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Table of Contents  
Year : 2018  |  Volume : 12  |  Issue : 4  |  Page : 848-854  

Comparison of efficacy of intra-articular plain bupivacaine and bupivacaine with adjuvants (dexmedetomidine and magnesium sulfate) for postoperative analgesia in arthroscopic knee surgeries: A prospective, randomized controlled trial

1 Department of Anesthesia and Critical Care, St John's Medical College and Hospital, Bengaluru, Karnataka, India
2 Department of Orthopedics, Division of Arthroscopy and Sports Surgery, St John's Medical College and Hospital, Bengaluru, Karnataka, India
3 Department of Intensive Care Unit, Columbia Asia Hospital, Bengaluru, Karnataka, India
4 Department of Biostatistics, St John's Medical College and Hospital, Bengaluru, Karnataka, India

Date of Web Publication18-Dec-2018

Correspondence Address:
Dr. Surbhi Gupta
Department of Anesthesia and Critical Care, St John's Medical College and Hospital, Bengaluru - 560 034, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aer.AER_153_18

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Context: Intra-articular (IA) bupivacaine and adjuvants are used in multimodal analgesia for knee arthroscopy. Aims: To evaluate the efficacy of IA plain bupivacaine and bupivacaine with adjuvants (dexmedetomidine and magnesium [Mg] sulfate) for postoperative analgesia in knee arthroscopy. Settings and Design: This was a randomized controlled study in a tertiary care hospital. Methodology: Fifty-four patients were randomly allocated to receive 20 ml of study drug, 0.25% bupivacaine (Group B), 0.25% bupivacaine with 0.5 μg/kg of dexmedetomidine (Group D), and 0.25% bupivacaine with 10 mg/kg of Mg sulfate (Group M). Duration of analgesia, visual analog score for pain at rest (VAS-R) and movement (VAS-M), and number of times rescue analgesics were given in the first 24 h of postoperative period were assessed. Vital parameters and any side effects of the drugs were also noted at immediate (0, 5, 10, 15, and 30 min, 1 h) and late postoperative period (2, 4, 6, 12 and 24 h). Results: Duration of analgesia was prolonged in bupivacaine-dexmedetomidine and bupivacaine-Mg sulphate groups as compared to bupivacaine alone (5.97 ± 1.76 h, 13.44 ± 7.87 h, and 14.61 ± 8.83 h in Groups B, D, and M, respectively; P = 0.001). The VAS-R and VAS-M were less with Group D and Group M compared to Group B (P = 0.002 in VAS-R and P = 0.004 in VAS-M). The number of times rescue analgesic used was more in the Group B (2.06 ± 0.8, 0.94 ± 0.8, and 0.89 ± 0.9 in Groups B, D, and M, respectively; P < 0.001). The hemodynamic parameters were comparable and no side effects were noted among the three groups. Conclusion: IA bupivacaine with adjuvants prolongs duration and improves quality of postoperative analgesia as compared to bupivacaine alone.

Keywords: Bupivacaine, dexmedetomidine, intra-articular, knee arthroscopy, magnesium sulfate, postoperative analgesia

How to cite this article:
Devi M M, Gupta S, Amaravathi R, Udupa S, Hegde A, Ghosh S. Comparison of efficacy of intra-articular plain bupivacaine and bupivacaine with adjuvants (dexmedetomidine and magnesium sulfate) for postoperative analgesia in arthroscopic knee surgeries: A prospective, randomized controlled trial. Anesth Essays Res 2018;12:848-54

How to cite this URL:
Devi M M, Gupta S, Amaravathi R, Udupa S, Hegde A, Ghosh S. Comparison of efficacy of intra-articular plain bupivacaine and bupivacaine with adjuvants (dexmedetomidine and magnesium sulfate) for postoperative analgesia in arthroscopic knee surgeries: A prospective, randomized controlled trial. Anesth Essays Res [serial online] 2018 [cited 2019 Jun 18];12:848-54. Available from:

