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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 34  |  Issue : 3  |  Page : 193-198

Comparison of clonidine and fentanyl as adjuvant in femoro-sciatic nerve block for postoperative analgesia – A prospective randomized controlled trial


1 Department of Anaesthesia, IGMC, Shimla, Himachal Pradesh, India
2 Department of Anaesthesia and Intensive Care, PGIMER, Chandigarh, India
3 Department of Orthopaedics, PGIMER, Chandigarh, India

Date of Submission12-Mar-2020
Date of Decision25-Apr-2020
Date of Acceptance12-Jul-2020
Date of Web Publication28-Dec-2020

Correspondence Address:
Dr. Neeru Sahni
Department of Anaesthesia and Intensive Care, PGIMER, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpn.ijpn_35_20

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  Abstract 


Introduction: Arthroscopic anterior cruciate ligament reconstruction (ACLR) is associated with moderate-to-severe postoperative pain which may delay hospital discharge as well as physiotherapy resulting in poor outcome. The aim of our study was to compare the effect of clonidine or fentanyl as adjuvant to bupivacaine in femoro-sciatic nerve block (FSNB) on the duration of pain-free period and requirement of rescue analgesic postoperatively. Materials and Methods: Sixty adult patients undergoing ACLR of the knee joint received subarachnoid block as anesthesia for surgery and FSNB for postoperative analgesia. Patients in Group C (control group) received 40 ml of 0.25% isobaric bupivacaine (20 ml in femoral and sciatic block each), whereas Group F (fentanyl group) received fentanyl (1 μg/kg) and Group CL (clonidine group) received clonidine (1 μg/kg) with 40 ml of 0.25% isobaric bupivacaine. The duration of pain-free period, rescue analgesic consumption, postoperative pain score, sedation levels and adverse effects were monitored along with hemodynamic parameters for 24 h postoperatively. Results: The patients in the clonidine group had longer pain-free period (10.06 ± 3.62 h) as compared to the fentanyl group (7.94 ± 3.62 h) and control group (4.59 ± 1.20 h) (P < 0.001). Postoperative pain scores were higher in the control group at the 4th, 8th, and 12th h and comparable between the fentanyl and clonidine groups. The total amount of rescue analgesic requirement was less in the clonidine group (71.25 ± 16.77 mg) than the fentanyl group (86.25 ± 36.71 mg) and control group (161.20 ± 50.34 mg) (P < 0.001). No clinically significant adverse effects were observed in any group. Conclusion: Clonidine as an adjuvant to bupivacaine in FSNB provides better postoperative analgesia compared to fentanyl by significantly prolonging the pain-free period and decreasing rescue analgesic requirement in postoperative period without any untoward side effect.

Keywords: Anterior cruciate ligament reconstruction, clonidine, femoro-sciatic nerve block, fentanyl, postoperative analgesia


How to cite this article:
Chaudhary UK, Panda N, Bharti N, Sahni N, Gandhi K, Batra YK, Dhillon MS. Comparison of clonidine and fentanyl as adjuvant in femoro-sciatic nerve block for postoperative analgesia – A prospective randomized controlled trial. Indian J Pain 2020;34:193-8

How to cite this URL:
Chaudhary UK, Panda N, Bharti N, Sahni N, Gandhi K, Batra YK, Dhillon MS. Comparison of clonidine and fentanyl as adjuvant in femoro-sciatic nerve block for postoperative analgesia – A prospective randomized controlled trial. Indian J Pain [serial online] 2020 [cited 2021 Apr 12];34:193-8. Available from: https://www.indianjpain.org/text.asp?2020/34/3/193/305144




  Introduction Top


Arthroscopic anterior cruciate ligament reconstruction (ACLR) of the knee joint is a commonly performed procedure resulting in moderate-to-severe postoperative pain leading to prolonged immobility, delayed physiotherapy, and overall poor outcome.[1] Among the various regional anesthetic techniques used to alleviate postoperative pain after arthroscopic ACLR, femoro-sciatic nerve block (FSNB) is associated with fewer side effects but provides limited duration of analgesia.[2] Adjuvants such as epinephrine, opioids, and alpha-2 agonists have been added to local anesthetic agents to prolong the duration of analgesia and improve the quality of FSNB.[3],[4]

