Comparative evaluation of prophylactic use of pregabalin, gabapentin and diclofenac sodium for prevention of succinylcholine-induced myalgia: A randomized, double-blinded studyCK Pandey1, ST Karna2, M Tandon1, VK Pandey1, A Singh2
1 Department of Anaesthesiology, Institute of Liver and Biliary Sciences, New Delhi, India
2 Department of Anaesthesiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.128801
Source of Support: None, Conflict of Interest: None
Context: Succinylcholine a depolarizing muscle relaxant with rapid onset, predictable course and short duration of action is associated with myalgia. Aim: The aim of this study is to evaluate the efficacy of pregabalin, gabapentin and diclofenac on the incidence and severity of succinylcholine-induced myalgia. Settings and Design: Tertiary Care Teaching Hospital. Materials and Methods: A total of 120 patients undergoing laparoscopic cholecystectomy were randomly assigned into three groups: Pregabalin group received 150 mg of pregabalin, gabapentin group received 600 mg of gabapentin and diclofenac group received 100 mg of diclofenac sodium orally 2 h prior to surgery. Anesthesia was induced with fentanyl 3 μg/kg, propofol 2-2.5 mg/kg and succinylcholine 1.5 mg/kg and was maintained with oxygen with sevoflurane in the air and intermittent vecuronium bromide. A blinded observer recorded post-operative pain scores on visual analog scale at different time intervals and myalgia at 24 h. Post-operative pain relief was provided with fentanyl based patient-controlled analgesia. Fentanyl consumption in 24 h was recorded as a primary outcome. Statistical Analysis: Patients' characteristics and total fentanyl consumption were compared using one-way ANOVA followed by post-hoc test. Pain score was compared amongst the groups using Kruskal Wallis test. Results: The myalgia occurred in 15, 14 and 13 patients in pregabalin, gabapentin and diclofenac sodium group respectively (P > 0.85). Patients in diclofenac group had significantly higher fentanyl consumption (674.85 ± 115.58 μg) compared with pregabalin group (601.87 ± 129.57 μg) (95% confidence interval [CI] = 34.8-120.7) and gabapentin group (612.29 ± 105.12 μg) (95% CI = 14.9-170.5). However, there was no significant difference in fentanyl consumption between pregabalin and gabapentin groups (95% CI = −34.8-120.7). There was a significant difference in visual analog score at time points 12, 18 and 24 h among the study groups. Conclusion: Pre-treatment with pregabalin, gabapentin and diclofenac had equal efficacy in reducing the incidence and severity of succinylcholine-induced myalgia. However, pre-treatment with pregabalin and gabapentin decreased post-operative pain scores and fentanyl consumption.
Keywords: Diclofenac sodium, gabapentin, pregabalin, succinylcholine-induced myalgia
Succinylcholine possesses unique properties of a rapid onset and a short duration of action, which makes it the drug of choice for rapid-sequence induction of anesthesia.  It produces profound neuromuscular block with excellent intubating conditions.  Succinylcholine is therefore a commonly used muscle relaxant for ambulatory and short surgical procedures, but is not without side-effects. 
The major side-effect associated with succinylcholine is post-operative myalgia and muscle stiffness, that can last for several days and may be a cause of significant discomfort to patients. , The exact underlying mechanism of succinylcholine-induced myalgia is not known, thus, different pre-treatment modalities have been attempted to reduce the incidence and severity of succinylcholine-induced myalgia. Non-depolarizing neuromuscular blockers,  lignocaine,  chlorpromazine,  benzodiazepines,  phenytoin,  ketorolac,  diclofenac,  vitamin C  and vitamin E  derivatives, remifentanil,  gabapentin  and magnesium sulphate,  have all been tried with variable success. Pregabalin, like gabapentin, is shown to be effective in several models of neuropathic pain, incisional injury, inflammatory injury and formalin-induced injury.  Studies have also reported that pregabalin has equivalent efficacy to gabapentin in the treatment of pain, but at a lower dose.  Therefore, in this randomized, double-blinded study, we compared the effect of prophylactic use of pregabalin, gabapentin and diclofenac sodium on succinylcholine-induced myalgia in subjects undergoing laparoscopic cholecystectomy.
The Institute's Ethics Committee approved the study protocol and written informed consent was obtained from each participant. The sample size calculation was based on an assumption that the incidence of post-operative myalgia was 70%.  Interventions, which decrease it to 35% with 30% variability among the groups would be of interest. The study required 31 patients in each group at a power of 80% (β = 80% and α = 0.05). Consecutive patients undergoing laparoscopic cholecystectomy were eligible for inclusion in the study. Patients who exceeded 20% of ideal body weight, who were older than 60 years or younger than 18 years, patients who had a history of central nervous system disorder, impaired renal functions, history of hypersensitivity to any of the study drugs, history of peptic ulcer disease or treatment with antacids, those who received analgesics within 24 h before scheduled surgery or received sedatives other than those determined by the study protocol were excluded from the study. Subjects on antidepressant and calcium channels blockers, those who could not demonstrate adequate skill to use patient-controlled-analgesia (PCA) pump, patients in whom succinylcholine was contraindicated and those in whom laparoscopic cholecystectomy was converted into open cholecystectomy were also excluded.