   Introduction Top

Arthroscopic knee surgeries are commonly performed for various diagnostic and therapeutic purposes. They are associated with variable postoperative pain. Adequate pain relief is a prerequisite for early mobilization, rehabilitation, and discharge of these patients. Acute postoperative pain management remains a challenge despite multimodal analgesic techniques. Several strategies have been tried to achieve optimal analgesia in these patients such as systemic medication with narcotics, nonsteroidal anti-inflammatory drugs, neuraxial analgesia (spinal/epidural), peripheral nerve blocks, intravenous (i.v.) patient-controlled analgesia, and use of periarticular (subcutaneous, intra-articular [IA]) local anesthetic infiltration.[1],[2]

A number of studies have been done to evaluate the efficacy of various IA drugs. These include local anesthetics (lignocaine, bupivacaine, ropivacaine, levobupivacaine), opioids (morphine, fentanyl, sufentanil, and pethidine), clonidine, dexmedetomidine, magnesium (Mg), ketorolac, tramadol, and neostigmine.[3],[4],[5],[6] Each has its own limitations such as short duration of action, restricted availability in the wards, and need for stringent monitoring for any side effects of the drug. Optimal modality would be to provide excellent analgesia with minimal side effects and lower opioid use and enhance rehabilitation. Systematic review and meta-analysis are available for IA use of bupivacaine, dexmedetomidine, and Mg sulfate in knee arthroscopy.[4],[5],[6] We chose to use IA bupivacaine (0.25%) and compare it with adjuvants, dexmedetomidine (0.5 μg/kg) and Mg sulfate (10 mg/kg), for postoperative analgesia. We hypothesized that the drug combination (bupivacaine with its adjuvants) will provide better postoperative analgesia, rehabilitation profile, and lessen complications in patients undergoing knee arthroscopy.

   Methodology Top

This prospective, double-blind, randomized controlled study was conducted from November 2015 to November 2017 in a tertiary care hospital. The study protocol was approved by the Institutional Review Board and was registered at (CTRI/2017/08/009502). Based on the pilot study and to observe a difference of at least 150 min in the time taken for the request of rescue analgesia between the groups, with 80% power and 5% level of significance, the sample size was estimated as 18 in each group [Flowchart 1].

Fifty four American Society of Anesthesiologists (ASA) Physical Status Classes I and II subjects aged 18–60 years of either sex and posted for elective knee arthroscopy under spinal anesthesia were recruited for the study. Excluded from the study were subjects with body mass index >35, allergies to any of the study drugs, known psychiatric illness, hepatic or renal abnormality, pregnant and lactating mothers, patients on long-term analgesic therapy, and any intraoperative conversion to general anesthesia (GA).

Preanesthetic check (PAC) was done, and informed consent was obtained from all the subjects. Randomization was done via computer-generated table, and opaque-sealed envelope was used for allocation. The study subjects were categorized into one of the three groups – Group B: 20 ml of bupivacaine 0.25%, Group D: 20 ml of bupivacaine 0.25% with dexmedetomidine (0.5 μg/kg), and Group M: 20 ml of bupivacaine 0.25% with Mg sulfate (10 mg/kg). Visual analog score (VAS) (0–10) was explained to the patient during the PAC. Demographic details (age, sex, weight, height, and ASA physical status) were noted. As a standard practice, the patients were fasted for 6 h and premedicated with tablet alprazolam 0.5 mg and tablet pantoprazole 40 mg at night prior and on the morning of the surgery.

In the operation theater, the standard routine monitoring was electrocardiography, noninvasive blood pressure, and pulse oximetry. i.v. access was secured, and balanced salt solution started. Spinal anesthesia was given with 3.5 cc of 0.5% heavy bupivacaine at L3–4 interspace via 25G Quincke spinal needle with patient in the sitting position following which the patient was placed supine with 30° head up. Surgery was performed after tourniquet inflation. At the end of surgery and before skin closure, 20 ml of the study drug was administered into the joint space by the operating surgeon. The tourniquet was kept inflated for further 15 min after the study drug injection and then deflated.

The time of injection of study drug was considered as time 0. Heart rate (HR), systolic blood pressure (BP), diastolic BP, mean arterial BP, pulse oximetry (SpO2), respiratory rate, VAS at rest (VAS-R – neutral position of the knee) and movement (VAS-M – flexion and extension of the knee), and Ramsay sedation score were noted at 0, 5, 10, 15, and 30 min and 1, 2, 4, 6, 12, and 24 h after injection of the study drug.

