Premedication with Diclofenac and Precurarization with Atracurium on Succinylcholine-Induced Myalgia in Laparoscopic Cholecystectomy: A Double-Blinded Randomized Study.

Background and Aims: Succinylcholine is the only available depolarizing neuromuscular blocker that has been widely used in the induction of anesthesia, and it is the drug of choice for rapid-sequence induction of anesthesia due to its rapid onset of effect and ultrashort duration of action owing to its rapid hydrolysis by acetyl-cholinesterase. Postoperative muscle pain (myalgia) and muscle stiffness are the most common side effects and are observed most frequently on the 1st postoperative day in ambulatory surgery. The use of succinylcholine in the induction of anesthesia and intubation in routine cases has been discouraged because of such adverse effects. However, because of its cost-effectiveness and easy availability, it is still used by some institutions routinely. This study aimed to study the efficacy of preoperative diclofenac along with atracurium precurarization in alleviating succinylcholine-induced myalgia. Materials and
Methods: It is a double-blind randomized comparative study carried out in a tertiary care hospital. The study sample was 60 and divided into two equal groups. All data entered in MS-Excel Sheet and Wilcoxon signed-rank test were done for nonparametric data and one-way ANOVA for the parametric data. The normal distribution of the study sample was tested by the Shapiro - Wilk test.
Results: The fasciculations in the test group were much less than in the control group with P < 0.00001. The results for the incidence of myalgia in the two groups were as follows: P value at 24 h was 0.00018 and at 48 h was 0.0028, respectively. Creatine kinase levels at preoperative and 24 h postoperative periods were 49.47 ± 7.24 in Group D, 53.30 ± 7.98 in Group B and 87.38 ± 15.16 in Group D, and 188.41 ± 33.27 in Group B, respectively.
Conclusion: Succinylcholine-induced myalgia has a complex pathophysiology. However, the preemptive use of diclofenac in combination with precurarization can alleviate the incidence and severity of succinylcholine-induced myalgia. Therefore, its use may be considered in routine cases for induction of anesthesia for facilitating laryngoscopy and endotracheal intubation. Copyright:

INTRODUCTION

Succinylcholine is the most common available depolarizing neuromuscular drug that is used in the induction of anesthesia and it is the drug of choice for rapid-sequence induction of anesthesia. Due to its faster onset of effect and ultra-short duration of action owing to its rapid hydrolysis by acetyl-cholinesterase, it is the preferred drug for induction. Postoperative muscle pain (myalgia) and muscle stiffness are commonly seen side effects and are observed most frequently on the 1st postoperative day in ambulatory surgery. The use of succinylcholine in the induction of anesthesia and intubation in routine cases is discouraged these days because of such adverse effects and availability of rocuroniu; however, because of its cost-effectiveness and easy availability, it is still used by many institutions routinely.

Creatine kinase has been used to quantify such tissue damage in many such studies on postoperative myalgia.[1] Fasciculation induced by depolarizing muscle relaxants is reflected in deranged biochemical parameters with raised serum creatine kinase concentration in many subjects after its administration.[1] It has been suggested that the underlying mechanism of muscle damage associated with the administration of succinylcholine may involve calcium-induced phospholipids degradation with the release of damaging products of fatty acid metabolism.[2]

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) may interrupt this prostaglandin-mediated destructive cycle and provide a rationale for their use in preventing succinylcholine-induced myalgia.[3]

Myalgia and tissue damage are the separate components of a complex picture of succinylcholine-induced tissue damage. Thus, the preemptive dose of diclofenac when used in combination with precurarization might be helpful in considerably reducing the incidence and severity of succinylcholine-induced myalgia. Therefore, in this study, we want to evaluate the efficacy of the preoperative dose of diclofenac in combination with atracurium precurarization, in decreasing succinylcholine-induced postoperative myalgia in patients undergoing laparoscopic cholecystectomy under general anesthesia.

MATERIALS AND METHODS

The study was reviewed by the Institutional Ethics Committee (No: 188 IEC RIMS dated December 21, 2019) and registered in the Clinical Trial Registry of India (CTRI/2021/02/031590). Our study followed the CONSORT guidelines for research as shown in Figure 1. Written informed consent was obtained for participation in the study and the use of the patient data for research and educational purposes. We followed the guidelines laid down in the Declaration of Helsinki (2013). It was a prospective randomized controlled study with double-blinding.