All patients were assessed the day before surgery by an anesthesiologist. The study protocol as well as the use of the PCA pump was explained. Anxiolysis was given with oral lorazepam 0.04 mg/kg on the evening before surgery and in the morning on the day of surgery. The subjects were also familiarized with the use of a 10 cm linear visual analogue scale (VAS) for pain (0 denotes no pain and 10 denotes worst imaginable pain).
The study drugs were masked by packing them in identical looking capsules containing pregabalin, gabapentin or diclofenac sodium. Each subject was assigned a computer generated randomization number. The subjects were sequentially allocated into one of the three groups to receive study medications (pregabalin, gabapentin or diclofenac) as per their randomization number and medications were administered by a blinded anesthesia resident.
Group I (Pregabalin group) patients received 150 mg pregabalin (two capsules of 75 mg each) 2 h. before scheduled surgery.
Group II (Gabapentin group) patients received 600 mg of gabapentin (two capsules of 300 mg each) 2 h. before scheduled surgery.
Group III (Diclofenac group) patients received 100 mg diclofenac (two capsules of 50 mg each) 2 h. before scheduled surgery.
In the operating room, standard monitoring (electrocardiogram, non-invasive blood pressure, heart rate, peripheral oxygen saturation) was used. An 18G intravenous cannula was inserted in the dorsum of the non-dominant hand. Anesthesia was induced with propofol 2.0-2.5 mg/kg, fentanyl 3 μg/kg and succinylcholine 1.5 mg/kg. Following succinylcholine administration, oral endotracheal intubation was performed after assessing for complete muscular relaxation. Sevoflurane in oxygen with FiO 2 0.5 was used to maintain anesthesia along with fentanyl 1 μg/kg/h. Vecuronium bromide 100 μg/kg was given after endotracheal intubation and subsequently 20 μg/kg was given intermittently as and when indicated. After completion of surgery, neuromuscular blockade was reversed with neostigmine 40 μg/kg and glycopyrrolate 10 μg/kg intravenously and subjects were extubated when adequate spontaneous ventilation was established. Patients were transferred to post-anesthesia care unit from where they were transferred to their respective wards.
Post-operative pain score was recorded by a blinded anesthesiologist using the VAS on arrival of patient to post-operative recovering area (VAS at 0 h.) and subsequently every 6 hourly (VAS at 6, 12, 18 and at 24 h.). Myalgia was defined as "muscle pain not related to surgical intervention."  The incidence and severity of myalgia was recorded by a blinded observer after 24 h of surgical intervention. The grading of myalgia was performed as follows. 
0 - Absence of muscle pain
1 - Stiffness limited to one area only
2 - Muscle pain or stiffness noticed spontaneously by patient, which may require analgesic therapy
3 - Generalized, severe or incapacitating discomfort.
Subjects received analgesia through intravenous PCA pump (fentanyl 1.0 mcg/kg on each demand with lockout interval of 10 min). The total fentanyl requirement in the first 24 h. was also recorded.
The data was analyzed by statistical software package for the social sciences (SPSS) 10 (SPSS, Chicago, IL, USA). Patients' characteristics and total fentanyl consumption were compared using one-way ANOVA followed by post-hoc test. The 95% of confidence intervals for fentanyl consumption were expressed for the mean of each of the groups. The Chi-square test was used to compare the grade of myalgia among the groups. Pain score was compared amongst the groups using Kruskal-Wallis test. A value of P < 0.05 was considered to be statistically significant.
A total of 120 patients of American Society of Anesthesiologists physical status I and II, scheduled for laparoscopic cholecystectomy were recruited from January 2011 to February 2012. Five patients were excluded because patients refused to take study medications. A total of 115 patients participated in the study, but eight patients were further excluded because laparoscopy cholecystectomy was converted into open cholecystectomy [Figure 1].
The sequence numbers were decoded. The groups were comparable with respect to age, body weight and gender distribution [Table 1]. There were no unintended drug effects in any of the groups. There was no statistical difference in fentanyl consumption between pregabalin and gabapentin groups [Table 2]. Patients of diclofenac group had significantly higher pain scores at 12, 18 and 24 h in comparison with pregabalin and gabapentin groups [Table 2]. Patients who received either pregabalin, gabapentin or diclofenac sodium had similar incidence of myalgia [Table 3]. Statistical analysis demonstrated that patients in diclofenac group had significantly higher fentanyl consumption (674.85 ± 115.58 μg) compared with pregabalin group (601.87 ± 129.57 μg) (95% confidence interval [CI] = 34.8-120.7) and gabapentin group (612.29 ± 105.12 μg) (95% CI = 14.9-170.5). However, there was no significant difference in fentanyl consumption between pregabalin and gabapentin groups (95% CI = −34.8-120.7). There was a significant difference in VAS at 12, 18 and 24 h among the study groups.
