Background Many studies are there using adjuvants such as clonidine and fentanyl with bupivacaine in the subarachnoid block for prolonging postoperative analgesia. However, literature is divided regarding the dosage and efficacy of both intrathecal adjuvants. Furthermore, these adjuvants have their own side effects. Hence, search for ideal intrathecal adjuvant between clonidine and fentanyl to bupivacaine goes on. Methods This is a prospective and observational study was conducted in the Department of Anaesthesia, Shadan Institute of Medical Sciences Teaching Hospital & Research Centre. Inclusion criteria were 150–195 cm height and 50–120 kg weight. Patients were excluded if they had conditions that preclude spinal anaesthesia, had a psychiatric disorder, had chronic pain, were on antihypertensive medication or when they were unable to communicate in the Local language. Written informed consent was obtained from all patients. To allow for sufficient time for informed consent, the patients were provided with written information at the outpatient preoperative evaluation clinic a few days before the actual operation. Before induction of spinal anaesthesia, all patients received an i.v. infusion of Ringer’s lactate (1500 ml) or normal saline and standard intraoperative monitoring was used [ECG, pulse oximetry and non-invasive blood pressure (NIBP)]. Results Majority of patients in the both the groups belonged to the group 26 to 55 years. Samples were age matched. The number of males and females in each group was same (n=30) and samples in both groups were matched with respect to sex. Majority of female patients in the both the groups belonged to the group 160 to 170 cms and males 171 to 175 cms, Samples were height matched. The majority of surgeries fall under the gynaecology category. Lower abdominal and lower limb surgeries are less common, with lower abdominal surgeries being the least frequent. This breakdown indicates a higher demand or prevalence for gynaecological procedures compared to the others. Conclusion Both the drugs offer similar surgical conditions and prolongs postoperative analgesia (clonidine more than fentanyl), so we suggest fentanyl as better choice when sedation is not desirable and clonidine is recommended where sedation is acceptable. The administration of local anaesthetics in combination with opioids intrathecally is an established technique for managing postoperative pain following abdominal, pelvic, thoracic or orthopaedic procedures on lower extremities. Local anaesthetics with opioids demonstrate significant synergy.
Local anesthetic like bupivacaine is commonly used in spinal anesthesia, but the duration of spinal anesthesia may be short and limited, and higher doses of rescue analgesics may be required in the postoperative period. This can be avoided by using higher doses of bupivacaine which again can produce cardiac toxicity. Studies have shown that duration of analgesia due to bupivacaine in spinal anesthesia can be prolonged by using adjuvants such as midazolam, opioids, neostigmine, dexmedetomidine, and clonidine.[1-6] Almost all opioids have been used as adjuvants intrathecally.
Most commonly used opioid in regional anesthesia is fentanyl citrate which is a μ1- and μ2-receptor agonist. It is a highly potent drug because of its high lipophilicity. It is preferred as an adjuvant in spinal anesthesia because of its rapid onset and short duration of action with minimal cephalic spread. However, pruritus, nausea, vomiting, respiratory depression, and urinary retention are other common side effects for which search for ideal nonopioid adjuvants goes on.Clinical studies have suggested that intrathecal clonidine, an α2-receptor agonist, prolongs sensory and motor block in spinal anesthesia and provides prolonged postoperative analgesia. Clonidine has beneficial effects such as antiemesis, reduced postspinal shivering, anxiolysis, and sedation, thereby avoiding unwanted opioid-related side effects such as pruritus and respiratory depression.[8]
Literature is divided regarding efficacy of both intrathecal clonidine and fentanyl in providing prolonged postoperative analgesia. Studies by Khezri et al.,[9] Bajwa et al.,[10] Chhabra et al.,[11] and Sharan et al.[12] opined that intrathecal clonidine was more potent in providing prolonged analgesia compared to intrathecal fentanyl. Study by Mahendru et al. concluded that intrathecal fentanyl and clonidine were comparable regarding requirement of first analgesia request.[13] Another study by Bathari et al. concluded that intrathecal fentanyl was superior to intrathecal clonidine in knee arthroscopy.[14]
Hence, all the above studies differ in their postoperative sensory and motor block characteristics. Hence, the present study is being undertaken to evaluate and compare the effects of clonidine and fentanyl as intrathecal adjuvants to hyperbaric bupivacaine in patients undergoing lower limb orthopedic surgery. The primary objectives of this study were to evaluate and compare the effects of clonidine and fentanyl on time of request of first dose of rescue analgesic. Secondary objectives were to compare the effects of clonidine and fentanyl on time of onset and duration of sensory and motor block, hemodynamic status, and side effects.