Figure 1

CONSORT flow diagram

Our research aimed to study the efficacy of a preoperative dose of diclofenac sodium in combination with atracurium precurarization in decreasing succinylcholine-induced myalgia. The secondary objectives of the study were to establish the association of fasciculation with postoperative myalgia and to study the association of creatine kinase with succinylcholine-induced myalgia. Inclusion criteria included patients who were scheduled to have laparoscopic cholecystectomy surgery, were 20–50 years old, of either sex and belonged to American Society of Anesthesiologists (ASA) Grade I. Those patients who have an allergy to the drugs used in our study, pregnancy, any neuromuscular disorder and any grade of hepatic or renal disease were excluded from the study. Any laparoscopic surgery converted to open surgery for any reason was excluded from our study. Allocation was done by using computer-generated random numbers in sealed envelopes. Double blinding was done by blinding the patients and the observer who assessed patients for myalgia. Operational definitions are as follows:

ASA Physical Status (ASA PS) Classification System was used to assess the patient preoperatively and only the patients belonging to ASA PS class I were included

Myalgia Grading Scale was used to grade myalgia as follows: 0 - Absence of muscle pain, 1 - Stiffness limited to one area only, 2 - Muscle pain or stiffness noticed spontaneously by the patient, which may require analgesic therapy, 3 - generalised, severe or incapacitating discomfort[3]

Fasciculation grading scale on a scale of 0–3, where 0 = absent, 1 = slight eyelid and facial fluttering, 2 = large muscle twitching, 3 = major limb movement.[4]

Patients were posted for laparoscopic surgery preanesthetic checkups, confirming their ASA status as Type-I and taking informed and written consent from them. The patients were chosen randomly by computerized random numbers. Accordingly, 30 patients were allocated into two groups, i.e., B and D. All patients received tablet ranitidine 150 mg and tablet metoclopramide 10 mg the night before surgery. Group B received the placebo as Cap. B-complex (orally) 1 h before the induction of anaesthesia and Normal saline 0.9% (intravenous [i.v.]) 3 min before the administration of succinylcholine, and Group D received Cap. diclofenac sodium 100 mg (orally) 1 h before the induction of general anaesthesia and Atracurium (i.v.) 0.05 mg.kg−1 3 min before the administration of succinylcholine. All the patients were premedicated 30 min before surgery with Ranitidine 50 mg i.v. and metoclopramide 10 mg i.v. Patients were preoxygenated with 100% O2 for 3 min with normal tidal volume or 3 deep inspirations with 100% O2 and then patients were induced with propofol 2 mg.kg−1 in slow incremental boluses followed by succinylcholine 1.5 mg.kg−1. Butorphanol 2 mg i.v. was used for intraoperative analgesia. Maintenance of anaesthesia was done with N2O + O2 + isoflurane - 1 MAC.

The outcomes were listed as primary and secondary outcomes. Myalgia was assessed by an observer who was blinded to the administration of drugs. Grading of myalgia was done on a scale of 0–3 according to the myalgia grading scale, 24 and 48 h after surgery. Patients with myalgia grading 1–3 were treated with injections of paracetamol 20 mg.kg−1 i.v., 2–4 times a day. Fasciculation after the administration of succinylcholine was assessed according to the fasciculation grading scale on a scale of 0–3. Creatine kinase levels were measured before induction and 24 h after surgery.

A pilot study on 11 patients revealed an incidence of 64% of succinylcholine-induced myalgia in our institution. Based on this assumption, our sample size was calculated as 55. Assuming an attrition rate of 10%, our sample size for this study came up as 60.

All data entered in MS-Excel Sheet and one-sample Wilcoxon signed-rank test were done for nonparametric data and one-way ANOVA for parametric data. The power of the study was kept at 80% with a type 1 error of 5%. The confidence limit of 95%, the P < 0.05 were considered significant. The normal distribution of the study sample was tested by the ShapiroWilk test. Statistical analysis was done with Number Analytics LLC.

RESULTS

The study sample was normally distributed for weight with W = 0.96 and P = 0.206. Table 1 shows the demographic profile of patients.

Table 1

Demographic profile

	Group D	Group B
Age	35.65±7.77	39.65±7.36
Sex (male: female)	10:16	16:10
Weight	59.03±9.55	63.30±11.9
Systolic BP	127.11±9.29	126.42±9.45

BP=Blood pressure

The incidence of fasciculation in the two groups was found to be significant with P < 0.00001 as shown in Table 2.

Table 2

Incidence of fasciculation

Grade	Group D	Group B
0	22	1
1	3	7
2	1	9
3	0	9
P	z=−4.2857, P<0.00001

The result is significant at P<0.05

The results for the incidence of myalgia in the two groups were significant at 24 h and 48 h postsurgery. The P value at 24 h was 0.00018 and at 48 h was 0.0028, respectively, as shown in Table 3.

Table 3

Incidence of myalgia

Myalgia Grading Scale	After 24 h		After 48 h
	Group D	Group B	Group D	Group B
0	17	5	22	10
1	8	6	4	11
2	1	10	0	5
3	0	5	0	0
P	0.00018		0.00288
	<0.05		<0.05

Table 4 shows the level of creatine kinase preoperatively and at 24 h postsurgery. The preoperative levels were comparable with P = 0.075 (>0.05), but the postoperative levels indicate very significant rise in creatine kinase in the control group.

