A Comparative Study for the Analgesic Efficacy and Safety Profile of Fentanyl versus Clonidine as an Adjuvant to Epidural Ropivacaine 0.75% in Lower Abdominal Surgeries

Abstract

Context:

Different adjuvants are coadministered with local anesthetics to improve the speed of onset and duration of analgesia, and to reduce the dose, the selection of which is often left to the choice of an anesthesiologist.

Aim:

The aim of this study was to compare the analgesic efficacy and safety profile of fentanyl and clonidine as an adjuvant to epidural ropivacaine anesthesia.

Setting and Design:

With institutional ethical committee clearance, a prospective, randomized, placebo-controlled double-blind clinical study was conducted at Vivekananda Polyclinic and Institute of Medical Sciences, Lucknow.

Material and Methods:

Two groups with thirty patients each were randomly allocated to receive 15–20 ml of 0.75% ropivacaine with 75 μg clonidine or 15–20 ml of 0.75% ropivacaine with 75 μg fentanyl, respectively. Block characteristics such as onset of analgesia, maximum level of sensory blockade, complete motor blockade, hemodynamic, time to two-segment regressions, time for rescue analgesia, time to complete motor recovery, and side effects were analyzed.

Results:

Results showed that the onset of blockade is faster when fentanyl is used as additives. Time for two-segment regression was earlier in fentanyl group but time for rescue analgesia was longer in clonidine group.

Statistical Analysis:

Two groups were compared by Student's t-test and Chi-square test; ANOVA and significance of mean difference bet were done by Newman–Keuls test.

Conclusion:

Addition of clonidine to epidural ropivacaine provides superior analgesia than the addition of fentanyl to epidural ropivacaine without much difference in side effect profile.

INTRODUCTION

Central neuraxial blockade in the form of epidural is very popular for lower abdominal and lower limb surgeries as these techniques avoid the disadvantages associated with general anesthesia such as airway manipulation, polypharmacy, and untoward effects such as postoperative nausea, vomiting, and need for supplemental intravenous analgesics. Epidural anesthesia can be used as sole anesthetic for lower abdomen surgeries as it can maintain continuous anesthesia after placement of an epidural catheter, thus making it suitable for procedures of long duration.[1] However, in recent years, a new long-acting local anesthetic drug ropivacaine has increasingly replaced bupivacaine for the said purpose because of its similar analgesic properties, lesser motor blockade, greater selectivity for sensory blockade, and cardiac stability.[2,3] The primary aim of this study was to compare the combination ropivacaine-clonidine and ropivacaine-fentanyl with respect to onset of analgesia, time to maximum sensory and complete motor blockade, time to two-segment regression and complete recovery of motor blockade, duration of analgesia, monitoring of hemodynamics, and side effects.

MATERIALS AND METHODS

“A comparative study for the analgesic efficacy and safety profile of fentanyl and clonidine as an adjuvant to epidural ropivacaine anesthesia in lower abdominal surgeries” was a prospective, randomized, placebo-controlled double-blind study carried out over a period of 18 months in our Institute of Medical Sciences, Lucknow, Uttar Pradesh, India. After approval by Hospital Ethical Committee and taking informed consent from 60 patients of either sex, age 20–60 years, the American Society of Anesthesiology I and II undergoing elective lower abdominal and lower limb surgeries were selected. Patients were randomly divided into two groups of 30 each using computer-generated random numbers.

• Group I: Ropivacaine plus fentanyl

• Group II: Ropivacaine plus clonidine group.

After a written informed consent and thorough preanesthetic checkup including relevant history and examination, patients received tablet Alprax 0.25 mg on the night before surgery. In the preoperative room, on the day of surgery, an intravenous line was secured with appropriate fluid started before epidural anesthesia with a purpose of coloading. Patient's baseline pulse rate and blood pressure, respiratory rate (RR), and SpO₂ were recorded in the operation theater. The participants were given epidural block in the sitting position in L2–L3 space with 18-gauge Tuohy needle only after all aseptic measure, epidural space was confirmed by loss of resistance technique. Epidural catheter was secured 3–5 cm into the epidural space. Then, 3 ml of 1.5% lignocaine with adrenaline (1:200,000) was injected through the catheter as a test dose and observed for any intravascular or intrathecal injection. After confirming catheter placement, 15 ml of 0.75% ropivacaine with 75 μg of fentanyl in Group “I” and 15 ml of 0.75% ropivacaine with 75 μg of clonidine in Group “II” were slowly injected through the catheter. Surgical procedure was initiated after establishment of adequate surgical analgesic effect with the level of up to T6-T7 dermatome. The modified Bromage scale was used to measure motor blockade. Standard monitoring was done with pulse oximetry, electrocardiogram, and noninvasive arterial blood pressure monitoring. Patients were monitored for severe hypotension, bradycardia, and other adverse effects such as anxiety, nausea, vomiting, pruritus, urinary retention, and shivering, these side effects were recorded and needful was taken care. Postoperative pain was assessed by visual analog scale (VAS). Duration of analgesia was assessed by VAS scores, a score of ≥4 was considered for the requirement of rescue analgesia. The onset of pain was managed with top up doses of 8 ml of plain 0.5% ropivacaine + 8 ml of normal saline. The categorical data were compared by Chi-square test. The outcome measures (pulse rate, systolic blood pressure, diastolic blood pressure, sedation score, and VAS score) of two groups were compared by one-way ANOVA followed by Tukey's post hoc test. All analyses were performed on Statistical Package of Social Sciences (SPSS, Lucknow, Uttar Pradesh, India) version 16.0.

