Prophylactic use of gabapentin for prevention of succinylcholine-induced fasciculation and myalgia: A randomized, double-blinded, placebo-controlled studyCK Pandey1, M Tripathi2, G Joshi2, ST Karna2, N Singh2, PK Singh2
1 Department of Anesthesiology, Institute of Liver and Biliary Sciences, New Delhi, India
2 Department of Anesthesiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
Background: Succinylcholine is used for rapid-sequence induction of anesthesia. Fasciculations and myalgia are adverse effects. The pretreatment modalities prevent or minimize its adverse effects. Aims: The present study is designed to evaluate the efficacy of gabapentin on the incidence of fasciculation and succinylcholine-induced myalgia. Settings and Design: The study was conducted at a tertiary care teaching hospital in a randomized, double-blinded, placebo-controlled manner. Materials and Methods: Patients of both genders undergoing laparoscopic cholecystectomy were randomly assigned to two groups. Patients in Group I (Gabapentin group) received 600 mg of gabapentin orally 2 h prior to surgery and patients in Group II (placebo group) received matching placebo. Anesthesia was induced with fentanyl 3 μg/kg, thiopentone 3-5 mg/kg and succinylcholine 1.5 mg/kg. All patients were observed and graded for fasciculations by a blinded observer and patients were intubated. Anesthesia was maintained with oxygen in air, sevoflurane and intermittent vecuronium bromide. After completion of surgery, neuromuscular blockade was reversed. A blinded observer recorded myalgia grade at 24 h. Patients were provided patient-controlled analgesia with fentanyl for postoperative pain relief. Statistical analysis: Demographic data, fasciculation grade, fentanyl consumption, and myalgia grade were compared using student t test and test of proportions. Results: The study included 76 American Society of Anesthesiologists' Grade I or II patients of either gender undergoing laparoscopic cholecystectomy. But only 70 patients completed the study. Results demonstrated that the prophylactic use of gabapentin significantly decreases the incidence and the severity of myalgia (20/35 vs. 11/35) (P<0.05) and decreases fentanyl consumption significantly in the study group (620+164 μg vs. 989+238 μg) (P<0.05) without any effects on the incidence and severity of fasciculations. Conclusions: Prophylactic use of gabapentin 600 mg in laparoscopic cholecystectomy decreases the incidence and severity of myalgia and fentanyl consumption.
Keywords: Fasciculation, gabapentin, succinylcholine-induced myalgia
Succinylcholine possesses the unique properties of rapid onset and short duration of action. It is the drug of choice for rapid-sequence induction of anesthesia.  Its side-effects include fasciculations, an increase in the serum potassium concentration, arrhythmias and myalgia. 
The incidence of succinylcholine-induced myalgia ranges from 41-92%.  Succinylcholine-induced myalgia is prominent in the muscles of the shoulder, neck, back, and abdomen. It is predominant in patients undergoing minor surgical procedures that permit early ambulation. The exact underlying mechanism of succinylcholine-induced myalgia is not known, but several mechanisms including increased myoplasmic calcium concentrations, membrane phospholipids' degradation, released free fatty acids and free radicals are suggested.  Different pre-treatment modalities have been used in an attempt to reduce the incidence and severity of fasciculations and myalgia including non-depolarizing neuromuscular blockers, local anesthetics, chlorpromazine, benzodiazepines, phenytoin, ketorolac, vitamin E derivatives, pretreatment with rocuronium and ramifentanil. ,,,,,,,
In the present randomized, double-blinded, placebo-controlled study we investigated the prophylactic use of gabapentin administration on succinylcholine-induced fasciculations and myalgia in subjects undergoing laparoscopic cholecystectomy.
The Institute's Ethics Committee approved this study protocol and written informed consent was obtained from each participant. The study duration was one year. The sample size calculation was based on an assumption that the incidence of postoperative 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 for a power of 80% (β=80% and α=0.05). Patients undergoing laparoscopic cholecystectomy were recruited except those who exceeded 20% of ideal body weight; who were older than 60 years or younger than 18 years; who had history of hypersensitivity to any drug, history of peptic ulcer disease; subjects who had received analgesics within 24 h before scheduled surgery or received sedatives other than those determined by the study protocol, subjects on antidepressant and calcium channels blockers, or those who could not demonstrate adequate skill to use patient-controlled-analgesia (PCA) pump, patients in whom succinylcholine was contraindicated and when laparoscopic cholecystectomy was converted into open cholecystectomy.
