• Users Online: 26
  • Print this page
  • Email this page


 
 
Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 18  |  Issue : 3  |  Page : 154-157

To evaluate efficacy of pregabalin for the prevention of etomidate-induced myoclonus: A prospective, randomized, placebo-controlled, double-blind study


1 Department of Anaesthesiology, Apollo Hospitals, Bilaspur, Chhattisgarh, India
2 Department of Anaesthesiology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
3 Department of Anaesthesiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Submission22-Jan-2021
Date of Decision26-May-2021
Date of Acceptance30-May-2021
Date of Web Publication11-Jun-2021

Correspondence Address:
Vinit Kumar Srivastava
Department of Anaesthesiology, Apollo Hospitals, Bilaspur - 495 006, Chhattisgarh
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/am.am_8_21

Rights and Permissions
  Abstract 


Context: The incidence of myoclonus after etomidate induction is 50%–80%. The present study evaluated the efficacy of oral pregabalin for the prevention of etomidate-induced myoclonus. Settings and Design: A prospective, randomized, placebo-controlled, double-blind study. Subjects and Methods: Seventy-four patients of the American Society of Anesthesiologists physical status Grade I or II scheduled for elective surgery under anesthesia were recruited. Following exclusion, 66 patients were randomized into two groups. In Group P patients received pregabalin 150 mg orally 1 h before induction of anesthesia and in Group C patients received placebo tablet. The primary outcome was the incidence and severity of myoclonus. The secondary outcome was the postoperative sedation level. Results: The incidence and severity of myoclonus were significantly decreased in Group P compared with Group C (P < 0.05). The postoperative sedation score was significantly higher in Group P compared to Group C (P > 0.05). Conclusion: Pretreatment with pregabalin 150 mg orally reduced the incidence and severity of etomidate-induced myoclonus however incidence of sedation was more.

Keywords: Etomidate, myoclonus, postoperative sedation, pregabalin


How to cite this article:
Srivastava VK, Agrawal S, Kumar S, Pandey A, Garewal S, Shree P. To evaluate efficacy of pregabalin for the prevention of etomidate-induced myoclonus: A prospective, randomized, placebo-controlled, double-blind study. Apollo Med 2021;18:154-7

How to cite this URL:
Srivastava VK, Agrawal S, Kumar S, Pandey A, Garewal S, Shree P. To evaluate efficacy of pregabalin for the prevention of etomidate-induced myoclonus: A prospective, randomized, placebo-controlled, double-blind study. Apollo Med [serial online] 2021 [cited 2021 Dec 6];18:154-7. Available from: https://www.apollomedicine.org/text.asp?2021/18/3/154/318261


  Introduction Top


Etomidate is an intravenous anesthesia induction agent of choice in patients with hemodynamic instability. It is preferred due to its favorable effects on hemodynamic due to minimal cardiovascular depression. Myoclonic movements and pain on injection are two unwanted effects of etomidate administration.[1] Myoclonus may be associated with increased chances of regurgitation and aspiration as well as increase myocardial oxygen demand. Myoclonus is observed in 50%–80% patients, more in unpremedicated patients. The use of sedative preoperative premedication is associated with the reduction of myoclonus. Pharmacologically the number of drugs have been tried to reduce the incidence of myoclonus with varying success. A commonly used drug includes gabapentin, dexmedetomidine, opioids, benzodiazepines, magnesium sulfate, lidocaine, muscle relaxants, thiopental, ketamine, and dezocine.[2],[3],[4],[5],[6],[7],[8],[9],[10] The choice of premedicant varies and depends on patients' characteristics as well as the type and duration of the surgery.

The mechanism of the use of various drugs to decrease the incidence and severity of myoclonus is not clear. The use of gabapentin is associated with the reduction of incidence and severity of myoclonic movements of etomidate.[2] Pregabalin is an analog of gabapentin, so we hypothesized that pregabalin may be effective as gabapentin for the prevention of myoclonic movements of etomidate. We conducted this study to evaluate preoperative oral pregabalin on the incidence and severity of myoclonus with etomidate.


