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 Table of Contents  
Year : 2019  |  Volume : 33  |  Issue : 3  |  Page : 147-150

Pain relief following arthroscopy: A comparative study of intra-articular bupivacaine, neostigmine, and clonidine

1 Department of Critical Care, Venkateshwar Hospital, New Delhi, India
2 Department of Anaesthesia, Pain and Peri-operative Medicine, Calicut, Kerala, India
3 Ortho and Sports Medicine, BMH, Calicut, Kerala, India

Date of Submission11-Dec-2018
Date of Decision07-Feb-2019
Date of Acceptance23-Oct-2019
Date of Web Publication5-Dec-2019

Correspondence Address:
Dr. M C Rajesh
Shrirang, Chevayur (PO), Calicut - 673 017, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpn.ijpn_66_18

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Background and Aims: Quality pain relief after arthroscopic knee surgery is not only a challenge but also a necessity for adequate postoperative rehabilitation after anterior cruciate ligament (ACL) repair. In the past, different agents were tried for pain relief by parenteral and intra-articular routes with varying results. The aim of the present study is to compare the analgesic effects of intra-articularly instilled bupivacaine, clonidine, and neostigmine in the postoperative period after ACL repair. Methods: This was a double-blind study on three groups of patients, wherein bupivacaine, clonidine, or neostigmine was instilled intra-articularly at the end of knee arthroscopic ACL repair and the postprocedure pain relief was assessed. All patients received subarachnoid block with the same volume (17.5 mg) of 0.5% bupivacaine heavy. Postoperative pain was assessed with the visual analog scale (VAS), and rescue analgesics were prescribed for a more than tolerable pain. Pain score was observed at definite intervals and rescue doses were charted in crosstabs. Efficiency of the three drugs in question was tested with Bonferroni technique. Results: VAS scores at 2 h, 6 h, and 12 h were lowest with bupivacaine followed by clonidine and neostigmine. The requirement of rescue analgesics was also in the same order. Conclusion: On the basis of this study, we conclude that intra-articularly instilled bupivacaine provides superior and long-lasting analgesia than clonidine and neostigmine.

Keywords: Anterior cruciate ligament, arthroscopic surgery, intra-articular analgesics, pain relief

How to cite this article:
Gupta V, Rajesh M C, Jos S, Ramdas E K. Pain relief following arthroscopy: A comparative study of intra-articular bupivacaine, neostigmine, and clonidine. Indian J Pain 2019;33:147-50

How to cite this URL:
Gupta V, Rajesh M C, Jos S, Ramdas E K. Pain relief following arthroscopy: A comparative study of intra-articular bupivacaine, neostigmine, and clonidine. Indian J Pain [serial online] 2019 [cited 2020 Sep 23];33:147-50. Available from: http://www.indianjpain.org/text.asp?2019/33/3/147/272388

  Introduction Top

To prevent muscle atrophy and maintain proper circulation and knee flexibility, it is desired to allow early weight bearing in the repaired leg after arthroscopy.[1] However, postoperative pain is a distressing problem following knee arthroscopy and is a hindrance to early mobilization. Opioids are the mainstay in the postoperative settings for pain relief. However, they can occasionally cause troublesome nausea, vomiting, or sedation. Different drugs were tried in the past through the intra-articular route to bypass the systemic side effects of analgesics. However, the analgesic efficacy of these intra-articularly instilled different agents is yet to be established.[1] Although different studies were conducted in the past, there is consensus of opinion regarding the need to have more comparative studies on the efficacy, side effects, and complications of the different types of analgesia.[2]

The present study aims to compare the effects of intra-articularly instilled bupivacaine, neostigmine, and clonidine following arthroscopic anterior cruciate ligament (ACL) repair. All the three agents in the study were tried in the past through intra-articular route.[3],[4] The primary outcome of the research was the duration of analgesia. The secondary outcome was pain intensity at various time intervals in the postoperative period and total rescue analgesic consumption (tramadol) over 12 h.

  Methods Top

We conducted a prospective, double-blind, randomized study of intra-articular injection of clonidine, bupivacaine, and neostigmine after knee arthroscopic ACL repair. The research was approved by the institutional ethics committee, and written informed consent after explaining the procedure was obtained from each participant.

