Effect of Fentanyl and Nalbuphine for Prevention of Etomidate-Induced Myoclonus.

BACKGROUND: Etomidate is a potent intravenous inducing agent with known undesirable side effects such as myoclonus and pain on injection in nonpremedicated patients. AIMS: The aim of this study is to compare the effect of fentanyl and nalbuphine in the prevention of etomidate-induced myoclonus. SETTINGS AND
DESIGN: Randomized double-blind, placebo-controlled, and prospective comparative study.
MATERIALS AND METHODS: A total of 120 patients were randomly allocated to one of the three groups containing 40 patients each for intravenous administration of fentanyl 2 μg/kg diluted in 10 mL normal saline (NS) (Group 1), nalbuphine 0.3 mg/kg diluted in 10 mL NS (Group 2), and only 10 mL NS (Group 3) over 10 min. All groups subsequently received 0.3 mg/kg etomidate by intravenous bolus injection over 15-20 s and were assessed for the severity of pain using Grade IV pain scale and observed for myoclonus for 2 min and graded according to clinical severity. Serum creatinine phosphokinase (CPK) levels were obtained prior and postetomidate injection. STATISTICAL ANALYSIS: Statistical analysis was performed by the SPSS program version 17.0 for Windows. Tests used are Shaipro-Wilk test, ANOVA, Tukey's multiple comparison test, Tamhane's T2, and the Chi-square test. For all statistical tests, P < 0.05 was considered statistically significant with 5% level of significance (α).
RESULTS: The incidence of myoclonus in Group 1 and 2 was 52.5% and 17.5%, respectively, whereas it was 92.45% in Group 3. There was no pain observed in 70%, 92.5%, and 50% of patients in Group 1, 2, and 3, respectively. There was a statistically significant difference in mean CPK level after induction among three groups (P < 0.001).
CONCLUSION: Nalbuphine is more effective than fentanyl in the prevention of etomidate-induced myoclonus and pain with the minimum rise in CPK levels.

INTRODUCTION

Etomidate is a carboxylated nonbarbiturate imidazole derivative widely used as an intravenous anesthetic induction agent. Due to a rapid onset of action and clearance, stable cardiovascular profile, and minimal respiratory side effects, it is widely used for hemodynamically unstable patients.[1] Other advantages being minimal histamine release and cerebral protection associated with its use. Apart from nausea and vomiting, superficial thrombophlebitis, hemolysis, electroencephalography (EEG) activation, and adrenocortical suppression etomidate have two well-known side effects, pain on injection and myoclonus, which have been discussed in various etomidate-associated studies.[2]

Myoclonus is defined as sudden, brief, involuntary muscle jerks either irregular or rhythmic. These movements are caused by muscular contractions. The incidence of myoclonus has been reported to be as high as 50%–80% in nonpremedicated patients.[3] The incidence of myoclonus due to etomidate depends on the dosage and speed of the injection.[4] Myoclonus can lead to muscle fiber damage, myalgia, and elevated serum potassium. These adverse effects can lead to regurgitation and aspiration in nonfasting emergency patients can raise intraocular pressure in open-globe injuries with the raised risk of prolapse of vitreous material,[5] and myocardial oxygen consumption can increase due to these muscle contractions which are deleterious in cases of the limited cardiovascular reserve.

Although the cause of etomidate-induced myoclonus is still not clear, several mechanisms have been postulated to explain myoclonus. It was reported that myoclonus resulted from temporal subcortical disinhibition, another reason could be that the inhibitory circuits are depressed earlier than the excitatory neuronal circuits after etomidate administration.[6] Studies have been done which showed that opioids and sedatives are helpful in decreasing the incidence of etomidate-induced myoclonus by subcortical inhibition.[3]

A large number of drugs, including neuromuscular blocking agents,[78] opioids,[9] dexmedetomidine,[510] midazolam,[611] propofol,[12] ketamine,[13] gabapentin,[14] and magnesium sulphate[1115] have been investigated for their ability to suppress these myoclonic movements. These drugs are; however, associated with side effects such as excessive sedation, delayed recovery, and respiratory inhibition.