  Subjects and Methods Top


After obtaining approval from the Institutional Ethical Committee and written informed consent from the patients, this prospective, randomized placebo-controlled study was conducted on seventy-four American Society of Anesthesiologists Grade I and II patients of either sex, age 20–60 years, undergoing elective surgery under general anesthesia. Patients with known sensitivity to study drug, history of drug or alcohol abuse, history of chronic pain or daily intake of analgesics, seizure disorder, and history of psychiatric illness were excluded from the study. Patients were randomly allocated with the help of a computer-generated randomized schedule using block randomization of variable block size was generated for two equal groups of 33 each.

  • Group P – Patients received tablet pregabalin 150 mg orally 1 h before the induction of anesthesia with sips of water
  • Group C – Patients received placebo tablet orally 1 h before the induction of anesthesia with sips of water.


The principal investigator allocated the drugs to particular patients. Another anesthesiologist blinded to the study group was responsible for case conduction. An anesthesiology registrar (SG) who was unaware of group allocation noted the incidence and severity of etomidate induced myoclonus and postoperative sedation score.

In the operation room, monitoring was done with 5-lead electrocardiogram, noninvasive blood pressure, pulse oximetry, and capnography. Preoxygenation was done by 100% oxygen through a face mask in both groups. Induction of anesthesia was achieved with intravenous etomidate 0.3 mg/kg injected, over 30 s. Anesthesiology registrar (SG) who was blinded to the group allocation noted the incidence and severity of myoclonus within 2 min after etomidate injection. Endotracheal intubation was achieved with injection vecuronium 0.1 mg/kg. Anesthesia technique was similar in all patients. After completion of the surgery, neuromuscular blockade was reversed with neostigmine (40 mcg/kg) and glycopyrrolate (10 mcg/kg).

The primary outcome was the incidence and severity of myoclonus evaluated on a four-point severity scale; grade 0 = no myoclonus; grade 1 = mild (movement at finger or wrist); grade 2 = moderate (movement at arm only, elbow or shoulder); and grade 3 = severe, generalized response or movement in more than one extremity.[2] The secondary outcome was the postoperative sedation level, assessed by the Ramsay sedation score. Any complications such as postoperative nausea vomiting, dizziness, somnolence, vertigo, confusion, blurred vision, dry mouth, and myalgia were also be noted and managed accordingly.

The sample size was estimated using a two-sided significance level. The reported incidence of etomidate-induced myoclonus was 76% in the control group of the gabapentin study (primary endpoint).[2] We assumed that the incidence of myoclonus will be reduced from 76% to 38% in Group P after drug treatment as based on a pilot study. For this reduction following treatment, one would need to include 27 patients in each group for results to be significant (with α =0.05 and β =0.20 [80% power]). We enrolled 33 patients in each group to account for 20% of potential dropouts or protocol violations.

Statistical analysis was performed using the statistical software Graph pad prism 7.0. The normality of data was assessed by the Kolmogorov–Smirnov test. Student's t-test for continuous variables and Chi-square test for categorical variables analyzed patient characteristic data. The incidence and severity of myoclonus (mild, moderate, and severe) between groups were analyzed using Fisher's exact test. Patient's sedation score was analyzed using the Mann–Whitney test. P <0.05 was considered statistically significant.


  Results Top


A total of 74 patients were assessed for eligibility, out of which 66 patients were included in the study after randomization and all 66 patients accomplished the study. Eight patients were eliminated on account of the patient's refusal to participate (five patients) and a history of preoperative analgesics consumption (three patients) [Figure 1].

Demographics were similar in the study groups [Table 1]. The overall incidence of myoclonus was 30% in Group P and 82% in Group C (P ≤ 0.0001). The grades of myoclonus observed were mild (67%), moderate (22%), and severe (11%) in Group P, while 14.8%, 55.5%, and 29.7%, respectively, in Group C [Table 2]. More patients in Group C had moderate-to-severe grades of myoclonus compared to Group P (P = 0.011). Absolute risk reduction with pregabalin was 57%, the relative risk reduction was 30%, and the numberneeded to treat was 2. The sedation score was significantly higher in Group P (2.03 ± 0.64 vs. 2.73 ± 0.72) (P < 0.001). There were no significant differences in other side-effects between the two groups.
Table 1: Demographic data