OBSERVATIONS AND RESULTS

A total of sixty patients were enrolled in the present study. The demographic profile of the patients was comparable. There was no significant difference in age, gender, weight, height, and duration of surgery [Table 1].

Table 1.

Physical parameters of the two groups

Hemodynamic characteristics

The baseline systemic arterial blood pressure [Figure 1] and mean heart rate (HR) [Figure 2] were comparable between the two groups. The mean values of systolic blood pressure did not statistically decline from baseline values. Both groups have shown an initial moderate fall in mean arterial blood pressure, which gradually returned to baseline values. Only 4 patients of Group I and 5 patients of Group II suffered hypotension and were managed with fluid and intravenous mephentermine 6 mg bolus when needed. Only 3 patients of Group I and 4 patients of Group II had bradycardia and were treated with bolus of intravenous atropine 0.6 mg.

Figure 1.

Intraoperative mean blood pressure

Figure 2.

Intraoperative heart rate

Sensory and motor block characteristics

The mean onset time of adequate sensory analgesia at T10 dermatome was 6.87 ± 0.35 min in Group I and 6.58 ± 0.66 min in Group II. The mean time to reach the highest level of T8 for sensory blockade was 7.50 ± 0.70 min in Group I and 8.00 ± 0.63 min in Group II. The mean time to reach the highest level of T6 for sensory blockade was 7.73 ± 0.64 min in Group I and 8.20 ± 0.03 min in Group II with no statistically significant difference. The mean total duration of sensory analgesia was 183.33 ± 16.47 min in Group I and 242.00 ± 19.72 min in Group II. The difference in total duration of sensory analgesia between groups was statistically highly significant. The mean time taken for motor blockade up to modified Bromage scale 3 was 15.33 ± 1.95 min in Group I and 19.03 ± 3.61 min in Group II. The mean duration of motor blockade was 168.83 ± 16.11 min in Group I and 178.50 ± 17.17 min in Group II. The difference in mean duration of motor blockade was statistically highly significant [Table 2].

Table 2.

Motor and sensory block characteristics

Side effects (If Any)

There was no significant difference (P > 0.05) in the percentage of bradycardia between Group I (10%) and Group II (13.3%). The percentage of hypotension was lower among Group I (13.3%) patients than Group II (16.7%); however, the difference was not statistically significant. The symptom of vomiting and nausea was higher among patients of Group I (16.7%) compared with Group II (10%). The respiratory depression was absent among all patients of both groups [Table 3].

Table 3.

Peri- and post-operative adverse effects

DISCUSSION

In recent years, regional blocks such as spinal, epidural, and a combination of spinal/epidural blocks with general anesthesia have gained widespread popularity in the field of anesthesia and have been well accepted. Regional blocks, by lowering the side effects associated with general anesthesia, contribute in reducing the postoperative duration of hospital stay.[4] The epidural route for postoperative analgesia has been widely used as a good method of analgesia. The addition of adjuvants markedly improves the quality of analgesia and reduces the dose of local anesthetics. In this study, we compared fentanyl and clonidine as an adjuvant to epidural ropivacaine anesthesia. The results of this study showed that there was no statistically significant difference in both groups in vital signs (HR, mean arterial pressure, and RR). The result of the present study demonstrated that duration of sensory and motor block (178.50 ± 17.75 min) and duration of analgesia were more in clonidine group than fentanyl group (242.00 ± 19.72 min) in the postoperative period. Hypotension was seen in five cases in clonidine group and in four cases in fentanyl group whereas bradycardia is seen in four cases in clonidine group and in three cases in fentanyl group. Nausea vomiting is seen in five cases in fentanyl group and in three cases in clonidine group. All the above results corresponded with many other studies done in recent times.