Opioids such as fentanyl, sufentanil, and morphine are commonly used to enhance the duration and intensity of peripheral nerve blocks but may be associated with significant side effects such as respiratory depression, pruritus, postoperative nausea and vomiting, and urinary retention.[5] Clonidine, an alpha-2 agonist, has been found to be effective to provide prolonged perioperative analgesia when used as an adjunct to local anesthetics in various peripheral nerve blocks with minimal side effects.[5],[6] Therefore, we planned this study to compare the efficacy and safety of fentanyl (1 μg/kg) and clonidine (1 μg/kg) added to bupivacaine in FSNB for postoperative analgesia in patients undergoing ACLR.


  Materials and Methods Top


This prospective randomized double-blind controlled trial was registered in the Clinical Trials Registry of India (CTRI/2014/05/004612). The study was performed in 18-month duration in orthopedic operating room after ethical committee approval of our institute, and postoperative data collection was done in recovery room and orthopedic ward. All surgeries were performed by a senior surgeon (MSD) using bone-patellar tendon technique, with standard portals, under tourniquet. Total 60 patients between 18 and 60 years of age, belonging to American Society of Anesthesiologists Status I or II, undergoing elective arthroscopic ACLR of the knee joint were enrolled in the study after obtaining written informed consent. Patients with body mass index (BMI) more than 30, infection at the site of block, coagulation disorders, and those unwilling to participate were excluded. Random allocation of patients into three groups was done using a computer-generated random number table, with numbers kept sequentially in opaque-sealed envelopes which were opened just before shifting the patient inside operation room. Patients assigned to Group C (control group) received 40 ml of 0.25% isobaric bupivacaine (20 ml in femoral block and 20 ml in sciatic block), Group F (fentanyl group) received 40 ml of 0.25% isobaric bupivacaine with 1 μg/kg of fentanyl, and Group CL (clonidine group) received 40 ml of 0.25% isobaric bupivacaine with 1 μg/kg of clonidine [Figure 1]. The total volume of drug was 40 ml in each group, and it was prepared by the anesthesiologist not involved in the management of the patients. The anesthesiologist who collected postoperative data, the surgeon, and the patients were also blinded to the group allocation.
Figure 1: CONSORT diagram

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During preanesthesia checkup, the patients were explained about the study protocol and the 11-point Verbal Rating Score (VRS), used for postoperative pain assessment, where 0 was no pain and 10 was worst imaginable pain. In operation room, after establishing standard monitoring and hydration with normal saline (7–8 ml/kg), FSNB was administered under complete aseptic condition. Femoral block was performed in supine position, 1 cm lateral and 1 cm inferior to femoral artery using a 22G, 5 cm needle with the help of peripheral nerve stimulator. The test drug (20 ml) was injected slowly after eliciting quadriceps extension at 0.5 mA current intensity. Sciatic nerve block was performed using classic approach of Labat with patients in lateral position and leg positioned superiorly in Sims' position and flexed at knee.[7] A line was drawn from the posterior superior iliac spine to the greater trochanter of the femur. The second line was drawn from the sacral hiatus to the greater trochanter, and the third line was drawn perpendicular and bisecting the first line. The intersection of the second and third lines was the point of entry of needle for placement of the sciatic nerve block. Using a peripheral nerve stimulator, a 22G 10 cm long needle was advanced until a plantar flexion motor response was elicited at 0.5 mA intensity and 20 ml of study drug solution was injected slowly. The onset of block was assessed as loss of pinprick sensation to a 22G hypodermic needle for both femoral and sciatic nerve distributions every 5 min for 20 min. Hemodynamic parameters such as heart rate (HR), blood pressure (BP), and pulse oximetry were measured regularly and recorded at 5-min intervals.

All patients received subarachnoid block (SAB) at L3–L4 level under aseptic precautions with 3 ml hyperbaric bupivacaine (0.5%) using a 25G spinal needle for intraoperative anesthesia, 20 min after receiving FSNB. The sensory level of SAB was assessed as loss of pinprick sensation above L5–S1 every 5 min after intrathecal injection until maximum level achieved. The motor block was assessed using the Modified Bromage Scale at the same time intervals. The duration of surgery, intraoperative blood loss, and total requirement of blood transfusion were noted. The incidence of intraoperative hypotension and bradycardia was recorded and managed accordingly. The hypotension is defined as a mean arterial pressure <60 mmHg or >25% decrease from baseline value and treated with boluses of 3–6 mg ephedrine. Bradycardia is defined as a pulse rate of <40 beat/min and treated with bolus of 0.6 mg atropine. A single surgeon operated all the cases which provided uniformity of surgical procedure.

