuronium was observed in 4 (10%) and 11 (27.5%) patients in the N 2 O and O 2 groups, respectively, (P <0.05). No patients reported moderate or severe pain. Conclusion: Inhalation of 50% N 2 O in O 2 reduces the incidence and severity of pain and the withdrawal reactions associated with rocuronium injection.
Keywords: Nitrous oxide, Pain, Rocuronium
|How to cite this article:|
Pandey A, Singh DL, Singh RN, Singh PL, Thokchom RS, Meitei J. Nitrous oxide for the prevention of rocuronium injection pain: A randomized, double-blind, controlled clinical trial. J Med Soc 2013;27:140-3
|How to cite this URL:|
Pandey A, Singh DL, Singh RN, Singh PL, Thokchom RS, Meitei J. Nitrous oxide for the prevention of rocuronium injection pain: A randomized, double-blind, controlled clinical trial. J Med Soc [serial online] 2013 [cited 2019 Dec 6];27:140-3. Available from: http://www.jmedsoc.org/text.asp?2013/27/2/140/121593
| Introduction|| |
In the present day practice of anesthesiology and critical care, it is very important to secure airway as early as possible. The time interval between suppression of pharyngeal and laryngeal reflexes by induction of anesthesia with muscle relaxants and intubation is critical. Succinyl choline has been the muscle relaxant of choice for intubation as well as rapid sequence intubation, as it provides excellent intubating conditions within 60 seconds. But, due to several side-effects caused by it, there has been constant search for better muscle relaxant, which has short onset of action and better pharmacological profile (lesser side-effects) than it.
Rocuronium bromide, a derivative of vecuronium, an aminosteroid, is a non-depolarizing muscle relaxant, with a rapid onset and an intermediate duration of action. It can be used as alternative to succinyl choline due to its rapid onset of action.  But, it commonly induces pain during intravenous injection with incidence of 33-80% and can lead to dislodgement of venous catheter or injury during intubation. ,,, It increases the stress and anxiety in patients just prior to surgeries. The pain is at times severe, with a burning sensation.  Rocuronium injection pain can elicit withdrawal movement of the arm or generalized movement of the body, even after loss of consciousness, during induction of anesthesia. These withdrawal movements may dislodge a venous catheter or cause injury during induction. 
Nitrous oxide is a commonly used gas in anesthesia practice as a carrier for inhalational anesthetic as well for its analgesic properties. It has been used for several types of pain relief for painful procedures ranging from dental procedures to migrainous headache and cancer. It has been used effectively to reduce the pain associated with propofol injection also, but its effect on reducing pain on rocuronium injection has not been extensively studied. 
In this study, we studied the effect of nitrous oxide on the pain and withdrawal response caused by rocuronium bromide injection.
| Materials and Methods|| |
After obtaining approval from the institutional ethics committee and written informed consent, 80 ASA physical status I or II aged between 18-65 years of both sexes were enrolled. Patients with chronic pain, with short term or long term analgesic treatment, with anticipated difficult airway, pregnancy, any psychiatric illness or any other disease or condition interfering with normal communication with observer of the study, any contraindication to N 2 O, known allergy to rocuronium, and patients receiving analgesics or sedatives were excluded from this study. Patients were informed that they would be receiving a drug at the start of their anesthesia that may make their arm "sting." They were told that they would be asked to score their pain on a 4-point scale (0-3), if any, after the drug had been given. They were, however, informed that they would be blinded to their group assignment.
On arrival at the operating room, an 18-G intravenous cannula was placed preoperatively in the largest vein on the dorsum of the hand, and an intravenous infusion of isotonic normal saline solution (0.9%) was started in all the patients. Every patient posted for surgeries received ondansetron 0.2 mg/kg i.v., ranitidine 50 mg i.v., and glycopyrolate 0.2 mg i.m. 1 (one) hour before surgery. Patients were randomized into two groups - Group N to receive inhalation of 50% N 2 O with oxygen (O 2 ) and group O to receive inhalation of 100% O 2 (Group O) for 2 minutes.
During this period, a screen was placed in front of the flow meters and the multiparameter monitor to obstruct the view of the investigator collecting the data of the group assigned to the patient. After the patient had inhaled either 50% N 2 O and O 2 mixture (Group N) or pure O 2 for 2 minutes (Group O), a sub-paralyzing dose of rocuronium 0.06 mg/kg (5 ml in volume) was injected over 10 seconds. The patients were observed and asked immediately if they had any pain in the arm and if their replies were found affirmative, their responses were assessed according to the verbal rating scale (0 - none, 1 - mild, 2 - moderate, 3 - severe). 
Assessment of Pain During Injection of Sub-paralyzing Dose of Rocuronium (Verbal Rating Scale)
Anesthesia was then induced with 2.5% thiopentone 5 mg/kg intravenously. When the eyelash reflex was abolished, an intubating dose of rocuronium 0.6 mg/kg was injected over 10 seconds and withdrawal movements, if any, were recorded. Any other adverse effects were also noted. Thereafter, all the patients received inj. tramadol 2 mg/kg, and further anesthesia was managed by using drugs and methods as preferred by the attending anesthesiologists.