As a standard practice, all subjects received routine analgesics with oral paracetamol 1 g 8th h. The first dose of this drug was given as soon as the patient reached the ward. Rescue analgesia (moderate pain when VAS-R is >4) was provided by i.v. tramadol 1 mg/kg.

The primary outcome was to assess the duration of analgesia (time to request for first rescue analgesia) in the immediate 24 h of the postoperative period. The secondary outcome was to note the number of times the rescue analgesics were given; VAS-R and VAS-M; and any side effects of the drugs such as bradycardia (HR <20% of baseline), hypotension (BP <25% of baseline), respiratory depression, sedation, pruritis, and nausea/vomiting. The data were tabulated in the excel sheet and analyzed for statistical significance using R statistical software version 3.5.0 (R Core team 2018- https ://

Statistical methods

The data were summarized by mean and standard deviation for normally distributed continuous variables else by median and 25th and 75th percentiles. Counts and percentages were reported for the categorical variables. Analysis of variance or Kruskal–Wallis test was used to compare the time taken for the rescue analgesic between the three groups of intervention. Post hoc comparisons were made using the Tukey's HSD test. Chi-square analysis was done for categorical data. Repeated-measure ANOVA was used to compare the vital parameters between the three groups over time. P < 0.05 was considered statistically significant.

   Results Top

The demographic profile (age, sex, height, weight, and ASA physical status) was comparable [Table 1] in all three groups. The duration of analgesia was prolonged in Group D (13.44 ± 7.87 h) and Group M (14.61 ± 8.83 h) when compared to Group B (5.97 ± 1.76 h) and showed significant statistical difference [Table 2], P = 0.001]. The VAS-R and VAS-M were less with adjuvants and statistically significant compared to bupivacaine alone [[Figure 1], P = 0.002 in VAS-R and P = 0.004 in VAS-M]. However, VAS was similar in both Group D and Group M (P = 0.92 for VAS-R and P = 0.96 for VAS-M). The number of times the rescue analgesics were given was higher in the control group when compared to the ones who had received adjuvants and was statistically significant [[Table 2], P < 0.001]. The intergroup difference of post hoc analysis is depicted in [Figure 2]. The hemodynamic parameters were comparable in the three groups and did not show any statistical significance [Table 3]. There were no side effects in any intervention group.
Table 1 : Demographic profile between the groups

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Table 2 : Assessment of quality of analgesia

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Figure 1: Visual analog score at rest and movement between the groups in the late postoperative period

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Figure 2: Post hoc analysis for quality of analgesia between the groups

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Table 3: Vital parameters between the groups

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   Discussion Top

Surgical excision and resection in knee arthroscopy produce postoperative pain which is caused by irritation of free nerve ending of synovial tissue, anterior fat pad, and joint capsule.[7] Multimodal analgesia has been used for postoperative pain relief. Relative efficacy of available analgesic modalities to measure clinically important outcomes (pain scores, opioid consumption, rehabilitation profile, quality of recovery, and complications) remains unknown.[1] IA analgesic agents are used as a simple and cost-effective approach. The IA route acts on peripheral receptors and provides analgesia locally with minimal systemic side effects. The local tissue binding to receptors can be increased, thereby enhancing the analgesic effect when there is a time interval between IA injection and tourniquet release.[8] Slower rate of absorption through poorly vascular IA surface decreases the amount of rescue medication.[3]

Local anesthetics such as bupivacaine, ropivacaine, and mepivacaine, exert chondrotoxicity by reducing chondrocyte viability and therefore are a concern in knee arthroscopy surgeries.[9] The incidence of chondrolysis following IA administration of bupivacaine in clinical practice seems to be low or possibly underreported.[10] Given equal efficacy for pain control after arthroscopic knee surgery across doses and a dose–response relationship for chondrotoxic effects, meta-analysis showed low dose of IA 50 mg bupivacaine is potentially the least harmful strategy.[4]

Bupivacaine is usually combined with adjuvants (opioids, neostigmine, Mg, tramadol, ketorolac, clonidine, and dexmedetomidine) to provide prolonged postoperative analgesia. Sun et al. conducted a systematic review and meta-analysis involving 1560 patients in 28 trials who underwent arthroscopic knee surgery.[4] Meta-regression and subgroup analyses were carried out to assess the effects of various treatment factors on efficacy and to evaluate the dose–response relationship of bupivacaine. VAS scores at 2, 4, 6, 12, and 24 h postoperatively were significantly lower, the number of patients requiring supplementary analgesia was lesser, and the time to first request for analgesia was longer in the IA bupivacaine group. They concluded that the use of single administration IA bupivacaine is effective for postoperative pain management in patients undergoing arthroscopic knee surgery.