Postoperatively, the patients were monitored in postanesthesia care unit or postsurgical ward for vitals, duration of analgesia, pain intensity, and any adverse effect by an anesthesia resident and the sister in-charge. The primary outcome of this study was the duration of pain-free period. The secondary outcomes were postoperative pain scores, rescue analgesic requirement, and any adverse effect. The duration of pain-free period (primary outcome) was defined as the time from the placement of FSNB to the administration of the first bolus of rescue analgesic medication. The participants were asked to rate their pain on VRS at 0, 1, 2, 4, 8, 12, 18, and 24 h in postoperative period. Rescue analgesic in the form of injection diclofenac (75 mg/bolus) was given slow intravenously when VRS was reported more than 3. Total doses of diclofenac used in each group in 24-h postoperative period were recorded and analyzed. The regression of SAB to L5–S1 was assessed at every 30 min by pinprick sensation, and the duration of motor block was assessed using the Modified Bromage Scale till the ability to flex hip joint. Sedation was assessed using the Modified Ramsay Sedation Scale. Any other postoperative complications such as pruritus, respiratory depression, nausea, vomiting, and urinary retention were noted.

Based on a previous study,[4] 19 patients were required in each group to ensure a 30% increase in a pain-free period with an alpha value of 0.05 and power of 80%. We enrolled total sixty patients in anticipation of attrition. Statistical analysis was done using SPSS Inc., Chicago, IL, USA, version 21. Parametric data such as HR and BP were compared and analyzed by one-way analysis of variation and Kruskal–Wallis test, whereas nonparametric data such as VRS and rescue analgesics were analyzed by Mann–Whitney U-test and Chi-square test. Pain-free period was analyzed using survival analysis and Cox regression analysis and was represented by Kaplan–Meier survival graph. P < 0.05 was considered statistically significant.


  Results Top


Patients in the three groups were comparable with regard to age, sex, height, weight, and BMI. The duration of surgery was about 90 min to 2 h in all the groups [Table 1]. The pain-free period was longer in the clonidine group (10.06 ± 3.62 h), followed by fentanyl group (7.94 ± 3.62 h) and control group (4.59 ± 1.20 h). The difference in pain-free period between the three groups was statistically significant (P < 0.001) [Table 2] and [Figure 2]. The requirement of rescue analgesic drug (diclofenac) in postoperative 24 h differs significantly in between the groups (P < 0.001). The requirement was least in the clonidine group (71.25 ± 16.77 mg), less in the fentanyl group (86.25 ± 36.71 mg), and maximum in the control group (161.20 ± 50.34 mg). The difference between the clonidine and fentanyl groups was also statistically significant (P < 0.001) [Table 2].
Table 1: Demographic data

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Table 2: Postoperative analgesia and duration of subarachnoid block

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Figure 2: Pain-free period in different groups depicted in Kaplan–Meier graph

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The duration of sensory block was longer in the clonidine group (5.5 ± 0.70 h) as compared to the fentanyl group (4.19 ± 1.04 h) and control group (3.74 ± 0.63 h) (P < 0.001). The duration of motor blockade was also prolonged in the clonidine group (3.63 ± 0.45 h) and fentanyl group (3.22 ± 0.94 h) as compared to the control group (2.84 ± 0.36 h), although the difference between the clonidine and fentanyl groups was not statistically significant [Table 2]. Postoperative pain scores at rest and movement were higher in the control group at the 4th, 8th, and 12th h and comparable between the fentanyl and clonidine groups [Table 3] and [Table 4].
Table 3: Postoperative pain scores (Verbal Rating Score) at rest

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Table 4: Postoperative pain scores (Verbal Rating Score) on movement

