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Original Article

Does preoperatively administered parecoxib prevent succinylcholine-associated myalgia? A randomized, placebo-controlled trial

Schreiber, J.-U.*; Mencke, T.; Pradarutti, S.*; Jeblick, S.*; Fuchs-Buder, T.

Author Information
European Journal of Anaesthesiology: April 2006 - Volume 23 - Issue 4 - p 332-337
doi: 10.1017/S026502150600007X
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Abstract

Introduction

Due to its unique pharmacological properties, succinylcholine still keeps its place in anaesthetic practice [1]. A frequent adverse effect of succinylcholine is myalgia that can last for several days in varying intensity. Myalgia may cause discomfort and can delay normal activity. This has led to the implication that succinylcholine may not be a suitable drug for ambulatory anaesthesia [2]. Results of a recent meta-analysis showed that parenteral pre-treatment with non-selective cyclooxygenase inhibitors such as aspirin or diclofenac may reduce the incidence of succinylcholine-related myalgia 24 h after anaesthesia [3]. In contrast, preoperative administration of intravenous (i.v.) ketorolac or oral aspirin did not lead to a decreased rate of myalgia 48 h after surgery [4,5].

Adverse effects may limit the use of non-selective cyclooxygenase inhibitors for the prevention of postoperative myalgia. Due to their pharmacological mechanism, agents as diclofenac may interfere with haemostasis and may cause an increase in intraoperative blood loss compared with selective cyclooxygenase 2 inhibitors [6]. For use in the ambulatory setting, an agent for parenteral administration with a rapid analgesic onset would be favourable.

The aim of this randomized, placebo-controlled trial was to test the effect of pre-treatment with parecoxib, a parenteral, selective cyclooxygenase 2 inhibitors, on incidence and severity of succinylcholine-associated myalgia over 72 h after anaesthesia. In addition, impairment of patients' activity was evaluated.

Material and methods

After Ethics Committee (Chamber of physicians of Saarland) approval and informed consent, 68 adult patients (ASA I–II) scheduled for minor surgery were planned for inclusion. Types of surgery were hernia repair, implant removal after osteosynthesis of the lower ankle and inguinal lymph node dissection. Exclusion criteria were chronic intake of non-steroidal anti-inflammatory drugs, obesity (body mass index (BMI) > 30 kg m−2), neuromuscular disease, acute or chronic inflammatory diseases and contraindications for parecoxib.

Incidence and severity of myalgia was evaluated with a standardized questionnaire (Appendix A) [7]. During the premedication visit, patients were informed about the questionnaire and the methodology of the numeric analogue scale (0 = no pain to 10 = worst pain). On the day before surgery, patients were allocated according to a computer generated randomization list to a pre-treatment group (group COX) or to a control group (group SAL). Midazolam 7.5 mg orally was used for premedication 1 h preoperatively. After placing an i.v. cannula, group COX received 40 mg parecoxib in 2 mL saline i.v. (Dynastat®; Pfizer, Karlsruhe, Germany); group SAL (control group) received 2 mL saline. For administration of the study drug, unlabelled syringes were used. These were prepared preoperatively by an assistant and according to the randomization scheme. The performing anaesthetist was blinded to the group assignment. Three minutes after administration of the study drug, induction of anaesthesia started with 1 μg kg−1 fentanyl i.v. Five minutes later, propofol 2 mg kg−1 i.v. was administered followed by succinylcholine 1 mg kg−1 after loss of consciousness. Sixty seconds later the patient's trachea was intubated. Anaesthesia was maintained with remifentanil 0.25 μg kg−1 min−1 and desflurane 0.5 minimal alveolar concentration (MAC). All patients received piritramide 3 mg i.v., a synthetic opioid for postoperative pain therapy, 20 min before the expected end of surgery. Postoperative pain therapy was standardized with oral diclofenac 50 mg twice a day and, if additional medication was needed, piritramide 0.05 mg kg−1 i.v.

All patients were visited at 24, 48 and 72 h after surgery by an investigator who was not aware of the group assignment. According to a standardized questionnaire, incidence, severity, and location of myalgia, and impairment of activity were assessed. To simplify data analysis, postoperative myalgia was graded as none, mild (numeric analogue scale 1–3), moderate (4–6) and severe (7–10). Muscle groups were divided into three regions (head/neck/shoulder, trunk and limbs).