With a web-based, computer-generated randomization table, to detect a 50% reduction at a significant level (α) of 5% and a power of study (1-β) of 80%, the study required at least 40 patients per group, estimating the frequency of 80% of patients who will experience pain or withdrawal movement on injection of rocuronium. Data were expressed as mean ± SD or numbers (percentages). In this study, all 80 patients completed the study. Data collected was then analyzed by using Statistical Package for Social Sciences (SPSS Inc., Chicago, IL, USA) Windows-based version 16.0. Patient's characteristics were analyzed by using one-way analysis of variance (ANOVA). Chi-square test was used for other statistical analysis (gender and injection related pain or withdrawal movement). 'P' value of less than 0.05 was considered significant.
| Results|| |
All the 80 patients completed the study. The demographic data were comparable among the two groups [Table 1].
The intensity of pain caused by the sub-paralyzing dose of rocuronium after the inhalation of either 100% O 2 (group O) or 50% N 2 O in O 2 (group N) was mild in 5 (12.5%) and 20 (50%) patients in group N and group O, respectively, (P < 0.001). Thirty-five (87.5%) patients in the group N and 20 (50%) patients in the group O reported no pain. No patients reported moderate or severe pain [Figure 1].
The incidence of withdrawal response after an intubating dose of rocuronium was observed in 4 (10%) and 11 (27.5%) patients in the group N and O, respectively, (P = 0.045) [Table 2].
| Discussion|| |
Pain is a common and distressing symptom of rocuronium injection pain and has been reported to range from 30-80% in different series of literatures. ,, It increases the stress and anxiety in patients just prior to surgeries. The pain is at times severe, with a burning sensation.  As well it has limited its use as alternative to succinylcholine.
In this study, the overall incidence of patients reporting pain after sub-paralyzing dose of rocuronium was 50% in group O (Control group) and 12.5% of patients in group N, which was similar to the incidence of pain reported by Sharma et al. i.e. 62.5% in group O and 10% in group N. However, the severity of pain in the present study was much lesser. No patient reported moderate or severe pain in comparison to the study done by Sharma et al.where they reported 2.5% incidence of severe pain and 37.5% incidence of moderate pain in group O and 5% incidence of moderate and 2.5% incidence of severe pain in group N.
The withdrawal reaction was 10% of the patients in group N in the present study compared to 15% patients in group N in the study done by Sharma et al.  In control group too, lesser number of patients showed withdrawal reactions i.e. 27.5% in the present study in comparison to 45% in the study done by Sharma et al. 
Numerous techniques have been used to reduce the incidence and intensity of this pain, however, with variable success. These include pre-treatment with thiopentone,  ondansetron,  tramadol,  fentanyl,  lidocaine ,, and nitrous oxide, , esmolol,  ketamine,  opioids like fentanyl,  ramifentanil,  centrally acting alpha 2 agonist dexmedetomidine,  anti-histaminics like phenaramine maleate,  injection of neutralized rocuronium,  and dilution of rocuronium solution. 
The exact mechanism of rocuronium-induced has not been ascertained; however, various theories have been proposed to explain the etiology of this pain. They include direct activation of C-nociceptors by the osmolality or pH of the solution, or activation by the release of endogenous mediators such as histamine, kinin and other substances mediating inflammation. ,,, Although the low pH of rocuronium may be a possible cause, injection of acidic solutions is generally associated not only with pain but also with perivenous edema and thrombophlebitis, which are rarely seen after rocuronium injection. , Local releases of mediators are suspected as the likely mechanism due to short-lasting nature of the pain with rocuronium. But, in the absence of associated erythema, histamine may not be the likely mediator.  Kininogen cascade similar to that associated with propofol pain may be responsible.  There seems no reason to exclude this mechanism.  Variability in pain has also been shown to be associated with variations in osmolality and pH of the solution of rocuronium infused  and gender  associated.
The most effective methods involve lidocaine or sodium bicarbonate pre-treatment or mixing these drugs with rocuronium. , However, even with the use of these drugs, the incidence of pain has been reported to be 20-28% with lidocaine and 10-14% with sodium bicarbonate. ,
Nitrous oxide has been used for more than 100 years, and its mechanism of action seems to be the antagonism of NMDA receptors in spinal cord and CNS. Due to its low cost, it is still in common use. It has been used for several types of pain relief for painful procedures as well as a carrier agent for other volatile anesthetic gases. ,
In this study, we evaluated the incidence of pain and withdrawal reactions associated with rocuronium injection pain and effect of nitrous oxide on it in north-eastern population of India. We found that incidence of pain and withdrawal reaction was lesser in the population under the study in comparison to their counter parts living in other regions of India. This difference can be difficult to explain, but may be associated with either different susceptibility of pain due to different genetic constitution of patients or higher number of patients with rural background in whom the pain threshold may be on the higher side.
| Conclusion|| |
Inhalation of nitrous oxide significantly decreased the pain and withdrawal reactions associated with rocuronium injection pain and can be cost-effective method in ameliorating the same.
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[Table 1], [Table 2]