Dexmedetomidine, a highly selective α2 adrenoceptor agonist, binding 8 times more avidly than clonidine; when used in systemic route provides anxiolysis, sedation, sympatholytic, antihypertensive, anesthesia sparing effects, and analgesia. The analgesic mechanism of this drug when given intra-articularly is not clearly defined, it may be similar to IA clonidine. It may act on presynaptic α2 adrenergic receptors and inhibit the release of norepinephrine at peripheral afferent nociceptors.[11] Local anesthetic effects produced may be related to inhibition of conduction of nerve signals through C and Aδ fibers. It may stimulate the release of encephalin-like substance at peripheral sites.[12]

Our study supports a better quality of analgesia with IA dexmedetomidine 0.5 μg/kg when compared to IA bupivacaine alone. The duration of analgesia was prolonged (13.44 ± 7.87 h in Group D vs. 5.97 ± 1.76 h in Group B; P < 0.001) and pain scores at rest and movement were relatively less (post hoc analysis showing P < 0.001 for VAS-R and P < 0.05 for VAS-M) in IA dexmedetomidine group. The number of times the rescue analgesics were given was lesser in Group D (Group D 0.94 ± 0.8 vs. Group B 2.06 ± 0.8; P = 0.001). Enhanced postoperative analgesia by IA dexmedetomidine in arthroscopic knee surgeries has been supported by various studies. Alipour et al. showed that IA dexmedetomidine 1 μg/kg prolonged postoperative analgesia when compared to placebo (21.97 ± 6.3 h vs. 9.26 ± 10.1 h, P < 0.001) and reduced the need for narcotics and analgesics in the postoperative period.[13] In another study, time to first request of analgesia with IA dexmedetomidine was 650 ± 156 min, unlike fentanyl which was 204.64 ± 36.48 min.[14] Manuar et al. found superior analgesic efficacy with IA 0.75% ropivacaine 10 ml when compared with IA fentanyl 50 μg and IA dexmedetomidine 100 μg alone (380.61 ± 22.97 min vs. 326.82 ± 17.13 min and 244.09 ± 20.09 min, respectively).[2] However, in the postoperative period, as adjuvant with 0.25% bupivacaine, IA dexmedetomidine (1 μg/kg) and IA dexamethasone (8 mg) enhanced the quality and duration of postoperative analgesia and decreased analgesic consumption.[15] Agarwal et al. also found that mean duration of analgesia was prolonged in IA dexmedetomidine group compared to control group (460.3 ± 38.95 min in dexmedetomidine vs. 370.27 ± 58.8 min in saline group) though lesser than morphine group (576.2 ± 67.09 min) when these adjuvants were added with 0.25% levobupivacaine in arthroscopic knee surgeries. The effect of analgesics and narcotics in the joint is due to existence of peripheral receptors in the joint and activation of opioid receptors at peripheral nerve endings.[16] Increasing the IA dose of dexmedetomidine to 2 μg/kg with 0.2% ropivacaine provided superior analgesic efficacy (duration of 757.30 ± 207.68 min, P < 0.05), better patient compliance, and no serious adverse effects, than with 1 μg/kg of dexmedetomidine with ropivacaine (433.2 ± 54.3 min) and plain ropivacaine (311.80 ± 61.56 min).[17] Meta-analysis also showed that dexmedetomidine intervention was associated with significantly decreased pain scores (standard mean difference = 0.84; 95% confidence interval [CI] = 1.24–0.44; P < 0.0001), reduced postoperative diclofenac sodium consumption (standard mean difference = 1.76; 95% CI = 3.32–0.21; P = 0.03), and improved duration of analgesic effect (standard mean difference = 1.78; 95% CI = 0.56–3.00; P = 0.004).[4]