Click here to view
Table 2: The incidence and severity of myoclonus

Click here to view
Figure 1: Study design

Click here to view



  Discussion Top


Etomidate is a preferred intravenous induction agent in hemodynamic compromised patients. Unfortunately, its use is associated with two common adverse effects, myoclonus and pain on injection. Myoclonus is differentiated from injection pain by the timing of assessment. The exact mechanism of etomidate-induced myoclonus is not known. Theories postulated are based on the following mechanisms. First, increased sensitivity of the cortical GABA neurons mediated interruption makes skeletal muscle susceptibility for spontaneous nerve transmission.[10],[11],[12] These events lead to myoclonic muscle contractions. Second, studies have postulated that myoclonus may be a form of convulsive seizure, similar to the mechanism of epilepsy.[13] Third, suppression of the cerebral cortex by etomidate before depressing subcortical neurons results in myoclonus.[14],[15]

Present modalities of suppression of etomidate-induced myoclonus include administration of midazolam, opioids, dexmedetomidine, lidocaine, magnesium sulfate, etc.[3],[4],[5],[6] Opioids effectively reduce this movement, but at the cost of undesirable side effects of nausea, vomiting, respiratory depression, apnea, and chest wall rigidity.[16],[17] Pretretment with dexmedetomidine 0.5–1 mcg/kg significantly reduced the incidence of myoclonus from 63.3% to 36.7% and 30%, respectively, however, higher doses (1 mcg/kg) resulted in significant hemodynamic derangements.[3] Benzodiazepine pretreatment has also reduced etomidate-induced myoclonus. Diazepam and flunitrazepam have not decreased myoclonic movements significantly.[18],[19] Various studies demonstrated that midazolam in the dose of 0.015 mg/kg reduced the incidence of myoclonus up to 80% compared to the placebo group, but the number of patients in these studies is 20 in each group.[11],[20] Gabapentin has also been reported to be effective in the treatment of myoclonus by reduction of subcortical disinhibition similar to benzodiazepine and opioids.[2]

Pregabalin is an analog of the inhibitory neurotransmitter GABA, however does not associate with GABA receptors or simulate the actions of GABA. Pregabalin binds potently to the α2δ subunit of “hyper-excited” voltage-gated calcium channels leading to reduced release of neurotransmitters (e.g. glutamate, noradrenaline, dopamine, substance P, and calcitonin gene-related peptide).[21] This decline in neurotransmitter release from synapses in neuronal tissues in the spinal cord and brain is probably going to attenuate neuronal hyperexcitability. Pregabalin also has been shown to modulate different potassium channels including KATP channels and reduce neuronal excitability; this mechanism of action may be responsible.[22]

Pregabalin absorption is not saturable, resulting in a linear pharmacokinetic profile, so dose regimens are straightforward. In case of gabapentin, careful titration of dose is required because of nonlinear pharmacokinetics. The oral bioavailability of pregabalin exceeds 90% with peak plasma concentration at 1 h. Therefore, pregabalin administration 1 h before induction matched to the peak effect of pregabalin.[23] Lower doses of pregabalin than that of gabapentin (2–4 fold lower doses) have a similar analgesic efficacy on neuropathic pain, which makes pregabalin more beneficial in terms of the adverse effects of dosage. Toth also concluded that pregabalin is six times more potent than gabapentin.[24] Yılmaz Çakirgöz et al. demonstrated that 800–1200 mg gabapentin is effective in preventing etomidate induced myoclonus.[2] We did not find any research about pregabalin and myoclonus in the literature; therefore, we chose the dose of pregabalin 150 mg that was most effective in the prevention of succinylcholine-induced fasciculation and pain during injection of propofol.[25]

The incidence of etomidate induced myoclonus in the control group was 82% and this was comparable to the results of other studies. Yılmaz Çakirgöz et al. demonstrated that the incidence of myoclonus in the gabapentin 800 mg and gabapentin 1200 mg group were 28% and 32%, respectively.[2] In our study, the incidence of myoclonus in the pregabalin group was 30%. It requires a lower dose and is associated with fewer dose-related adverse effects, while still maintaining the same incidence of myoclonus. Pregabalin premedication also has several advantages, as it decreases preoperative anxiety and reduces anesthetic agent's requirement and also decreases intra- and postoperative analgesics requirement. Both pregabalin and gabapentin increase side effects versus placebo and these side effects are dose related. Pregabalin group was associated with a higher incidence of sedation compared to the control group. We selected 150 mg pregabalin dose because this is the starting dose recommended by various authors with minimal side effects.[25],[26] In the pregabalin group, none of the patients were deeply sedated (Ramsay sedation scale of 4) and all patients were communicable in the postoperative period and follow order.