The pretreatment drug for preventing myoclonic movements should be short acting, not have a significant effect on respiration and hemodynamics, and should not prolong recovery time from anesthesia.[5]

With this background, we planned this study and chosen fentanyl and nalbuphine as there have been no reported comparison studies between fentanyl and nalbuphine as a better pretreatment option in the prevention of myoclonus due to etomidate. However, other agonist-antagonist butorphanol[1617] has been compared with fentanyl[16] in preventing etomidate-induced myoclonus but no study till date has been done comparing fentanyl and nalbuphine, so we made an effort in the present study to compare these two opioids. Hence, in this study, we have compared the potency of fentanyl and nalbuphine in terms of prevention of etomidate-induced myoclonus which is the primary outcome of this study. Effectiveness in the prevention of pain following etomidate injection and rise in serum creatinine phosphokinase (CPK) level due to myoclonus were considered to be the secondary outcome of this study.

MATERIALS AND METHODS

This placebo-controlled, randomized, double-blind prospective comparative study was conducted over the period of 12 months after approval from the Institutional Ethical Committee SRHU/HIMS/ETHICS/2017/131.

With complete enumeration from October 20, 2017 to October 19, 2018, and continuous sequencing under three groups, namely, Group 1 (fentanyl), Group 2 (nalbuphine), and Group 3 (control), 120 patients of either sex, age between 18 and 60 years ASA physical Status I and II posted for middle ear surgery were included in the study. We have selected middle ear surgery patients in this study because not a single-adverse effect of etomidate has been reported in patients having middle ear disease like chronic suppurative otitis media. Second, middle ear surgeries require good hemodynamic stability which can be achieved with etomidate. Patients who were allergic to study drugs, pregnant females, having uncontrolled chronic diseases or neurological illness, and admitted for emergency procedures were excluded from the study. Patients were explained in detail about anesthetic technique during preanesthetic evaluation, and a written and informed consent were taken. Patients were kept nil per oral 6 h before surgery. All patients were premedicated with tablet alprazolam 0.25 mg and tablet ranitidine hydrochloride 150 mg in the morning on the day of surgery with a sip of water. The patient was taken into the operation theater (OT) and after placement of 18G IV cannula intravenous fluid was started. Patients were monitored for noninvasive blood pressure (BP), heart rate (HR), electrocardiography, and oxygen saturation (SpO2). Age, weight, and sex of patients were recorded. Patients were randomized by computer-generated code into three groups in the operating room before surgery by an anesthesiologist who prepared the medication and handed over the study drug to another anesthesiologist who injected the drug and recorded the patient's data who was blind to the treatment group allocation. We took 40 patients per group for this study as below:

Group 1 received fentanyl 2 μg/kg diluted in 10 mL normal saline (NS)

Group 2 received nalbuphine 0.3 mg/kg diluted in 10 mL NS

Group 3 control 10 mL NS.

In the OT patient received the study drugs over a period of 10 min infusion using a syringe pump. The patient was preoxygenated for 3 min with 100% oxygen, and induction was done by the injection etomidate 0.3 mg/kg over 15–20 s. During etomidate injection, severity of pain on injection was assessed using Grade IV pain scale:[18] 0 = no pain, 1 = mild (pain reported only when asked), 2 = moderate (pain reported without being asked or reported when asked and there were associated behavioral symptoms), and 3 = severe (verbal response, grimacing, pulling the arm, and tearing eye). Following etomidate injection patient was observed for myoclonus and graded accordingly:[18] 0 = no myoclonus, 1 = mild myoclonus (small movements in one body segment such as finger or wrist), 2 = moderate (slight movements in 2 or more muscle areas such as face or shoulder), and 3 = severe (intense movement in 2 or more muscle areas, sudden adduction of extremity). Two blood samples were taken one preoperatively and one just before intubation for CPK level following etomidate injection. HR, mean arterial pressure (MAP), and SpO2 readings were recorded preinduction, during induction, and 5 min after intubation. After taking second blood sample, patients in the control group later received fentanyl 2 μg/kg as analgesia.