Data are presented as means (±SD) or absolute values. χ2-test, Fisher's-exact test, and U-test were used as appropriate. A P <0.05 was considered significant. The number-needed-to-treat (NNT) was calculated [8]. The NNT indicated how many patients have to receive pre-treatment with parecoxib to prevent postoperative myalgia in one of them who would have had myalgia had they all received saline. We regarded an NNT <5 as clinically relevant. For statistical calculations SigmaStat® 2.0 for Windows® (Jandel Corporation, San Rafael, CA, USA) and Microsoft Excel® X for Macintosh® (Microsoft Corporation, Redmont, WA, USA) were used. Calculation of sample size was based on previous studies [9,10]. When assuming a myalgia incidence of 60% in the control group, 34 patients per group were needed to detect a 55% reduction in myalgia with pre-treatment (α = 0.05, β = 0.2).

Results

Due to protocol violation (unexpected major surgery) one patient of the COX group was excluded from data analysis; consequently, data from 67 patients were analysed. Patient characteristics data, duration of anaesthesia and consumption of additional analgesic medication were comparable between the two groups (Table 1). In the COX group, seven patients reported myalgia compared with 11 patients in the SAL group; P = 0.2. The number of episodes of myalgia in the COX group did not differ significantly from the SAL group (13 vs. 21 episodes, P = 0.175) (Table 2). In the SAL group, one patient requested additional analgesics due to myalgia. In the COX group, no such requests were reported. The number of patients who felt limited in their activity due to myalgia, and the severity of myalgia was not significantly different between the two groups; P = 0.11 (Table 3). The NNT to prevent myalgia in one patient compared with saline was 9 (95% confidence interval, 3 to −10). No adverse drug reactions that could possibly be related to parecoxib were observed.

Table 1
Table 1:
Patient characteristics data.
Table 2
Table 2:
Incidence of postoperative myalgia.
Table 3
Table 3:
Severity and location of myalgia, and impairment of activity.

Discussion

The present study examined for the first time whether parecoxib might reduce succinylcholine-related myalgia. The main finding was that preoperatively administered parecoxib failed to reduce incidence and intensity of myalgia over 72 h after anaesthesia.

Several studies have shown a significantly decreased incidence of myalgia following preoperative administration of a parenteral non-selective cyclooxygenase inhibitor such as aspirin or diclofenac [9,11]. In contrast, a preoperatively administered dose of intravenous ketorolac failed to reduce myalgia over 48 h after anaesthesia [4]. The authors of this study explained their result through the short duration of action of ketorolac. Another reason might have been the limited dose of ketorolac i.v. (10 mg) that was used in this study. Thus, the rationale to use parecoxib in our study was that this agent has a longer duration of action but a comparable onset of analgesic activity compared with ketorolac [12,13]. We used a bolus dose of parecoxib 40 mg. This corresponds to the highest single bolus dose that is recommended by the manufacturer, and we assumed that this dose had comparable analgesic properties as 30 mg of ketorolac. Moreover, parecoxib does not impair platelet function [14], and it was at least as efficient or even superior to ketorolac in different pain models [15,16]. It was also analgesic following preoperative administration [17].

It has been reported that the incidence of succinylcholine-related myalgia varies between 1.5% and 89% [18]. A variety of other factors may influence the incidence and severity of myalgia (e.g. type and location of surgery, ambulation, intubation trauma). To minimize any confounding factors on succinylcholine-induced myalgia, we limited the type of surgery to minor interventions. Postoperative evaluation of succinylcholine-associated myalgia was done with an established questionnaire that allows distinction between succinylcholine-associated myalgia and other forms of postoperative myalgia [7]. Also postoperative pain therapy was standardized.

The incidence of myalgia in the control group was lower compared with our recent study on patients undergoing minor eyes, nose, throat surgery [10]. This difference may be due to the different surgical settings. Other factors as the method of evaluation of postoperative myalgia and postoperative pain therapy were comparable between the two trials.

It could be hypothesized that the use of diclofenac for postoperative pain therapy interfered with the incidence of postoperative myalgia. So far, no data are available on the effect of non-steroidal anti-inflammatory drugs on established succinylcholine-associated myalgia. Moreover, it is unclear whether cyclooxygenase inhibitors have advantages compared to other regimens (e.g. opioids) regarding a decreased rate of postoperative myalgia. To avoid any dose-related effect of diclofenac on mylagia, a standard dose was used in all patients. Due to the design, our study should be sensitive enough to detect a prophylactic effect of parecoxib if there was one.