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The intraoperative and postoperative mean arterial pressure was comparable among the groups. Although the HR was lower in the clonidine group as compared to the fentanyl and control groups for up to 4 h postoperatively, this was not clinically significant and did not require any pharmacological intervention. The sedation scores were comparable among the groups [Table 5]. None of the patients had deep sedation. None of the patients had pruritus or respiratory depression. Four patients in the fentanyl group and two in the control group complained of postoperative nausea and vomiting.
Table 5: Postoperative sedation score

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  Discussion Top


SAB is commonly used for lower-limb procedures due to superior level of blockade and cost-effectiveness, but it has the drawback of shorter duration of postoperative analgesia. Perioperative pain management has been a major challenge for anesthesiologists to reduce postoperative morbidity and improve functional recovery after orthopedic surgery. Peripheral nerve block for postoperative analgesia is considered superior to epidural block as it is not associated with serious side effects such as hypotension, urinary retention, and neurological complications, and it also allows early anticoagulant therapy in postoperative period.[8] A meta-analysis by Grape et al.[2] suggested that addition of sciatic nerve block to femoral nerve block has a distinct advantage of significant reduction in consumption of opioid analgesics in postoperative period following total knee arthroplasty as compared to the use of femoral block alone.

In the present study, all our patients had adequate pain relief during postoperative period, and none of the patients required opioids. The addition of 1 μg/kg clonidine to 0.25% bupivacaine in FSNB provided the longest duration (10.06 ± 3.62 h) of postoperative analgesia with least requirement of rescue analgesics. Addition of fentanyl or clonidine in FSNB also prolonged the duration of sensory and motor blocked after spinal anesthesia.

Chaudhary et al.[9] used a similar technique of SAB with FSNB in patients undergoing knee orthopedic surgeries and added clonidine (0.5 μg/kg) or dexmedetomidine (0.5 μg/kg) to 0.125% levobupivacaine. The duration of analgesia in the clonidine group was about 7 h as compared to 10 h in our study. This difference is probably because we used higher doses of clonidine (1 μg/kg).

Clonidine, an alpha-2 adrenergic receptor agonist, is known to prolong the analgesic duration of peripheral nerve blocks, but the exact mechanism of action is still unclear. Literature suggests both mechanisms, vasoconstriction in periphery which is alpha-2 adrenoceptor mediated or centrally mediated analgesia. However, the predominant mechanism seems to be due to inhibition of current that serves the purpose of restoring nerves from hyperpolarized state to resting potential.[10] It has been found that clonidine produces dose-dependent prolongation of postoperative analgesia when used with low concentration (0.125%–0.25%) of local anesthetics in peripheral nerve blocks. In a study by Casati et al.,[6] addition of 1 μg/kg clonidine to 0.75% ropivacaine in FSNB provided only 3-h delay in the first request for pain medication after hallux valgus repair, whereas in another study, 2 μg/kg clonidine added to 0.125% bupivacaine (0.125%) provided about 20 h of postoperative analgesia in pediatric patients undergoing ACLR.[3] The effect of clonidine is less pronounced when used with high concentration of local anesthetics. In a study, conducted by Couture et al.,[11] the authors did not observe a significant difference between pain scores and duration of sensory analgesia with addition of clonidine (1 μg/kg) to combination of bupivacaine (0.5%) and adrenaline (1:200,000) in FSNB in patients undergoing ACLR.

Previous studies have also reported that clonidine provided longer duration of analgesia when used in FSNB as compared to intrathecal or intra-articular route. Tran et al.[3] found superior analgesic effect with addition of clonidine to bupivacaine in FSNB in pediatric patients undergoing arthroscopic ACLR along with fewer side effects as compared to intra-articular administration of combination of bupivacaine-clonidine and morphine. In another study by Sahni et al.,[12] addition of 1 μg/kg clonidine with 0.25% bupivacaine in FSNB along with SAB for knee arthroscopic surgeries provided more prolonged postoperative analgesia as compared to the use of clonidine in the same dose intrathecally or intra-articularly. The duration of pain-free period with the use of clonidine in FSNB in this study was about 9 h which is almost similar to our study.