Only patients belonging to the American Society of Anesthesiologists (ASA) Grade 1 and 2 between the age group of 15 and 45 years of either sex coming for ACL repair were included in the study. A total of 60 patients were included in the study with 20 patients in each group. During the preanesthetic evaluation, patients were introduced about the usage of VAS for postoperative pain assessment.

Only surgeries performed by the same surgeon were included in the study to avoid the difference in variability of tissue handling. Any change of surgical plan during perioperative period, known allergic to any of the drugs in the study, or patients who insisted on general anesthesia were excluded from the study.

The study involves administration of 20 ml of 0.25% bupivacaine (Drug A), 150 μg of clonidine (Drug B) diluted to 20 ml with normal saline, and 500 μg of neostigmine (Drug C) again diluted to 20 ml using normal saline injected intra-articularly at the end of surgery. Both the surgeon instilling the drug and the anesthesiologist assessing the pain in the postoperative period were blinded about the drug.

All patients received injection midazolam 2 mg and injection ranitidine 50 mg as premedication. Perioperatively, noninvasive blood pressure, pulse oximeter, and electrocardiogram (lead 11 and V5) were applied for monitoring.

After the administration of spinal anesthesia with 17.5 mg of 0.5% bupivacaine at L3/L4 interspace, injection of diclofenac sodium 75 mg intramuscularly was administered. All patients underwent surgery under thigh tourniquet inflated to 300–350 mm of Hg.

Toward the end of surgery, Drug A, B, or C was randomly administered by the surgeon through the arthroscope just before closing the incision under strict aseptic conditions. The drugs were prepared by the staff nurse and handed over to the surgeon in an unlabeled syringe. Tourniquet was released 10 min after drug administration. Placebo was not administered keeping in view of the ethical aspect that no patient who is a part of the study be devoid of sufficient analgesics for pain alleviation. All patients were assessed by the same person (who was blinded about the group assignment of patients) in the postoperative care unit.

The assessment of pain was done using VAS at 0, 2, 6, and 12 h. Rescue analgesic injection of tramadol 50 mg intravenously (diluted to 10 ml with distilled water and given slowly over 10 min) was provided to any patient who reported a pain score of more than 3 on VAS.

The mean pain scores and the time to first analgesics as well as average number of rescue analgesics given in the first 12 h period were noted.

Statistical analysis

The pain scores and analgesic requirements during the first 12 h were compared between the groups using repeated measures ANOVA. Age and sex were analyzed by Chi-square and one-way ANOVA, where appropriate. The statistical packages used were MS Excel and SPSS for Windows 10, IBM, Chicago, USA.

After the statistical analysis of the data was done, the pharmacological profile of the three drugs was asked for, because it was a double-blind study.

  Results Top

There was no much difference with respect to demographic features such as age and sex [Table 1]. In Drug A group, the mean age of patients was 29 ± 6.43 years, whereas in Group B it was 30 ± 6.55 years and in Group C it was 29.4 ± 7.29, which is statistically insignificant and is not influencing the outcome of the study. There was no statistically significant difference with reference to ASA class and duration of surgery.
Table 1: Age and sex distribution

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The mean pain scores of Drug A, B, and C at 0 h was zero as no patient reported to have pain in all the three groups.

At 2 h, the mean pain score of Drug A was 0.55 ± 0.94. It was 1.25 ± 1.55 for Drug B, whereas for Drug C, it was 2.65 ± 2.08 [Figure 1]. When the pain score was assessed at 6 h, the mean pain score reported for Drug A was 2.10 ± 1.21 and for Drug B 2.50 ± 1.54, whereas for Drug C, it was 3.70 ± 1.50 [Figure 2]. At 12 h, the mean pain score for Drug A was 2.85 ± 1.27 and for Drug B 3.80 ± 1.88, whereas for Drug C it was 5.05 ± 1.76 [Figure 3]. Thus, the mean pain scores at 2, 6, and 12 h were lower for Drug A than Drug B, which in turn was lower as compared to Drug C.
Figure 1: Distribution of pain scores at second hour

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Figure 2: Distribution of pain scores at 6th hour

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Figure 3: Distribution of pain scores at twelfth hour

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In Drug A group, 17 (85%) of the patients did not require any rescue analgesics as their reported pain scores did not exceed the VAS score of 3 during the first 12 h postoperative period. Of 20 patients, 1 (5%) required one dose of rescue analgesic and 2 (10%) patients required two doses of the same. In Group B, 11 (55%) patients did not ask for any rescue analgesic; 4 (20%) asked for one dose of rescue analgesic and 5 (25%) were administered two doses of rescue analgesics. In Group C, 3 (15%) did not require any rescue analgesic, whereas 5 (25%) required one dose and 6 (30%) patients required two doses of rescue analgesic.