Postoperative myalgia has been described as a complex mechanism with different steps [18]. Furthermore it has been postulated that succinylcholine-related tissue damage and myalgia are separate entities [5]. In the study by Laurence, no relationship between the usage of succinylcholine, changes in biochemical markers as creatine kinase, and the incidence of myalgia was found [19]. Recent data showed that there is no evidence for a significant inflammatory reaction contributing to myalgia [10]. This led to the assumption that the primary effect of cyclooxygenase inhibitors on myalgia is not directly related to damage of muscular tissue and subsequent inflammatory reaction but to the influence on the effect of prostaglandines in nociception. Kahraman and colleagues observed a decrease of prostaglandin E2-like activity in patients pre-treated with the cyclooxygenase inhibitor diclofenac before succinylcholine compared with a control group [11]. Additionally, there is some evidence for a pre-emptive analgesic effect of non-selective cyclooxygenase inhibitors as ketorolac and selective cyclooxygenase 2 inhibitors [20,21]. In this context, a preventive administration of an intravenous long-acting cyclooxygenase 2 inhibitor to avoid myalgia might be rationale. Our data show that the administration of parecoxib 40 mg i.v. immediately before induction of anaesthesia does not lead to a clinically relevant reduction of myalgia at any time during the follow-up. This result is in contrast to the findings of a recent meta-analysis that found a clinically relevant effect of preoperatively administered non-selective cyclooxygenase inhibitors on postoperative myalgia 24 h after anaesthesia [3]. Moreover, neither the severity of myalgia nor the limitation of patients' activity related to myalgia was significantly influenced by the pre-treatment. Also the consumption of piritramide as an additional analgesic was comparable in both groups.

We cannot exclude that earlier administration of parecoxib would improve its efficacy; however, in an ambulatory setting, a longer pre-treatment interval might be impracticable.

Recent reports about severe adverse effects with parecoxib in different surgical settings suggested that this agent could possibly be harmful in patients with an increased perioperative risk [22,23]. This begs the question as to whether the use of parecoxib is generally justified to avoid a comparatively minor problem as postoperative myalgia. However, in our study no parecoxib-related adverse effects were observed.

In conclusion, the results of this trial show that preoperatively administered parecoxib does not significantly reduce succinylcholine-related myalgia over 72 h. The use of parecoxib for the prevention of postoperative myalgia does not seem to be justified.

Acknowledgements

The authors thank Sarah Klein, BS (University of the Saarland, Homburg, Germany), Natascha Schlaich, MD (Department of Anaesthesiology and Critical Care Medicine, University Hospital of the Saarland, Homburg, Germany) and Oliver Fürst, MD (Department of Anaesthesiology and Critical Care Medicine, University Hospital of the Saarland, Homburg, Germany) for their assistance in data acquisition. Support for this study was given solely from institutional resources.

Appendix A

Postoperative questionnaire for myalgia study

Patient ID:

Date of surgery:

Type of surgery:

Follow-up: 24 h 48 h 72 h

  1. Do you have any stiffness or soreness in your body besides headache and pain at the surgical side? yes___ no___
  2. Have you been up? yes___ no___
  3. Is there pain and stiffness in the muscles? yes___ no___
  4. In which sites do you have the muscle pain/stiffness? Jaw___ Throat___ Neck___ Shoulders___ Arm___ Chest___ Abdomen___ Back___ Buttocks___ Thighs___ Calves___ Generalized___ Buttocks___ Thighs___ Calves___ Generalized___
  5. When did you first noticed the pain? ____
  6. Rate the muscle stiffness/pain on score (0 being no pain and 10 worst pain ever) only on the sites to be painful by the patient. Jaw___ Throat___ Neck___ Shoulders___ Arm___ Chest___ Abdomen___ Back___ Buttocks___ Thighs___ Calves___ Generalized___
  7. What makes the muscle stiffness/pain worst? Movement___ Rest___
  8. Describe the muscle pain/stiffness in your (patient's) own words.
  9. Do you think the muscle pain is restricting your activity? yes___ no___
  10. Is the muscle pain preventing you from getting out of bed? yes___ no___
  11. Have you ordered any extra pain medication because of the muscle pain? yes___ no___
  12. Are you taking your prescribed pain medication to help your surgical pain___ or your muscle pain___?

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Keywords:

NEUROMUSCULAR BLOCKING AGENTS, succinylcholine; CYCLOOXYGENASE INHIBITORS, parecoxib; COMPLICATIONS, myalgia

© 2006 European Society of Anaesthesiology