Different routes and regimens of dexmedetomidine for postoperative analgesia have been evaluated. Al-Metwalli et al. in their study compared 1 μg/kg of dexmedetomidine in IA and i.v. route and found that IA route enhanced postoperative pain relief (6 h IA vs. 1 h in i.v.), reduced the need for postoperative analgesia, and prolonged the time to first request of analgesia (IA 312 ± 120.7 min vs. i.v. 102.1 ± 54.4 min).[7] Transient sedation and reduction in HR and mean arterial pressure were noted in the i.v. group. The lack of systemic effects in IA group was related to the use of small dose and slow absorption through poorly vascular IA surface.[3] Modest analgesic effect in i.v. route with side effects such as hypertension and bradycardia may restrict the use of large bolus dose.[18] We did not have any adverse effects with dexmedetomidine. Our results were similar to the meta-analysis which showed no increase in hypotension (Risk Ratio [RR] = 0.93; 95% CI = 0.14–5.92; P = 0.94), bradycardia (RR = 4.93; 95% CI = 0.91–26.58; P = 0.06), and nausea and vomiting (RR = 1.96; 95% CI = 0.31–12.58; P = 0.48).[5]

Dexmedetomidine 2.5 μg/kg when used as a premedicant via buccal route for knee arthroscopy under spinal anesthesia, provided equal level of anxiolysis, sedation, and more evident analgesia than intramuscular (IM) dexmedetomidine (buccal 321.3 ± 140.4 min vs. 302.1 ± 120.5 min with IM).[19] Ismail et al. compared 5 μg of intrathecal (IT) dexmedetomidine to IA route (1 μg/kg) as an adjunct to bupivacaine in knee arthroscopy. Both IA and IT route had a role in attenuation of inflammatory mediators (C-reactive protein) and surgical stress response. The analgesia provided by IA was superior to IT route (mean time of first analgesic request was 413 ± 34 min in IA vs. 359 ± 30 min in IT).[20]

N-methyl D-aspartate (NMDA) receptors are located centrally and peripherally in the joints, muscles, and skin. They affect central nociceptive transmission, modulation, and sensitization of acute pain states.[21] Mg is an efficacious adjunct to postoperative analgesia when used i.v., IT, and epidural routes. IA route of Mg has been confirmed in meta-analysis and various orthopedic procedures.[6],[21],[22] It exerts its antinociceptive effect by blocking NMDA receptors and also decreases the entry of extracellular calcium into cells, thereby exhibiting chondrocyte protective effect too.[23] No defined dose of Mg as IA analgesic agent is mentioned in literature, but the median effective concentration of Mg to block NMDA receptor is 400 and 600 μM.[21] Even low concentration of Mg (500 mg) is efficient for pain relief in knee arthroscopy;[22] hence, we standardized the dose to 10 mg/kg in our study.