Our clinical study has demonstrated that 150 mg of pregabalin, 600 mg of gabapentin and 100 mg of diclofenac given orally 2 h. pre-operatively has equal efficacy to decrease succinylcholine-induced myalgia and its severity. However, pretreatment with pregabalin and gabapentin had decreased post-operative pain scores at 12, 18 and 24 h and fentanyl consumption during a study period of 24 h.
Succinylcholine provides satisfactory intubating conditions with a rapid onset and short duration of action. , It produces profound neuromuscular block with excellent intubating conditions. Succinylcholine is a commonly used muscle relaxant for ambulatory anesthesia, but myalgia after its use is a known side-effects with reported incidence ranging from 41% to 92%.  Succinylcholine-induced myalgia is most frequent on first post-operative day and in ambulatory surgery. , Because early ambulation increases the likelihood of the development of myalgia and its severity, patients undergoing laparoscopic cholecystectomy constitute an ideal group for investigation of the study end point.
Succinylcholine-induced myalgia has been reported to be due to the contraction of the intrafusal muscle fibers, likely to cause spindle damage and subsequent muscle pain.  In vitro studies have demonstrated that excessive repetitive contractile activity of muscle is associated with increased calcium uptake, activation of phospholipase A 2 , generation of arachidonic acid and synthesis of prostaglandins, which may induce inflammation.  It is also postulated that calcium influx into muscles causes an increase in muscle damage and pain.  Since intracellular calcium accumulation is important for enhancing the speed and strength of the intrafusal muscle fibers, an effect of pregabalin and gabapentin on voltage gated calcium channels are possible. Pregabalin and gabapentin bind to the α2 -d-subunit of voltage dependent calcium channels,  reducing calcium influx into glutamatergic terminals, thus inhibiting the potassium induced release of endogenous excitatory amino acids aspartate and glutamate. , The inhibition of excitatory amino acid release reduces postsynaptic excitability, providing one reasonable explanation for the antinociceptive efficacy of pregabalin and gabapentin in post-operative pain. , The above facts may be a plausible explanation for the efficacy of pregabalin and gabapentin in reducing the incidence of myalgia.
Since gabapentin is effective for prevention of succinylcholine-induced myalgia and pregabalin is an analogue of gabapentin, we assumed that pregabalin should also be effective for prevention of myalgia. Pregabalin is reported to have equal efficacy as gabapentin for the treatment of neuropathic pain.  However, Bockbrader et al. have demonstrated that pregabalin has greater analgesic activity (2.5 times of gabapentin) in rodent models of neuropathic pain.  Pregabalin also has better bioavailability (90%) and is rapidly absorbed. It requires lower dosages and is associated with fewer dose-related adverse events. , Though the primary objective of this study was not to compare doses of pregabalin and gabapentin, we found that 150 mg of pregabalin was equivalent to 600 mg of gabapentin for prevention of myalgia and control of post-operative pain.
It is been demonstrated that non-steroidal anti-inflammatory drugs (NSAIDs) did not prevent fasciculations but reduced myalgia, which suggests that myofibrillar disruption and pain arise by different processes. , A significant reduction in post-operative myalgia was reported with aspirin 600 mg given 1 h before surgery.  The efficacy of NSAIDs suggests that there is an inflammatory genesis for myalgia and prostaglandins may be involved.  The use of diclofenac sodium may have interrupted the prostaglandin-mediated destructive cycle and this provides a rationale for its efficacy in preventing post-operative myalgia.
Patients in pregabalin, gabapentin and diclofenac groups had similar incidence of myalgia [Table 3]. The severity of muscle pain in study groups was also similar. Fentanyl consumption was significantly lower in pregabalin and gabapentin group during the study period of 24 h post-operatively. It seems that pregabalin, gabapentin and diclofenac are equally effective on succinylcholine induced myalgia. However, pregabalin and gabapentin significantly decreased post-operative surgical pain scores compared with diclofenac.
Our clinical study has demonstrated that pregabalin (150 mg), gabapentin (600 mg) and diclofenac sodium (100 mg) have equal efficacy in reducing the incidence and severity of succinylcholine-induced myalgia. However, pretreatment with pregabalin and gabapentin also decreased post-operative pain scores and fentanyl consumption, thus, may be preferred over diclofenac sodium.
[Table 1], [Table 2], [Table 3]