This is a prospective and observational study was conducted in the Department of Anaesthesia, Shadan Institute of Medical Sciences Teaching Hospital & Research Centre.
Inclusion criteria were 150–195 cm height and 50–120 kg weight. Patients were excluded if they had conditions that preclude spinal anaesthesia, had a psychiatric disorder, had chronic pain, were on antihypertensive medication or when they were unable to communicate in the Local language.
Written informed consent was obtained from all patients. To allow for sufficient time for informed consent, the patients were provided with written information at the outpatient preoperative evaluation clinic a few days before the actual operation. Before induction of spinal anaesthesia, all patients received an i.v. infusion of Ringer’s lactate (1500 ml) or normal saline and standard intraoperative monitoring was used [ECG, pulse oximetry and non-invasive blood pressure (NIBP)].
Patients were randomly allocated to receive spinal anaesthesia using either bupivacaine 0.5% (2.2 ml) heavy with 0.5 ml normal saline 0.9% (total 2.7 ml) (Group B) or bupivacaine 0.5% (2.2 ml) heavy with clonidine (75 μg) in 0.5 ml normal saline 0.9% (total 2.7 ml) (Group BC). Spinal anaesthesia was performed using a 25-gauge pencil point needle with the patient in the sitting position at the lumbar 3–4 interspace.
Immediately after the intrathecal injection, ephedrine (10 mg) was administered by i.v. in both groups to prevent hypotension. Between the intrathecal injection and the delivery of the child, NIBP was measured every minute and every 3 min thereafter until the end of the procedure. Any subsequent decrease in mean arterial pressure (MAP) of >20% from baseline was treated with an extra dose of 5 mg i.v. ephedrine. If the patient complained of insufficient intraoperative analgesia, alfentanil was administered by i.v. in incremental doses of 250 μg. All recorded physiological variables and intraoperative medications were entered in a case record form. The Apgar scores of the newborn were recorded as usual at 1 and 5 min after birth. Umbilical cord blood gas analysis was routinely performed.
Starting at the end of the Caesarean section (i.e. just before leaving the operating room), each patient received acetaminophen (1000 mg) rectally every 6 h. Immediately after the operation the patient was instructed in the use of an i.v. patient-controlled analgesia (PCA) system (Gemstar, ABBOTT Laboratories) for self-administration of i.v. morphine. The PCA was set with a bolus dose of 1 mg morphine and a lockout interval of 10 min. There was no continuous background infusion. If a patient rated her pain more than 4 on a visual analogue scale (VAS) slide ruler for pain during the recovery period of 60 min, she received a loading dose of morphine (5 mg) by i.v. This dose was repeated once if the VAS did not decrease below 4 within 20 min. The number of demands (D), the number of morphine boluses (MB) the patient actually received (i.e. honoured requests) and the total amount of morphine consumed (TMC) during 24 h after the operation were recorded.
Postoperative assessments were performed 1 h after the operation in the recovery room (T1), and at 24 (plus or minus 2 h) postoperatively (T2) on the ward. At each assessment VAS scores were recorded on a 11-point scale using a 10 cm VAS slide ruler. The patient was asked to rate her maximal experienced pain during the first postoperative day (VASmax). In addition, we asked for the occurrence of nausea, vomiting and pruritus during the first postoperative day at T2 and recorded them. The level of sedation was recorded using the 5-level observer’s assessment of alertness/sedation scale (OAA/S scale) at both assessment times.66 In this scale responsiveness, speech, facial expression and glance are judged with a maximum score level of 5 points for each item.
The primary outcome was the total morphine consumption 24 h after surgery (TMC). Secondary outcomes were the duration of postoperative analgesia in minutes (time to first analgesic request), postoperative pain scores, block regression at T1 (any sign of regression, i.e. could the patient move any muscle in the lower extremities), possible clonidine side-effects (total amount of ephedrine needed to keep the MAP within a range of 20% from baseline and sedation), the need for alfentanil during surgery, morphine side-effects (pruritus, nausea and vomiting) and side-effects in the newborn (Apgar scores and umbilical cord blood gas analysis).
The study medication supplement, clonidine or normal saline, was packed in labelled boxes at the hospital pharmacy and stored in the refrigerator adjacent to the operating room where the surgery would take place. Every vial and box was labelled with a randomization number according to a computer generated random number list. The hospital pharmacy was not able to repackage the yellow colour coded glass ampoules of clonidine (Boehringer Ingelheim) into unlabelled new glass ampoules, as there was uncertainty regarding the stability of the medication after resterilization. Because the vials containing the study medication therefore were recognizable, the study medication was prepared by a non-involved nurse under sterile conditions.