In the present study, we compared fixed dose of pregabalin and placebo for the prevention of myoclonus, so further studies are required with different dose-response titration for the prevention of myoclonus. The number of patients is too small for broad generalization therefore results of our study should not be made for high-risk hemodynamically compromised patients or geriatric populations with comorbidities.


  Conclusion Top


Pretreatment with oral pregabalin (150 mg) 1 h before induction of anesthesia significantly reduced the incidence and severity of etomidate-induced myoclonus but at the cost of increased sedation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Kaneda K, Yamashita S, Woo S, Han TH. Population pharmacokinetics and pharmacodynamics of brief etomidate infusion in healthy volunteers. J Clin Pharmacol 2011;51:482-91.  Back to cited text no. 1
    
2.
Yılmaz Çakirgöz M, Demirel İ, Duran E, Özer AB, Hancı V, Türkmen ÜA, et al. Effect of gabapentin pretreatment on myoclonus after etomidate: A randomized, double-blind, placebo-controlled study. Braz J Anesthesiol 2016;66:356-62.  Back to cited text no. 2
    
3.
Luan HF, Zhao ZB, Feng JY, Cui JZ, Zhang XB, Zhu P, et al. Prevention of etomidate-induced myoclonus during anesthetic induction by pretreatment with dexmedetomidine. Braz J Med Biol Res 2015;48:186-90.  Back to cited text no. 3
    
4.
Alipour M, Tabari M, Azad AM. Comparative study evaluating efficacy of sufentanil versus midazolam in preventing myoclonic movements following etomidate. J Anaesthesiol Clin Pharmacol 2016;32:29-32.  Back to cited text no. 4
[PUBMED]  [Full text]  
5.
Sedighinejad A, Naderi Nabi B, Haghighi M, Biazar G, Imantalab V, Rimaz S, et al. Comparison of the effects of low-dose midazolam, magnesium sulfate, remifentanil and low-dose etomidate on prevention of etomidate-induced myoclonus in orthopedic surgeries. Anesth Pain Med 2016;6:e35333.  Back to cited text no. 5
    
6.
Gultop F, Akkaya T, Bedirli N, Gumus H. Lidocaine pretreatment reduces the frequency and severity of myoclonus induced by etomidate. J Anesth 2010;24:300-2.  Back to cited text no. 6
    
7.
Nooraei N, Solhpour A, Mohajerani SA. Priming with atracurium efficiently suppresses etomidate-induced myoclonus. Acta Anaesthesiol Taiwan 2013;51:145-8.  Back to cited text no. 7
    
8.
Mizrak A, Koruk S, Bilgi M, Kocamer B, Erkutlu I, Ganidagli S, et al. Pretreatment with dexmedetomidine or thiopental decreases myoclonus after etomidate: A randomized, double-blind controlled trial. J Surg Res 2010;159:e11-6.  Back to cited text no. 8
    
9.
Wu GN, Xu HJ, Liu FF, Wu X, Zhou H. Low-dose ketamine pretreatment reduces the incidence and severity of myoclonus induced by etomidate: A randomized, double-blinded, controlled clinical trial. Medicine (Baltimore) 2016;95:e2701.  Back to cited text no. 9
    
10.
Lv Z, Fang J, Zhu J, Liang B, Li F, Jiang S, et al. Intravenous dezocine pretreatment reduces the incidence and intensity of myoclonus induced by etomidate. J Anesth 2014;28:944-7.  Back to cited text no. 10
    