Statistical analysis

Statistical analysis was performed with the Statistical Package for the Social Science System version SPSS 17.0 (Inc, Chicago, IL, USA). Continuous variables are presented as mean ± standard deviation, and categorical variables are presented as absolute numbers and percentage. Data were checked for normality before statistical analysis using the Shaipro–Wilk test. Normally-distributed continuous variables were compared using the ANOVA. If the value of P was significant and variance was homogeneous, Tukey's multiple comparison test was used to assess the differences between the individual groups; otherwise, Tamhane's T2 test was used. Categorical variables were analyzed using the Chi-square test. For all statistical tests, value of P < 0.05 was considered statistically significant with 5% level of significance (α).

RESULTS

A total of 120 patients completed this study. There was no statistically significant difference among the three groups regarding the age, sex, and weight [Tables 1–3].

Table 1

Age-wise distribution of population among three groups

	Mean±SD			P
	Group 1 (n=40)	Group 2 (n=40)	Group 3 (n=40)
Age (years)	31.21±11.69	31.23±13.79	29.33±11.18	0.732

SD=Standard deviation

Table 3

Weight-wise distribution of population among three groups

	Mean±SD			P
	Group 1 (n=40)	Group 2 (n=40)	Group 3 (n=40)
Weight (kg)	58.50±11.68	55.41±9.31	56.79±9.16	0.393

SD=Standard deviation

Regarding the evaluation of myoclonus (for 2 min) among the three groups, it was observed that there was a statistically significant difference in the distribution of patients when compared among the three groups (P < 0.001). Further, as per post-hoc analysis, it was observed that there was a statistically significant difference in distribution of patients when compared between Group 1 versus Group 2 (P = of 0.011), Group 1 versus Group 3 (P < 0.001), and Group 2 versus Group 3 (P < 0.001) [Table 4 and Figure 1].

Table 4

Incidence of myoclonus among the 3 groups [Figure 1]

Severity of myoclonus (after 2 min)	Frequency (%)			P	Group 1 versus Group 2	Group 1 versus Group 3	Group 2 versus Group 3
	Group 1 (n=40)	Group 2 (n=40)	Group 3 (n=40)
No	19 (47.5)	33 (82.5)	3 (7.5)	<0.001	0.011	<0.001	<0.001
Mild	12 (30)	5 (12.5)	2 (5)
Moderate	6 (15)	1 (2.5)	17 (42.5)
Severe	3 (7.5)	1 (2.5)	18 (45)

Figure 1

Evaluation of myoclonus (after 2 min)

Regarding evaluation of pain among the three groups, it was observed that there was a significant difference in the distribution of patients when compared among the three groups (P = 0.006). Further, as per post-hoc analysis, it was observed that there was a significant difference in the distribution of patients when compared between Group 1 versus Group 2 (P = 0.043) and Group 2 versus Group 3 (P < 0.001) [Table 5 and Figure 2].

Table 5

Severity and frequency of pain among the 3 groups [Figure 2]

Severity of pain	Frequency (%)			P	Group 1 versus Group 2	Group 1 versus Group 3	Group 2 versus Group 3
	Group 1 (n=40)	Group 2 (n=40)	Group 3 (n=40)
No	28 (70)	37 (92.5)	20 (50)	0.006	0.043	0.329	<0.001
Mild	11 (27.5)	3 (7.5)	18 (45)
Moderate	1 (2.5)	0 (0.0)	1 (2.5)
Severe	0 (0)	0 (0.0)	1 (2.5)

Figure 2

Severity of pain

Higher CPK level was noted in Group 3 than that of the Group 1 and Group 2. There was a statistically significant difference in mean CPK level after induction among the three groups (P < 0.001) [Table 6 and Figure 3].

Table 6

Creatinine phosphokinase levels at different time intervals among the 3 groups [Figure 3]

CPK level	Mean±SD			P	Group 1 versus Group 2	Group 1 versus Group 3	Group 2 versus Group 3
	Group 1	Group 2	Group 3
Before induction	62.38±21.26	59.67±22.95	61.77±30.92	0.881	0.880	0.994	0.928
After induction	84.17±42.17	71.51±26.53	116.62±30.05	<0.001	0.216	0.001	<0.001

CPK=Creatinine phosphokinase, SD=Standard deviation

Figure 3

Comparison of creatinine phosphokinase before and after induction among the groups

Regarding hemodynamics, there was no significant difference in MAP and HR at baseline and before induction among the three groups. At before intubation and 5 min after intubation, there was a statistically significant high MAP and HR in Group 3 as compared to that of Group 1 and Group 2, and there was no difference in mean MAP and HR between Group 1 and Group 2 [Tables 7 and 8]. There was no significant difference in mean SpO2 level at all the stages among the three groups. Further, no significant difference in SpO2 level was observed within any of the two groups [Table 9].