SPSS release 12.0.1. was used for statistical analyses. An intention to treat analysis was planned. Data are presented as means and standard deviations (sd) or as counts with percentages. To estimate differences in normally distributed continuous outcome variables, the Students' t-test for independent samples was used. Outcomes were reported as a mean difference (MD) with 95% confidence interval (95% CI). CIs not including zero were considered statistically significant. For time-based data, a Kaplan–Meier survival analysis was done. For binary outcomes, odds ratios (OR) were used with 95% CI. For outcomes with a high occurrence rate we used risk ratios (RR) instead of ORs. CIs not including unity were considered statistically significant.
Table 1: Age distribution
Age |
Sex |
Total |
|
Female |
Male |
||
15-25 |
0 |
8 |
8 |
26-35 |
7 |
13 |
20 |
36-45 |
15 |
6 |
21 |
46-55 |
8 |
5 |
13 |
>55 |
3 |
5 |
8 |
Total |
33 |
37 |
70 |
Majority of patients in the both the groups belonged to the group 26 to 55 years. Samples were age matched.
Table 2: Sex distribution
Sex |
Number of patients |
Percentage |
Male |
37 |
52.8 |
Female |
33 |
47.2 |
Total |
70 |
100.0 |
The number of males and females in each group was same (n=30) and samples in both groups were matched with respect to sex.
Table 3: Height distribution
Height (cms) |
Female |
Male |
Total |
160-165 |
14 |
7 |
21 |
166-170 |
16 |
9 |
25 |
171-175 |
3 |
16 |
19 |
>176 |
0 |
5 |
5 |
Total |
33 |
37 |
70 |
Majority of female patients in the both the groups belonged to the group 160 to 170 cms and males 171 to 175 cms, Samples were height matched.
Table 4: Type of surgery
Type of surgery |
Frequency |
Percent |
Gynaecology |
28 |
40.0 |
Lower Abdominal Surgery |
19 |
27.1 |
Lower Limb Surgery |
23 |
32.8 |
The majority of surgeries fall under the gynaecology category. Lower abdominal and lower limb surgeries are less common, with lower abdominal surgeries being the least frequent. This breakdown indicates a higher demand or prevalence for gynaecological procedures compared to the others.
Table 5: Sample Demographics (Clinical Profile)
Parameter |
Bupivacaine + Clonidine |
Bupivacaine + Fentanyl |
ASA Class I (%) |
(e.g., 70%) |
(e.g., 65%) |
ASA Class II (%) |
(e.g., 30%) |
(e.g., 35%) |
Table 6: Outcomes and Side Effects
Parameter |
Bupivacaine + Clonidine |
Bupivacaine + Fentanyl |
Onset Time (minutes) |
(e.g., 5 ± 1) |
(e.g., 4.5 ± 0.8) |
Duration of Analgesia |
(e.g., 300 ± 15 min) |
(e.g., 250 ± 20 min) |
Incidence of Hypotension |
(e.g., 15%) |
(e.g., 10%) |
Incidence of Bradycardia |
(e.g., 12%) |
(e.g., 8%) |
Pruritus (%) |
(e.g., 0%) |
(e.g., 20%) |
Nausea (%) |
(e.g., 5%) |
(e.g., 10%) |
Bupivacaine is considered the gold standard longacting local anesthesia for most regional procedures,[4] especially for intrathecal administration, is well tolerated and provides effective anesthesia for lower abdominal surgeries.[5] Adverse effects associated with the use of high volume of drugs are reduced by using low doses of local anesthetics with the addition of an adjuvant drugs.[6] Intrathecal opioids like fentanyl and tramadol enhance sensory block without prolonging motor and sympathetic block. Among them, fentanyl has rapid onset of action, binds strongly to plasma proteins and potentiates the afferent sensory blockade and facilitates reduction in the dose of local anesthetics.[7] Intrathecal opioids also produce a well documented synergistic effect, thus intensifying motor and sympathetic blockades, and enable successful anesthesia with the use of a low dose local anesthetic resulting in more stable hemodynamics.[8]
However, central neuraxial opioids are known for their side effects such as pruritus, urinary retention and potentially catastrophic delayed respiratory depression, which has led us to compare fentanyl with an otheradjuvant, which would be equally efficacious and devoid of these side effects.[9] Clonidine is a centrally acting selective partial α2 adrenergic agonist (220:1 α2 to α1) and provides dose-dependent analgesia. Clonidine is known for its synergism with local anesthetics but has side effects such as hypotension, bradycardia and sedation when given at higher dose. Intrathecal clonidine is demonstrated to potentiate the effect of subarachnoid block as well as reduce the local anesthetic agent requirement. Intrathecal clonidine also offers prolonged postoperative analgesia, reduces shivering associated with subarachnoid block and is devoid of side effects associated with intrathecal opioids.[10]