The day before surgery, all patients were assessed preoperatively; study protocol and the use of the PCA pump were explained. All patients received oral lorazepam 0.04 mg/kg on the evening before surgery and in the morning on the day of surgery. Subjects were randomly assigned to one of the two groups using a computer-generated table of random numbers, to receive medications (gabapentin or matching placebo).
Group I (Gabapentin group) patients received 600 mg gabapentin (two capsules of 300 mg each) 2 h before scheduled surgery.
Group II (Placebo group) patients received two capsules of matching placebo 2 h before scheduled surgery.
In the operating room, standard monitoring was used. An 18G intravenous cannula was inserted in the dorsum of the non-dominant hand. The anesthesia was induced with thiopentone 3-5mg/kg, fentanyl 3 μg/kg and succinylcholine 1.5 mg/kg. Fasciculations were evaluated by a blinded observer and were graded as follows: 
0. No fasciculation
1. Mild, fine fasciculations at the eyes, neck, face or fingers without limb movement
2. Moderate fasciculations occurring bilaterally or obvious limb movement
3. Severe when widespread, sustained fasciculation.
Anesthesia was maintained with oxygen in air and sevoflurane supplementation. Vecuronium bromide 100 μg/kg was given after endotracheal intubation. Fentanyl 1 μg/kg/h was infused during surgery and vecuronium bromide 20 μg/kg was given intermittently was given as and when indicated. After completion of surgery, neuromuscular blockade was reversed with glycopyrolate 10 μg/kg and neostigmine 40 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.
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 done 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. Generalized, severe or incapacitating discomfort.
Subjects received analgesia via PCA pump (fentanyl 1.0 μg/kg on each demand with lockout interval of 10 min). The side-effects and the total fentanyl requirement in the first 24 h were also recorded.
The data was analyzed by statistical software package statistical package for the social sciences (SPSS) 10 (SPSS, Chicago, IL, USA). The patients' characteristics (age and weight) were compared using Student "t" test. The test of proportion was applied to test the gender distribution. The consumption of fentanyl in groups was analyzed by using student t test. The test of proportion was used to compare the grade of fasciculations and myalgia between the groups.
Seventy-six patients of American Society of Anesthesiologists physical status I or II, who underwent laparoscopic cholecystectomy were recruited for this randomized, double-blinded, placebo-controlled study. Six patients were excluded from the study (laparoscopy was converted into open cholecystectomy in two patients and four patients could not use PCA pump appropriately).
The groups were comparable with respect to age, body weight, and gender distribution [Table 1]. The result of the study demonstrated that patients who received 600 mg gabapentin had significantly lower incidence of myalgia [Table 2]. In the gabapentin group 15 patients out of 35 had myalgia whereas 24 patients out of 35 had myalgia in the placebo group (P value 0.03). The severity of myalgia was also less in the gabapentin group compared to placebo (11 and 4 vs. 14 and 10 of myalgia Grade 1 and 2 respectively). The incidence of myalgia Grade 2 was significantly less (P value 0.01) compared to myalgia Grade 1 in the gabapentin group whereas there was no statistical difference in the placebo group. We did not encounter myalgia Grade 3 in any of the groups in our study. The consumption of fentanyl was also significantly less in the gabapentin group compared to the placebo group (620.60±164.19 μg vs. 989.80± 238.39 μg) (P value 0.001). Our study did not demonstrate any significant change in the incidence of fasciculations between the groups. We did not find any association between the incidence of fasciculations and myalgia [Table 2].
Placebo was used in this clinical trial because there is no established and effective treatment available for succinylcholine-induced fasciculation and myalgia. Similar treatment PCA pumps with fentanyl were instituted in both the groups to manage their pain. Because gabapentin has been reported to be effective in many painful conditions, ,, we assumed that gabapentin may be of interest for preventing succinylcholine-induced fasciculations and myalgia.
The patients in the gabapentin group had lower incidence of myalgia (15/35) compared to the control group (24/35) (P value 0.03) [Table 2]. The severity of muscle pain in the study group was also significantly less. Only 4 out of 15 patients had myalgia Grade 2 in the gabapentin group, compared to 10 out of 24 patients in the placebo group. Fentanyl consumption was significantly lower in the gabapentin group (620.60+164.19 μg) compared to the control group (989.80+238.39 μg) (P value 0.001) during the study period of 24 h postoperatively.