Hence, the mean rescue doses for Drug A were lesser as compared to Drug B, which in turn was lesser as compared to Drug C. The mean survival time in Drug A group was 11 h, i.e., at the 11th h postoperative, patients in the group asked for rescue analgesic whereas in Drug B group the mean survival time was 10 h and in Drug C group it was 6 h [Table 2].
Table 2: Numer of rescue doses

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No major adverse events on hemodynamics (more than 10% drops in pulse rate and systolic blood pressure) or drug sensitivity (minor drug rashes to severe anaphylaxis) were noted in any of the three groups.

  Discussion Top

When dealing with the idea of early mobilization of patients after arthroscopic ACL repair, the most challenging issue for the surgeon is quality pain relief of the patient. The best possible analgesia should give complete long-lasting pain relief with minimal side effects and preferably with only local site of action. This prompted many researches for intra-articular instillation of analgesics.

Analgesic effect of intra-articularly instilled bupivacaine,[5],[6],[7] clonidine,[8],[9] and neostigmine[10],[11] is studied separately in different studies. However, in our research, we have attempted to compare the analgesic efficacy of three different agents through intra-articular routes.

The advantage of intra-articular administration is its peripheral action with minimal side effects.[12],[13],[14] Way back in 1998, Buerkle et al. have shown the analgesic effectiveness of intra-articular neostigmine in rats in response to thermal stimuli.[15] Since then, there are a lot of research going on with regard to intra-articular installation of analgesics.

In a recent, prospective, double-blinded, randomized controlled trial conducted in the Indian context, Sivapurapu et al. showed the superiority of bupivacaine–clonidine combination over bupivacaine alone and bupivacaine–morphine mixture.[3] However, in our research, when we compared clonidine and bupivacaine separately, bupivacaine has found to have an edge over clonidine.

The analgesic effects of neostigmine is by muscarinic presynaptic inhibition of neostriatal glutamatergic afferents.[16] The study by Datta and Madhusudanan showed that intra-articular neostigmine 500 μg decreased the need for supplementary opioid requirements significantly following arthroscopy.[11] When compared to neostigmine, bupivacaine has a denser analgesic effect.[11] Our study has also shown a superiority of intra-articular bupivacaine compared to neostigmine.

Limiting the use of opioids and employing multimodal analgesia is the key to enhanced recovery after surgery program,[17] and use of intra-articular analgesics with local action provides ideal substitute for opioids.

There are some limitations of the study such as the adverse effect of local anesthetics on postoperative chondrolysis[18] and limiting the postoperative observation to 12 h. Large randomized controlled studies which involve long-term follow-up of patients are required to exactly predict the effects of local anesthetics on chondrocyte formation and lysis.

  Conclusion Top

Adequate pain control in the immediate postoperative period especially during its peak intensity is a challenge, but a necessity. Intra-articular installation of nonopioids is an excellent choice because of their nonsedating features. This will facilitate early physiotherapy and better recovery.