Table 7

Mean arterial pressure at different time intervals among the 3 groups

MAP (in mm hg)	Mean±SD			P	Group 1 versus Group 2	Group 1 versus Group 3	Group 2 versus Group 3
	Group 1 (n=40)	Group 2 (n=40)	Group 3 (n=40)
Baseline	96.71±12.39	95.33±11.35	95.79±8.54	0.848	0.840	0.926	0.981
Before induction	92.52±9.71	89.74±13.15	90.33±10.22	0.493	0.500	0.649	0.970
Before intubation	88.48±13.6	89.51±10.77	99.33±12.13	<0.001*	0.923	<0.001*	0.002*
5 min after intubation	85.24±12.67	80.72±9.84	95.35±10.40	<0.001*	0.165	<0.001*	<0.001*

MAP=Mean arterial pressure, SD=Standard deviation, P< 0.05 *significant

Table 8

Heart rate at different time intervals among the 3 groups

HR (beats/min)	Mean±SD			P	Group 1 versus Group 2	Group 1 versus Group 3	Group 2 versus Group 3
	Group 1 (n=40)	Group 2 (n=40)	Group 3 (n=40)
Baseline	79.43±15.90	74.59±15.69	77.9±11.93	0.323	0.302	0.886	0.581
Before induction	76.98±14.84	72.44±14.84	78.67±12.67	0.137	0.323	0.854	0.132
Before intubation	76.76±16.62	74.51±15.02	86.44±13.48	0.002*	0.782	0.013*	0.002*
5 min after intubation	72.41±15.97	69.03±11.03	80.95±15.08	0.001*	0.537	0.025*	0.001*

SD=Standard deviation, HR=Heart rate, P<0.05 *significant

Table 9

Oxygen saturation at different time intervals among the 3 groups

SpO2 (%)	Mean±SD			P	Group 1 versus Group 2	Group 1 versus Group 3	Group 2 versus Group 3
	Group 1 (n=40)	Group 1 (n=40)	Group 1 (n=40)
Baseline	99.83±0.79	99.97±0.16	100.00±0.00	0.242	0.384	0.265	0.970
Before induction	99.95±0.22	100.00±0.00	99.97±0.16	0.397	0.363	0.804	0.751
Before intubation	99.95±0.22	100.00±0.00	99.97±0.16	0.397	0.363	0.804	0.751
5 min after intubation	99.90±0.37	100.00±0.00	100.00±0.00	0.081	0.125	0.132	1.000

SpO2=Oxygen saturation, SD=Standard deviation

DISCUSSION

This study evaluated the effectiveness comparing nalbuphine and fentanyl in preventing etomidate-induced myoclonus. There was no statistically significant difference among the groups with respect to their demographic profile in terms of age, weight, and sex and this finding did not have any clinical implications on the study.

Regarding the severity of pain after the injection etomidate, it was observed that there was a significant difference in the distribution of patients when compared among the three groups (P = 0.006). In this study, the incidence of pain in patients with no pretreatment was more than in patients who are pretreated with fentanyl and nalbuphine. Vijayaragavan et al. found out in their study that there was a decrease in incidence of pain (3.33%) on injection of etomidate on pretreatment with 5 μg/kg dose of fentanyl as compared to 2 μg/kg dose for which the incidence rate was 30%.[19] In this study, we have found the similar incidence of pain 32.5% on pretreatment with 2 μg/kg dose of fentanyl. The study done by Korttila et al. also concluded that the incidence of pain with fentanyl was 32%,[20] which is consistent with this study. However, in this study, the incidence of pain is less in nalbuphine (7.5%) pretreated group as compared to the fentanyl (32.5%) pretreated group, this might be due to the fact that we have used 0.3 mg/kg dose of nalbuphine, effective dose range of nalbuphine 0.2–0.4 mg/kg,[2122] which has more analgesic property than 2 μg/kg dose of fentanyl, since equianalgesic dose of iv nalbuphine and fentanyl is said to be 0.2 mg/kg and 2 μg/kg, respectively.[23]