Succinylcholine is a depolarizing neuromuscular blocking agent which provides satisfactory intubating conditions with a rapid onset and short duration of action. ,, Though newer non-depolarizing muscle relaxants have similar properties like succinylcholine, they have not replaced it to date.  Myalgia after the use of succinylcholine is well known with the reported incidence ranging from 41-92%.  Succinylcholine-induced postoperative myalgia is most frequent on the first postoperative day in ambulatory surgery. , Thus, patients who had undergone laparoscopic cholecystectomy were an appropriate study group for investigating succinylcholine-induced myalgia. It is also suggested that there may be a baseline incidence of postoperative myalgia in laparoscopic surgery which is not related to the choice of muscle relaxant.  This suggests that postoperative myalgia is multi-factorial in origin and succinylcholine is only one contributing factor. , The proposed mechanisms to succinylcholine-induced myalgia are: increased myoplasmic calcium concentration, membrane phospholipid degradation, released free fatty acids and free radicals and damage to delicate muscle spindles. ,,,, Investigators have shown that, in vitro, excessive repetitive contractile activity was associated with increased calcium uptake, activation of phospholipase A 2 , generation of arachidonic acid and synthesis of prostaglandins which may induce delayed onset of inflammation.  It is also postulated that influx of calcium into muscles caused an increase in muscle damage and pain.  Calcium influx enhances the speed and strength of the fasciculations and the contraction of the intrafusal muscle fibers, which increases the likelihood of spindle damage and subsequent muscle pain.  Succinylcholine-induced fasciculation is thought to be related to a prejunctional agonistic action on the nicotinic receptors that results in rapid firing,  whereas, myalgia is supposed to be due to the contraction of the intrafusal muscle fibers, likely to cause spindle damage and subsequent muscle pain.  To attenuate this problem, many agents like propofol, thiopentone, non-depolarizing muscle relaxants, benzodiazepines, aspirin, phenytoin, rocuronium, ramifentanil and lignocaine have been used. ,,,,,,,,, There is no standard treatment available for the condition and the plethora of available pretreatment is evidence of our poor understanding of the pathophysiology of this problem. Pretreatment with non-depolarizing muscle relaxants prevents both fasciculations and myalgia with the risk of potentially serious adverse effects.  A recent study Fatemeh et al., demonstrated that the incidence and severity of fasciculations are significantly decreased by pretreatment with atracurium, however, pretreatment with atracurium did not exert beneficial effects on postoperative myalgia.  Maddineni et al., observed that there is no difference in postoperative myalgia when propofol was substituted for thiopentone but Kararmaz et al., showed that high-dose propofol reduces both the incidence and severity of myalgia. , Midazolam appears to be ineffective in attenuating either fasciculations or postoperative myalgia, in contrast to the results of previous studies using diazepam.  The effects of lidocaine are being explained by their cell membrane-stabilizing properties.  It has 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. , The efficacy of NSAIDs suggests that there is an inflammatory genesis and prostaglandins may be involved.  The etiology of succinylcholine-induced myalgia, however, remains obscure.
Since intracellular calcium accumulation is important for enhancing the speed and strength of the fasciculations and the contraction of the intrafusal muscle fibers, an effect of gabapentin on voltage-gated calcium channels is possible.  Gabapentin is known to bind to the α2 -δ-subunit of voltage-dependent calcium channels.  It reduces 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 conceivably leads to reduced postsynaptic excitability, providing one reasonable explanation for the antinociceptive efficacy of gabapentin in postoperative pain. , The above facts provide a plausible explanation for the antinociceptive efficacy of gabapentin in reducing the incidence of myalgia. The same could not be substantiated for the incidence of fasciculation. There was no statistically significant difference in the incidence of fasciculations between gabapentin and control groups demonstrating that there is no relationship between fasciculations and myalgia. This observation is in agreement with the findings of earlier studies. ,,,,,
Our clinical study demonstrated that a 600-mg single oral dose of gabapentin given 2 h preoperatively significantly decreased the incidence and severity of succinylcholine-induced myalgia but without effect on fasciculations in patients undergoing laparoscopic cholecystectomy. Pretreatment with gabapentin decreased postoperative fentanyl consumption during the study period, but it failed to demonstrate an association between the intensity of fasciculation and myalgia. Considering this, we suggest using gabapentin 600 mg preoperatively to minimize the incidence and severity of succinylcholine-induced myalgia.
[Table 1], [Table 2]