11.
Hüter L, Schreiber T, Gugel M, Schwarzkopf K. Low-dose intravenous midazolam reduces etomidate-induced myoclonus: A prospective, randomized study in patients undergoing elective cardioversion. Anesth Analg 2007;105:1298-302, table of contents.  Back to cited text no. 11
    
12.
Gancher S, Laxer KD, Krieger W. Activation of epileptogenic activity by etomidate. Anesthesiology 1984;61:616-8.  Back to cited text no. 12
    
13.
Voss LJ, Sleigh JW, Barnard JP, Kirsch HE. The howling cortex: Seizures and general anesthetic drugs. Anesth Analg 2008;107:1689-703.  Back to cited text no. 13
    
14.
Doenicke AW, Roizen MF, Kugler J, Kroll H, Foss J, Ostwald P. Reducing myoclonus after etomidate. Anesthesiology 1999;90:113-9.  Back to cited text no. 14
    
15.
Herrera-Peco I, Wix-Ramos R, Domínguez-Gadea L, Meilán-Paz ML, Martínez-Chacón JL, de Dios E, et al. Changes in cerebral perfusion induced by etomidate in patients with temporal lobe epilepsy. Rev Neurol 2009;49:561-5.  Back to cited text no. 15
    
16.
He L, Ding Y, Chen H, Qian Y, Li Z. Butorphanol pre-treatment prevents myoclonus induced by etomidate: A randomised, double-blind, controlled clinical trial. Swiss Med Wkly 2014;144:w14042.  Back to cited text no. 16
    
17.
Kelsaka E, Karakaya D, Sarihasan B, Baris S. Remifentanil pretreatment reduces myoclonus after etomidate. J Clin Anesth 2006;18:83-6.  Back to cited text no. 17
    
18.
Korttila K, Tammisto T, Aromaa U. Comparison of etomidate in combination with fentanyl or diazepam, with thiopentone as an induction agent for general anaesthesia. Br J Anaesth 1979;51:1151-7.  Back to cited text no. 18
    
19.
Castillo Monsegur J, Villalonga Morales A, Nalda Felipe MA. Pharmacological prevention of myoclonias during anesthesia induction with etomidate. Comparative study of fentanyl, flunitrazepam and pancuronium. Rev Esp Anestesiol Reanim 1987;34:270-2.  Back to cited text no. 19
    
20.
Schwarzkopf KR, Hueter L, Simon M, Fritz HG. Midazolam pretreatment reduces etomidate-induced myoclonic movements. Anaesth Intensive Care 2003;31:18-20.  Back to cited text no. 20
    
21.
Thorpe AJ, Offord J. The alpha2-delta protein: An auxiliary subunit of voltage-dependent calcium channels as a recognized drug target. Curr Opin Investig Drugs 2010;11:761-70.  Back to cited text no. 21
    
22.
Gajraj NM. Pregabalin: Its pharmacology and use in pain management. Anesth Analg 2007;105:1805-15.  Back to cited text no. 22
    
23.
Bockbrader HN, Radulovic LL, Posvar EL, Strand JC, Alvey CW, Busch JA, et al. Clinical pharmacokinetics of pregabalin in healthy volunteers. J Clin Pharmacol 2010;50:941-50.  Back to cited text no. 23
    
24.
Toth C. Substitution of gabapentin therapy with pregabalin therapy in neuropathic pain due to peripheral neuropathy. Pain Med 2010;11:456-65.  Back to cited text no. 24
    
25.
Choi E, Kim D, Jeon Y. Comparative study between 2 different doses of pregabalin and lidocaine on pain following propofol injection: A double-blind, randomized clinical consort study. Medicine (Baltimore) 2016;95:e5153.  Back to cited text no. 25
    
26.
Srivastava VK, Agrawal S, Nimbhorkar VK, Mishra A, Sharma S, Panda PK. Prophylactic use of pregabalin for prevention of succinylcholine-induced fasciculation and myalgia: A randomized, double-blinded, placebo-controlled study. Braz J Anesthesiol 2016;66:165-70.  Back to cited text no. 26
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2]



 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
Abstract
Introduction
Subjects and Methods
Results
Discussion
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed1207    
    Printed31    
    Emailed0    
    PDF Downloaded84    
    Comments [Add]    

Recommend this journal