This study shows that the incidence of myoclonus is more in no pretreatment group (92.5%), whereas it reduced in fentanyl (52.5%) and nalbuphine (17.5%) pretreated groups. Results in the study by Isitemiz et al. also showed that myoclonus incidence was 85% and 40% in the group with no pretreatment and group fentanyl, respectively.[18] In this study, incidence of myoclonus is more which can be attributed to the fact that our speed of administration of etomidate is over 15–20 s while in Isitemiz et al. study, they have given the same dose of etomidate over 20–30 s. Stocham et al. reported that premedication with fentanyl decreases etomidate-induced myoclonus in a dose-dependent manner, but it increased the risk of apnea. They observed that none of the patients who received premedication with 500 μg fentanyl 5 min before anesthesia induction using etomidate had a myoclonus, but all developed apnea. Respiratory depression was less when 100 μg fentanyl was given, and the rate of myoclonus was 33%. Fentanyl (100 μg) given 5 min before etomidate has been found to reduce the incidence of myoclonus to 50% of that observed in the controls.[24] Because of the maximum onset time of fentanyl, 5–8 min,[24] the timing of the pretreatment in this study is 10 min. Hence, to avoid bias, we have used 10 min pretreatment time in both fentanyl and nalbuphine pretreated groups. A study by Fassoulaki showed no influence on the myoclonic rate when the patients were treated with fentanyl 100 μg 2 min before etomidate. This was probably due to the timing of fentanyl given.[25]

In this study, the incidence of severe myoclonus was observed in 45% of patients in no pretreatment group, and was 7.5% and 2.5% in pretreatment with fentanyl and nalbuphine, respectively. He et al.[17] conducted a clinical trial to test a hypothesis that pretreatment with butorphanol might reduce the incidence and severity of myoclonus induced by etomidate by comparing two groups one to receive either 0.015 mg/kg of butorphanol (n = 54) and another to receive saline (n = 54) intravenously. At 2 min after infusion of butorphanol or saline, 0.3 mg/kg etomidate was given. He concluded that the incidence of myoclonus was significantly lower in Group butorphanol than in Group saline. Butorphanol is a synthetic and strong analgesic with both narcotic agonist and antagonist properties like nalbuphine. Study done by Kewalramani et al.[16] compared butorphanol and fentanyl administered before the induction of etomidate to reduce the myoclonic movements. Incidence of myoclonus was 6.7% and 10%, respectively, and hence, they concluded that the incidence and severity of etomidate-induced myoclonus were better reduced by combination of midazolam with butorphanol than midazolam with fentanyl if administered before induction. Since we have taken nalbuphine in place of butorphanol in this study, and both these synthetic opioids share similar properties, therefore, it is in accordance with this study that nalbuphine is better than fentanyl in reducing the incidence of etomidate-induced myoclonus. Henceforth, this study showed that pretreatment with nalbuphine in a dose of 0.3 mg/kg iv is more potent than pretreatment with fentanyl in a dose of 2 μg/kg iv in reducing the incidence of etomidate-induced myoclonus without any side effects such as nausea, vomiting, apnea, and bradycardia.

Doenicke et al. observation showed that low doses of etomidate reduce the incidence of myoclonus, and their EEG data are consistent with the assumption that subcortical disinhibition is a possible origin of myoclonus during anesthesia with etomidate. Fentanyl and midazolam are the drugs which are known to inhibit subcortical neuronal activity, supports this study in conjunction with fentanyl-mediated reduction in etomidate-induced myoclonus.[3]