As we already know that clonidine augments blockade of local anesthetic agents by increasing the conductance of potassium ions, preferably in the myelinated nerve at node of Ranvier, thus enhancing the differential blockade. It also exerts vasoconstriction effect on smooth muscles, which results in a decreased absorption of local anesthetic agent and eventually prolongs the duration of analgesia.[5] Clonidine is lipophilic and as a result is quickly redistributed systemically despite neuraxial injection. It, therefore, has both central and peripheral effects. Clonidine produces sympatholysis and reduced blood pressure by its action in brainstem, spinal cord, and periphery, which is opposed by direct vasoconstriction from α-2 adrenergic agonist in periphery. Clonidine has a potent regressive effect on HR within 15–90 min of epidural administration.[6] When used as an adjuvant, it has a decreasing effect on HR.[7,8] In studies by Baptista et al.,[9] Voje and Manohin,[10] and Chand et al.,[11] they all did not observe any change in hemodynamics when low dose of clonidine was used. Despite lowering effect on HR and blood pressure, incidence of bradycardia and severe hypotension was not significant, thus ascertaining that the dosage used in this study is safe to be used in clinical practice. However, in a study done by Castro and Eisenach, when factors such as molecular weight, lipid solubility, cerebrospinal fluid pharmacokinetics, analgesic effect, and duration of analgesia of clonidine compared to fentanyl were similar, but also the onset of analgesic effect of fentanyl started faster and lasted longer according to their finding.[12] De Kock et al.[13] evaluated the association of small dose of intrathecal ropivacaine 8 mg with different doses of intrathecal clonidine (15, 45, 75 μg) in four groups, for ambulatory surgery and in support of low-dose ropivacaine. Sagiroglu et al.[14] used 15 μg and 30 μg clonidine as adjuvant in 1% ropivacaine (12 mg), they found significant prolongation of sensory and motor block with higher dose of clonidine in their respective studies. Kawaraguchi et al.,[15] Baptista et al.,[16] Gupta et al.[17] also found similar results. Chaudhary et al.[18] found that there was no significant difference in hemodynamic changes with addition of intrathecal fentanyl to low-dose ropivacaine in elderly patients. The oxygen saturation was also similar across the time intervals and similar between the groups. Gupta et al. also observed that addition of small amount, i.e., 20 μg of intrathecal fentanyl to ropivacaine has accelerated the time of onset of sensory and motor block.[17] Fentanyl has been widely used as an adjuvant to local anesthetics for enhancement of analgesia without intensifying motor and sympathetic block thus resulting in lower incidence of hypotension, early recovery, and mobilization.[19] Curatolo et al.[20] and Gecaj-Gashi et al (2012)[21] also observed that addition of clonidine reduces the onset time for blocks and enhances the duration of block when added to ropivacaine, while no such difference has been reported by Duma et al.[22] when they used clonidine in brachial plexus block as an adjuvant. Rather different results were seen when addition of fentanyl to local anesthetics offered no advantage over the administration of local anesthetic alone for short surgical procedure in children done under caudal analgesia.[23] In a study by Shukla et al., patients in Group I (ropivacaine + fentanyl) required analgesia supplementation slightly earlier in the postoperative period as compared to Group II (ropivacaine + clonidine), but this difference was not statistically significant.[24] In earlier studies, addition of fentanyl produced only a slight change in quality and duration of analgesia after administration of 2% lidocaine with epinephrine[25] or after administration of 0.125% of bupivacaine.[26] However, according to Apostolos and Georgios,[27] ropivacaine plus fentanyl administered through Patient Epidural controlled Analgesia (PECA) compared with ropivacaine plus clonidine guarantee higher quality analgesia but these findings can be because of higher dose of fentanyl (2 μg/ml) than clonidine (1 μg/ml).

Now side effects such as hypotension and bradycardia are expected of extradural clonidine in adults and depend on the dose administered.[28] Extradural opioids are well known for their emetic effect while clonidine has antiemetic property when administered orally[29] or intravenously.[30] Respiratory depression is an expected but unwanted side effect of extradural opioids, but respiratory depression is not seen probably due to smaller dose of fentanyl used.[31] The attempts made earlier for dose determination concluded that 75 μg of clonidine is the optimal epidural dose when added to bupivacaine for analgesia as smaller doses were not serving the purposes of adequate analgesia while larger doses were associated with bradycardia, hypotension, sedation, and other side effects.[32]

CONCLUSION

Our study establishes clonidine as superior adjuvant drug compared to clonidine in epidural ropivacaine for patients undergoing elective surgeries under epidural anesthesia in terms of prolonged duration of motor and sensory blockade without a significant increase in adverse effect. Moreover, the safety profile of both groups was almost comparable when used as an adjuvant in epidural analgesia.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.