Bondok and Abd El-Hady found a prolonged duration of analgesia with Mg 500 mg (667 ± 198 min) compared to saline group (49 ± 13 min).[24] Elsharnouby et al. showed that the group receiving IA Mg and bupivacaine had reduced postoperative pain scores (VAS-R and VAS-M; P < 0.0001), a longer analgesic duration (P < 0.0001), and lower 24 h analgesic use compared with the other groups receiving IA bupivacaine, Mg, or saline alone.[23] No side effects were detected from IA injection of Mg and bupivacaine during the 24-h period after surgery. The analgesic effect was by both pharmacodynamics (delayed uptake of bupivacaine from the joint) and pharmacokinetics (antagonism of NMDA receptors and inhibitory effect for calcium channels) of the drug.[24] Mg along with levobupivacaine (1.5 g Mg with 50 mg levobupivacaine) when compared to levobupivacaine (100 mg) alone has shown increased efficacy by prolonging duration of analgesia, reduced narcotic consumption and with no side effects in the postoperative period. Both VAS-R and VAS-M were significantly lower in the early postoperative period (P < 0.01). The synergistic action of Mg with levobupivacaine and anti-inflammatory effect of Mg may have contributed to the quality of analgesia with the combination.[25] Farouk and Aly compared IA Mg (150 mg) and morphine (2 mg) with bupivacaine when used alone and in combination after arthroscopic meniscectomy.[26] The duration to first analgesic request was significantly longer with morphine, Mg, and bupivacaine combination (947 ± 194 min) than Mg–bupivacaine combination (610 ± 154 min), bupivacaine–morphine combination (645 ± 168 min), or bupivacaine (320 ± 105 min) alone. Thus, with synergistic interaction via central and peripheral mechanisms, Mg potentiates opioid analgesic effects. The analgesic effects are maintained with Mg whether it is hyperosmolar (550 mOsm/L) or isotonic (320 mOsm/l) solution.[24],[27] Mg 4% (800 mg, 320 mOsm/L) was compared with equivalent volume of 0.5% bupivacaine in outpatient knee arthroscopy meniscectomy procedures. The patients treated with Mg had longer median duration of postoperative analgesia (528 min vs. 317 min, P < 0.0001).[27] The postoperative pain score (mean difference − 0.41, 95% CI − 0.87–0.04, P = 0.07) and time interval for the first analgesic request (mean difference −6.25, 95% CI 5.22–7.29, P < 0.00001) were significant in the meta-analysis too.[6] We noted similar beneficial effects of IA Mg with prolonged postoperative analgesia (Group M 14.61 ± 8.83 vs. Group B 5.97 ± 1.76 h, P < 0.001). VAS-R (P < 0.001) and VAS-M (P < 0.001) were also significantly less with Mg and bupivacaine combination than with bupivacaine alone. No side effects of bradycardia, hypotension, nausea, vomiting, pruritis, or sedation were noted in our study.

To the best of our knowledge, it is the first time a comparison has been done between the IA adjuvants, dexmedetomidine (0.5 μg/kg) and Mg (10 mg/kg). Our study showed similar results in duration of analgesia (13.44 ± 7.87 h in Group D and 14.61 ± 8.83 h in Group M), VAS-R (P = 0.92) and VAS-M (P = 0.96), number of times rescue medications used (0.94 ± 0.8 in Group D and 0.89 ± 0.9 in Group M) for both dexmedetomidine and Mg groups. The post hoc analysis between the two groups did not show any statistical significance (P > 0.5). There are no equipotent doses mentioned in the literature between the two drugs. We have used lower doses and did not have any known side effects of these drugs (bradycardia, hypertension, hypotension, nausea, vomiting, pruritis, or sedation) in our study subjects. The surgeries performed in our study ranged from simple to complex procedures [Table 4]. Duration of surgery was comparable in the three groups and not statistically significant. Majority of the surgeries were completed in <2.5 h.
Table 4: Knee surgeries performed

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While pharmacological interventions in acute pain relief have an important role in patient satisfaction, newer techniques are being established these days. Synovial fluid replacement with sodium hyaluronate following arthroscopic knee surgery conferred statistically significant improvements in pain and function scores compared with bupivacaine in the short term (3–6 weeks).[28]

Further studies are recommended to improve our understanding of the dose and concentration of the drugs on the chondrotoxicity in arthroscopic surgeries. To add more evidence, multicenter studies are warranted to test the plasma concentration of the drugs in various patient population (race, ethnicity, and age). The trend of arthroscopic surgeries toward day care procedures may allow short GA as the mainstay of management. IA analgesic agents injected just before end of surgery in cases done under GA will enable one to know the efficacy of these agents in the immediate postoperative period. In our study, one of the limitations was that VAS-R and VAS-M score of 0 was noted in the first 2 h postoperatively due to the continuing action of spinal anesthesia.

   Conclusion Top

IA bupivacaine with adjuvants (dexmedetomidine 0.5 μg/kg or Mg 10 mg/kg) prolongs duration and improves quality of postoperative analgesia as compared to bupivacaine alone. However, both dexmedetomidine and Mg with bupivacaine are equally efficacious and may be used as an alternative to bupivacaine alone for better pain control in knee arthroscopy surgeries.

Financial support and sponsorship

The study was funded by departmental resources.

Conflicts of interest

There are no conflicts of interest.

   References Top

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  [Figure 1], [Figure 2]

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


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