The present study clearly showed the analgesic supremacy of intra-articularly instilled bupivacaine 0.25% over clonidine 150 μg which is superior to 500 μg of neostigmine. A cause of concern with intra-articular bupivacaine is postoperative chondrolysis. A large prospective study with longer follow-up is needed to comment on this.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Drosos GI, Stavropoulos NI, Katsis A, Kesidis K, Kazakos K, Verettas DA, et al. Post-operative pain after knee arthroscopy and related factors. Open Orthop J 2008;2:110-4.  Back to cited text no. 1
Pinheiro LQ, Neri Junior E, Fernandes RM, Cardozo RT, Rezende PR. Reconstruction of the anterior cruciate ligament: Comparison of analgesia using intrathecal morphine, intra-articular morphine and intra-articular levobupivacaine. Rev Bras Ortop 2015;50:300-4.  Back to cited text no. 2
Sivapurapu V, Murugharaj SS, Venkata SS. Comparison of intra-articular analgesics in arthroscopic anterior cruciate ligament reconstruction surgeries: A randomized controlled trial. J Anaesthesiol Clin Pharmacol 2017;33:391-6.  Back to cited text no. 3
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Kayacan N, Boztug N, Arici G, Karsli B, Erman M. The effect of intra-articular neostigmine, tramadol, tenoxicam and bupivacaine on postoperative pain. J Ambul Surg 2002;10:29-32.  Back to cited text no. 4
Joshi GP, McCarroll SM, O'Brien TM, Lenane P. Intraarticular analgesia following knee arthroscopy. Anesth Analg 1993;76:333-6.  Back to cited text no. 5
Sun QB, Liu SD, Meng QJ, Qu HZ, Zhang Z. Single administration of intra-articular bupivacaine in arthroscopic knee surgery: A systematic review and meta-analysis. BMC Musculoskelet Disord 2015;16:21.  Back to cited text no. 6
Nahravani M, Tekye SM, Alipour M, Makhmalbaf H, Aghaee MA. Analgesia following arthroscopy – A comparison of intra-articular bupivacaine and/or midazolam and or fentanyl. Arch Bone Jt Surg 2017;5:28-31.  Back to cited text no. 7
Senapati S, Basu A, Bhattacharya D, Hazra S, Sarkar D, Dandapat P. Comparison of analgesic effect of intra-articular administration of levobupivacaine and clonidine versus ropivacaine and clonidine in day care knee arthroscopic surgery under spinal anesthesia. Indian J Pain 2016;30:38-42.  Back to cited text no. 8
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Sun R, Zhao W, Hao Q, Tian H, Tian J, Li L, et al. Intra-articular clonidine for post-operative analgesia following arthroscopic knee surgery: A systematic review and meta-analysis. Knee Surg Sports Traumatol Arthrosc 2014;22:2076-84.  Back to cited text no. 9
Alagol A, Calpur OU, Usar PS, Turan N, Pamukcu Z. Intraarticular analgesia after arthroscopic knee surgery: Comparison of neostigmine, clonidine, tenoxicam, morphine and bupivacaine. Knee Surg Sports Traumatol Arthrosc 2005;13:658-63.  Back to cited text no. 10
Datta R, Madhusudanan TP. Pain relief following arthroscopy-a comparative study of intra-articular bupivacaine, morphine and neostigmine. Med J Armed Forces India 2004;60:123-7.  Back to cited text no. 11
Das A, Majumdar S, Kundu R, Mitra T, Mukherjee A, Hajra BK, et al. Pain relief in day care arthroscopic knee surgery: A comparison between intra-articular ropivacaine and levobupivacaine: A prospective, double-blinded, randomized controlled study. Saudi J Anaesth 2014;8:368-73.  Back to cited text no. 12
Gentili M, Juhel A, Bonnet F. Peripheral analgesic effect of intra-articular clonidine. Pain 1996;64:593-6.  Back to cited text no. 13
Brill S, Plaza M. Non-narcotic adjuvants may improve the duration and quality of analgesia after knee arthroscopy: A brief review. Can J Anaesth 2004;51:975-8.  Back to cited text no. 14
Buerkle H, Boschin M, Marcus MA, Brodner G, Wüsten R, Van Aken H. Central and peripheral analgesia mediated by the acetylcholinesterase-inhibitor neostigmine in the rat inflamed knee joint model. Anesth Analg 1998;86:1027-32.  Back to cited text no. 15
Barral J, Galarraga E, Bargas J. Muscarinic presynaptic inhibition of neostriatal glutamatergic afferents is mediated by Q-type ca2+ channels. Brain Res Bull 1999;49:285-9.  Back to cited text no. 16
Tan M, Law LS, Gan TJ. Optimizing pain management to facilitate enhanced recovery after surgery pathways. Can J Anaesth 2015;62:203-18.  Back to cited text no. 17
Bojescul JA, Wilson G, Taylor DC. Idiopathic chondrolysis of the ankle. Arthroscopy 2005;21:224-7.  Back to cited text no. 18


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2]


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