Fentanyl, a short-acting lipophilic opioid, provides analgesia by acting on opioid receptors in peripheral nerve terminals and prolonging the analgesic effect of local anesthetic drugs. In our study, patients in the fentanyl group also had lower pain scores and reduced rescue analgesic consumption as compared to the control group. Our findings are consistent with the previous study by Karakaya et al.,[13] who also reported a significant increase in the duration of block and postoperative analgesia when 100 μg fentanyl was added to 0.25% bupivacaine in axillary brachial plexus block. In another study, addition of fentanyl even in lesser dose of 75 μg to bupivacaine (0.25%) for supraclavicular brachial plexus block has also been reported to significantly increase the duration of analgesia when compared to bupivacaine alone.[14] None of the studies evaluated the effect of adding fentanyl with bupivacaine in FSNB.

Magistris et al.[15] did not observe any significant difference in the duration of analgesia with addition of fentanyl (1 μg/kg) to ropivacaine (0.75%) in combined sciatic femoral nerve block for hallux valgus reconstruction surgery. Multiple other studies have also failed to show a benefit from perineural use of fentanyl as an adjunct to ropivacaine and lidocaine for prolongation of peripheral nerve blocks. Fentanyl failed to prolong the duration of axillary blocks with ropivacaine[16] or lidocaine plus epinephrine,[17] supraclavicular blocks with mepivacaine plus epinephrine,[18] and sciatic/femoral blocks with ropivacaine.[4] While it is possible that fentanyl may be effective for prolonging peripheral nerve blocks with bupivacaine, the evidence regarding its efficacy is conflicting.[19]

The use of clonidine or fentanyl in doses of 1 μg/kg in our patients caused minimal hemodynamic changes perioperatively. Although the mean HR and systolic BP were lower in the clonidine group as compared to other two groups but the values remained within clinically normal range. Therefore, no patient required any pharmacological intervention for any haemodynamic compromise. The decreased HR returned back to preoperative baseline value around 4 h after administration of clonidine, possibly because of drug metabolism. Erlacher et al.[20] used 150 μg clonidine in brachial plexus block and reported stable hemodynamics throughout the entire study period.

As sedation is a common side effect of the use of adjuvants such as clonidine and fentanyl, we monitored all patients for sedation using the Modified Ramsay Sedation Score. Although patients in the clonidine group had higher sedation scores during perioperative period, this was clinically insignificant, and none of the patients required any airway protection. The other side effects such as pruritus and postoperative nausea and vomiting were not seen in patients receiving clonidine.

The main limitation of this study was the use of nerve stimulation technique to facilitate nerve block. In the present study, the FSNB was administered before SAB due to the use of nerve stimulation technique. With the use of ultrasound-guided technique, the block may have been given after the surgery or with reduced volume of drug. We used low concentration of bupivacaine to avoid toxicity because of high volume of the drug used (40 ml), and SAB was given to provide adequate relaxation during surgery.

We concluded that addition of clonidine (1 μg/kg) as an adjunct to bupivacaine (0.25%) in FSNB prolonged the pain-free period and reduced requirement of rescue analgesic better than fentanyl (1 μg/kg) after ACLR surgery without producing any significant adverse effect.


  Conclusion Top


We concluded that addition of clonidine (1μg/kg) as an adjunct to bupivacaine (0.25%) in FSNB, prolonged the pain free period and reduced requirement of rescue analgesic better than fentanyl (1μg/kg) after ACL reconstruction surgery without producing any significant adverse effect.

Financial support and sponsorship

This study was financially supported by PGIMER, Chandigarh.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Fischer HB, Simanski CJ, Sharp C, Bonnet F, Camu F, Neugebauer EA, et al. A procedure-specific systematic review and consensus recommendations for postoperative analgesia following total knee arthroplasty. Anaesthesia 2008;63:1105-23.  Back to cited text no. 1
    
2.
Grape S, Kirkham KR, Baeriswyl M, Albrecht E. The analgesic efficacy of sciatic nerve block in addition to femoral nerve block in patients undergoing total knee arthroplasty: A systematic review and meta-analysis. Anaesthesia 2016;71:1198-209.  Back to cited text no. 2
    
3.
Tran KM, Ganley TJ, Wells L, Ganesh A, Minger KI, Cucchiaro G. Intraarticular bupivacaine-clonidine-morphine versus femoral-sciatic nerve block in paediatric patients undergoing anterior cruciate ligament reconstruction. Anesth Analg 2005;101:1304-10.  Back to cited text no. 3
    