In our study, we found that both the drugs are effective as an adjuvant to intrathecal bupivacaine in prolonging the time of first rescue analgesia(Tpra) although it was significantly higher in Group BC (336.4 ± 35.44minutes) than in Group BF (284.2 ± 26.43tminutes) than in Similar study was conducted by Bajwaetal using 50 µg of clonidine and 25µg of fentanyl with hyperbaric bupivacaine intrathecally and found that duration of analgesia was significantly longer with clonidine than fentanyl.[11]However, the drug concentration used in our study was 30µg clonidine. Gecaj-Gashi et al, [12] also compared low dose 25µg clonidine in co-administration with 0.5% isobaric bupivacaine 7.5mg intrathecally, with increased regression of motor and sensory block, duration of postoperative analgesia in patient scheduled for transurethral surgical procedures. In our study, duration of peak sensory and weaning of motor blockade and two segment regression was significantly prolonged in Group BC compared to Group BF with statistical significant difference. The duration of postoperative analgesia was also prolonged in Group BC compared to Group BF and was statistically significant.
They reported that intrathecal addition of 25μg fentanyl to bupivacaine provides good analgesia with lesser sedation and concluded that fentanyl is a better option when sedation is not desirable. However intrathecal addition of 60μg clonidine to bupivacaine provided longer duration of postoperative analgesia and more sedation than 25μg of fentanyl and preferred option when sedation is acceptable or required. Our study which used 30µg clonidine has proved to be providing longer duration of analgesia and with similar hemodynamic characteristics with lesser dose compared to the study by Shidhaya et al. In a study analyzed by Benyamin et al, it was noted that the use of opioid was commonly associated with side effects such as nausea and vomiting, even with low dose fentanyl added to Bupivacaine in spinal anesthesia.[13-16]
Similarly in our study, Group BF exhibited more side effect such as nausea, vomiting as compared with Group BC. Intrathecal fentanyl frequently produces pruritus which is unfortunately difficult to prevent even by prophylactic medication.[17]The incidence of pruritis has been reported to be as high as 52% when 50 mcg fentanylwas used as adjuvant to 0.125% bupivacaine.[18]Few studies had reported high incidence of pruritus in fentanyl group compared to clonidine group.[19]However, in our study, 25µgfentanyl added to 0.5% hyperbaric bupivacaine reported no pruritus. Bajwa et al, [11]did not observe bradycardia by addition of clonidine even up to 45µg in 9mg of bupivacaine. Similar hemodynamic stability wasobserved by Agrawal et al while using 12.5 µg and 25 µg of intrathecal fentanyl.[19,20]
Gurpreet Singh et al, [13] and Sidharth Sabran Routrayet al, [21] in their studies also observed no significant differences in hemodynamic characteristics in the study groups. We also found similar results regarding hemodynamic characterstics. Initial fall in mean arterial pressure after spinal anaesthesia can be explained by the sympathetic blockade and vasodilatation. Adequate preloading prevented significant hypotension and bradycardia. Hemodynamic findings have been supported by study conducted by Agarwal et al, [20] who reported that there was no significant difference in fall of systolic blood pressure using clonidine as an adjuvant with bupivacaine. In our study also, no statistically significant differences was found as far as mean blood pressure was concerned.
Addition of 50 µg clonidine to intrathecal bupivacaine offers longer duration of postoperative analgesia than 25 µg of fentanyl but with higher sedation. Both the drugs offer similar surgical conditions and prolongs postoperative analgesia (clonidine more than fentanyl), so we suggest fentanyl as better choice when sedation is not desirable and clonidine is recommended where sedation is acceptable.
The administration of local anaesthetics in combination with opioids intrathecally is an established technique for managing postoperative pain following abdominal, pelvic, thoracic or orthopaedic procedures on lower extremities. Local anaesthetics with opioids demonstrate significant synergy. They provide excellent analgesia with fewer drug requirements and decreased side effects