Table 4

Creatine kinase level

	Preoperative		After 24 h
	Group D	Group B	Group D	Group B
CK level	49.47±7.24	53.30±7.98	87.38±15.16	188.41±33.27
P	F-statistic value=3.285		F-statistic value=198.60
	P=0.0759		P=0

CK=Creatine kinase

DISCUSSION

Succinylcholine is the most widely used depolarizing neuromuscular blocking agent because of its faster onset and ultrashort duration of action.[3] There are several disadvantages, among which muscle pain is a common complaint. Succinylcholine-induced myalgia is often an ignored complication of general anesthesia. In our study, 15 patients complained of myalgia in the control group while only 1 patient had myalgia above Grade 1. According to Wong and Chung, the incidence of succinylcholine-induced myalgia in surgical patients ranges from 1.5% to 89.6%.[5] Pain and stiffness caused by succinylcholine may last for 2–6 days and range in intensity from mild malaise and tenderness to generalized and severe pain.[6] Pain after 48 h postsurgery in Group B was in 16 patients, while in Ggroup D only 4 patients had pain (CL 95%; P = 0.00288). The gastric insufflation for laparoscopic surgery often leads to severe postoperative pain. There is increased intracellular calcium, increased phospholipid disintegration and increased free radicals leading to increased membrane permeability, which causes alteration in cellular integrity and results in pain.[7] Another theory suggests that due to fasciculation and contractions of muscle fibers, there is a shearing force at the onset of phase one block, causing muscle damage resulting in pain.[8] There is no correlation between the elevation of creatine phosphokinase and the development of muscle pain, but the increase in the serum potassium concentration is higher in patients who develop pain than in those who do not.[9]

Analgesia used to blunt surgical pain also addresses myalgia due to succinylcholine. This may be the reason for the paucity of myalgia cases after general anaesthesia. The use of atracurium in precurarizing dose reduces the incidence of fasciculation and myalgia thereby reducing postoperative muscle pain.[3] Schreiber et al. in a meta-analysis showed that nondepolarizing muscle relaxants, lidocaine, or magnesium may be used for the prevention of succinylcholine-induced fasciculation.[10] Our study revealed that fasciculations were more in Group B as compared to Group D (z = −4.28; P = 0.00001).

In our study, the raised intraabdominal pressure might have been the cause of the rise in creatine kinase due to the stretching of abdominal muscle fibres. There is a direct correlation between myalgia, fasciculation, and creatine kinase level. We tested for the same and found that there was a significant rise in fasciculation (P < 0.00001), myalgia postoperatively (P at 24 h = 0.00018) and CK values at 24 h (P = 0) in Group B as compared to Group D but on comparing the correlations between the two groups, the results were not significant. The Fisher r-to-z transformation was used to compare fasciculation and creatine kinase levels between the two groups. The results yielded were z = 0.37 and P = 0.71, which failed to establish any relation between fasciculation and creatine kinase. Similar results were obtained with myalgia and creatine kinase levels. The raised intra-abdominal pressures, which were between 12 and 16 mmHg in our study sample, may have raised creatine kinase levels enough to not establish any correlation between myalgia and creatine kinase levels.[11] There is a lot of biochemical activity occurring after vigorous muscle contractions, which tends to increase creatine kinase and may cause muscle damage and pain.[12] Exercise-related muscle damage is similar to succinylcholine-induced fasciculation leading to myalgia. There may not be any actual muscle damage, but muscle pain may be there. In the absence of any mechanical muscle damage, it remains a question as to whether raised CK after exercise does represent a degree of actual muscle damage or some form of disruption in energy control processes or some other molecular reaction mechanism.[13]

Our hypothesis is that using diclofenac sodium and atracurium in a precurarizing dose will yield less pain owing to decreased inflammation in muscles and less fasciculation if any. Succinylcholine-induced myalgia has been effectively managed by diclofenac sodium as shown by Rahimi et al.[14] Fasciculation and myalgia in our study, when compared in the two groups, resulted in P values of 0.00001 and 0.00018, respectively. Due to the precurarization and anti-inflammatory action of diclofenac, myalgia and fasciculation were blunted and resulted in less postoperative pain and discomfort. The rise in creatine kinase levels was also impeded in the precurarization group as compared to the control group. The anti-inflammatory effect of diclofenac resisted the release of pro-inflammatory cytokines and muscle damage.[15] Therefore, in our study, the effects of precurarization with atracurium and preemptive use of NSAIDs such as diclofenac resulted in less postoperative muscular pain and enhanced patient comfort.

CONCLUSION

Succinylcholine-induced myalgia is often overlooked by postoperative caregivers. Muscle pain, apart from surgical pain, causes psychological distress and discomfort. The pathophysiology of succinylcholine-induced myalgia is complex. However, preemptive use of diclofenac along with precurarization can alleviate the incidence and severity of succinylcholine-induced myalgia, so that the use of succinylcholine can be considered in routine cases for the induction of anesthesia for facilitating laryngoscopy and endotracheal intubation. Various drugs are available for precurarization, such as atracurium, vecuronium, and rocuronium. NSAIDs such as diclofenac, being long-acting competitive cyclo-oxygenase inhibitor, provides prolonged analgesic effect by inhibiting prostaglandin-mediated pathogenesis of succinylcholine-induced myalgia.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.