Nalbuphine is an opioid agonist-antagonist (kappa agonist, μ antagonist) of the phenanthrene series which was synthesized in an attempt to provide analgesia without the undesirable side effects of the pure agonists.[26] It has been proposed that stimulation of the three opioid receptors, namely, mu kappa and delta binding sites act synergistically in evoking the anti-electroshock effect of nalbuphine, and that this pharmacological effect may be attenuated when one of these binding sites is blocked.[27] This hypothesis explains this study of nalbuphine mediated decrease in the incidence of etomidate-induced myoclonus. Other studies done with butorphanol having similar characteristics like nalbuphine also justify the action of nalbuphine in decreasing the incidence of myoclonus by etomidate.[1617]

We have taken account of HR, BP, and SPO2 vital parameters in this study as their values can be of significance in determining the adverse effects of opioids such as bradycardia, hypotension, or apnea before induction. However, no such events occurred in opioid pretreated groups in this study. Before intubation and 5 min after intubation, we recorded these parameters in view of myoclonus-induced hyperdynamic circulation after inducing with etomidate and to note the opioids response in reducing sympathetic activity. There was no significant difference in mean systolic BP (SBP), diastolic BP (DBP), MAP, and HR at baseline and before induction among three groups. At before intubation and 5 min after intubation, there was significant high SBP, DBP, MAP, and HR in Group 3 as compared to that of the Group 1 and Group 2, and there was no difference in mean SBP, DBP, MAP, and HR between Group 1 and Group 2. However, there was no significant difference in mean SpO2 level at all the stages among three groups. Similarly, Isitemiz et al.[18] observed MAP and HR measurements after induction were significantly lower in fentanyl group as compared to the no pretreatment group. Ko et al.[28] also found the SBP, DBP, MAP, and HR to be significantly lower in case of fentanyl pretreated group as compared to control in after induction and after intubation scenario.

Myoclonus is defined as sudden jerks typically lasting 10–50 ms, with the duration of movements rarely longer than 100 ms.[29] Myoclonus is usually a positive phenomenon, causing synchronized muscle contractions in single or multiple muscle groups.[30] CPK is an enzyme found mainly in the heart, brain, and skeletal muscle. When muscle tissue is damaged, CPK leaks into the blood. Myoclonus can lead to muscle fiber damage, myalgia, and elevated serum potassium. Although the mechanism of etomidate induced myoclonus is still not clear, several studies suggest that it may represent a type of seizure.[12] However, some cases are also reported which showed that etomidate has caused generalized tonic clonic seizures.[313233] In this study, we made an attempt to quantify the myoclonus biochemically by measuring CPK levels before and after giving etomidate and calculating the difference in CPK levels. In all the three groups, we have taken the first blood sample for CPK in preoperative room, and second sample 2 min after clinically assessing the severity of myoclonus after inducing with etomidate. However, to the best of our knowledge, no study has correlated CPK levels after etomidate-induced myoclonus. Since it has been proven that etomidate causes myoclonus and myoclonus is a form of seizure activity which comes under classification of seizures sub-category of focal motor seizures. One study demonstrated that serum CPK level may occur postictally and appear to be related to the intensity of muscular activity,[34] which support our hypothesis that groups pretreated with fentanyl and nalbuphine show decline in myoclonus activity, hence, less muscular activity than control group, thereby showing less rise or no rise in CPK levels comparatively to control groups.

Limitation

The absence of any recording of the onset time of myoclonus within the 2-min observation period and of its duration was a limiting factor for this study which might have provided us with useful information on the optimal pretreatment time. Second, we could have assessed the adverse effects associated with the pretreatment drug so that a better pharmacological agent devoid of side effects is found to prevent etomidate-induced myoclonus.

CONCLUSION

We conclude nalbuphine and fentanyl both were far more effective in the prevention of pain and myoclonus caused by etomidate induction than placebo but nalbuphine emerged to be most potent among the rest. This was supported by our hypothesis that nalbuphine was associated with minimum rise in serum CPK level postetomidate induction followed by fentanyl and placebo.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Table 2

Gender-wise distribution of population among three groups

	Frequency (%)			P
	Group 1 (n=40)	Group 2 (n=40)	Group 3 (n=40)
Sex
Female	21 (52.5)	20 (50)	18 (45)	0.792
Male	19 (47.5)	20 (50)	22 (55)
Total	40 (100)	40 (100)	40 (100)