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Bansal L, Attri JP, Verma P. Lower limb surgeries under combined femoral and sciatic nerve block. Anesth Essays Res 2016;10:432-6.  Back to cited text no. 4
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Kirksey MA, Haskins SC, Cheng J, Liu SS. Local anesthetic peripheral nerve block adjuvants for prolongation of analgesia: A systematic qualitative review. PLoS One 2015;10:e0137312.  Back to cited text no. 5
    
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Casati A, Magistris L, Fanelli G, Beccaria P, Cappelleri G, Aldegheri G, et al. Small-dose clonidine prolongs postoperative analgesia after sciatic-femoral nerve block with 0.75% ropivacaine for foot surgery. Anesth Analg 2000;91:388-92.  Back to cited text no. 6
    
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Labat G. Regional Anesthesia: Its Technic and Clinical Application. Philadelphia: WB Saunders; 1922.  Back to cited text no. 7
    
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Fowler SJ, Symons J, Sabato S, Myles PS. Epidural analgesia compared with peripheral nerve blockade after major knee surgery: A systematic review and meta-analysis of randomized trials. Br J Anaesth 2008;100:154-64.  Back to cited text no. 8
    
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Chaudhary SK, Verma RK, Rana S, Singh J, Gupta B, Singh Y. Ultrasound-guided femoro-sciatic nerve block for post-operative analgesia after below knee orthopaedic surgeries under subarachnoid block: Comparison between clonidine and dexmedetomidine as adjuvants to levobupivacaine. Indian J Anaesth 2016;60:484-90.  Back to cited text no. 9
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Pöpping DM, Elia N, Marret E, Wenk M, Tramèr MR. Clonidine as an adjuvant to local anesthetics for peripheral nerve and plexus blocks: A meta-analysis of randomized trials. Anesthesiology 2009;111:406-15.  Back to cited text no. 10
    
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Couture DJ, Cuniff HM, Maye JP, Pellegrini J. The addition of clonidine to bupivacaine in combined femoral-sciatic nerve block for anterior cruciate ligament reconstruction. AANA J 2004;72:273-8.  Back to cited text no. 11
    
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Sahni N, Panda NB, Jain K, Batra YK, Dhillon MS, Jagannath P. Comparison of different routes of administration of clonidine for analgesia following anterior cruciate ligament repair. J Anaesthesiol Clin Pharmacol 2015;31:491-5.  Back to cited text no. 12
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Karakaya D, Büyükgöz F, Bariş S, Güldoğuş F, Tür A. Addition of fentanyl to bupivacaine prolongs anesthesia and analgesia in axillary brachial plexus block. Reg Anesth Pain Med 2001;26:434-8.  Back to cited text no. 13
    
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Magistris L, Casati A, Albertin A, Deni F, Danelli G, Borghi B, et al. Combined sciatic-femoral nerve block with 0.75% ropivacaine: Effects of adding a systemically inactive dose of fentanyl. Eur J Anaesthesiol 2000;17:348-53.  Back to cited text no. 15
    
16.
Fanelli G, Casati A, Magistris L, Berti M, Albertin A, Scarioni M, et al. Fentanyl does not improve the nerve block characteristics of axillary brachial plexus anaesthesia performed with ropivacaine. Acta Anaesthesiol Scand 2001;45:590-4.  Back to cited text no. 16
    
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Fletcher D, Kuhlman G, Samii K. Addition of fentanyl to 1.5% lidocaine does not increase the success of axillary plexus block. Reg Anesth 1994;19:183-8.  Back to cited text no. 17
    
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Kardash K, Schools A, Concepcion M. Effects of brachial plexus fentanyl on supraclavicular block. A randomized, double-blind study. Reg Anesth 1995;20:311-5.  Back to cited text no. 18
    
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Axelsson K, Gupta A. Local anaesthetic adjuvants: Neuraxial versus peripheral nerve block. Curr Opin Anaesthesiol 2009;22:649-54.  Back to cited text no. 19
    
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Erlacher W, Schuschnig C, Koinig H, Marhofer P, Melischek M, Mayer N, et al. Clonidine as adjuvant for mepivacaine, ropivacaine and bupivacaine in axillary, perivascular brachial plexus block. Can J Anaesth 2001;48:522-5.  Back to cited text no. 20
    


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  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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