PAIN Effect of intra-articular dexmedetomidine on postoperative analgesia after arthroscopic knee surgery

British Journal of Anaesthesia 101 (3): 395 9 (2008) doi:10.1093/bja/aen184 Advance Access publication June 20, 2008 PAIN Effect of intra-articular dexmedetomidine on postoperative analgesia after arthroscopic knee surgery R. R. Al-Metwalli, H. A. Mowafi, S. A. Ismail, A. K. Siddiqui, A. M. Al-Ghamdi, M. A. Shafi and A.-R. El-Saleh Department of Anaesthesia, Faculty of Medicine, King Faisal University, Saudi Arabia Corresponding author: Department of Anaesthesiology, King Fahd University Hospital, PO Box 40081, Al-Khobar 31952, Saudi Arabia. E-mail: hany_mowafi@hotmail.com, hany.mowafi@gmail.com Background. Alpha-2-adrenergic agonists have peripheral analgesic effects. We have assessed the potential analgesic effect of dexmedetomidine after intra-articular administration in arthroscopic knee surgery. Methods. Sixty patients undergoing arthroscopic knee surgery were randomly assigned into three groups in a double-blind placebo controlled study. The control group received i.v. and intra-articular saline, the intra-articular group received i.v. saline and intra-articular dexmedetomidine, and the i.v. group received i.v. dexmedetomidine and intra-articular saline. Haemodynamic changes, pain visual analogue scale (VAS), sedation score, the time to first postoperative analgesic request, and the total postoperative analgesic use during the first 24 h were evaluated. Results. Dexmedetomidine administration resulted in a significant reduction in pain scores for 6 h after operation in the intra-articular group but only for 1 h in the i.v. group. The time to first postoperative analgesic request was longer in the intra-articular group [312.0 (SD 120.7) min] compared with the control group [71.0 (50.1) min] and the i.v. group [102.1 (54.4) min] (P,0.001). Total diclofenac requirement was significantly lower in the intra-articular group [90.0 (46.2) mg] than in the control group [165.0 (52.2) mg] and in the i.v. group [129.3 (54.3) mg] (P,0.05). Conclusions. Intra-articular dexmedetomidine enhanced postoperative analgesia after arthroscopic knee surgery, with an increased time to first analgesic request and a decreased need for postoperative analgesia. Br J Anaesth 2008; 101: 395 9 Keywords: analgesia, postoperative; analgesic techniques, intra-articular; analgesics nonopioid, diclofenac; surgery, orthopaedic; sympathetic nervous system, dexmedetomidine Accepted for publication: May 22, 2008 Arthroscopic knee surgery is commonly performed on day-case basis. However, postoperative pain may be an obstacle for discharge and early rehabilitation. Several analgesic strategies, such as systemic medication, central or peripheral blocks, and intra-articular drug administration, have been used to control pain after arthroscopic knee surgery. 1 However, none is free from limitations such as the need for special equipment and monitoring or the risk of complications that may delay discharge or cause re-admission. Several studies have demonstrated that intra-articular injection of a 2 -adrenoceptor agonists such as clonidine or its derivative, apraclonidine, provided effective analgesia after arthroscopy. 2 5 Dexmedetomidine, a highly selective a 2 -adrenoceptor agonist, binds the a 2 -receptors up to eight times more avidly than clonidine. 6 Systemic dexmedetomidine has sedative, anxiolytic, analgesic, and anaestheticsparing effects. 67 Previous studies have shown that systemic dexmedetomidine administration before initiation of regional anaesthesia provides a postoperative analgesic effect in arthroscopic knee surgery but with some adverse haemodynamic effects. 8 9 However, the effects of intra-articular dexmedetomidine on postoperative pain relief after knee arthroscopy were not examined. Therefore, this study was # The Board of Management and Trustees of the British Journal of Anaesthesia 2008. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Al-Metwalli et al. designed to assess the analgesic effects of intra-articular dexmedetomidine in a double blind, randomized placebocontrolled manner in patients undergoing arthroscopic knee surgery under general anaesthesia. Methods This study follows the regulations and ethical guidelines adopted by the National Institute of Health (http://ohsr.od. nih.gov/guidelines/index.html). After local research committee approval and an informed written patient consent, 60 adult patients of ASA I or II, undergoing elective arthroscopic partial menicectomy under general anaesthesia, were included in the study. Patients were excluded if they had a history of cardiac disease, impaired renal or hepatic function, and hypertension treated with a-methyldopa, clonidine, or b-adrenergic blockers, or if they had used opioid or non-opioid analgesics within the previous 24 h or had any contraindication to the study drugs. Patients were randomly allocated using an online research randomizer (http://www. randomizer.org) into three groups (20 patients each). The control group received saline i.v. and intra-articularly, the intra-articular group received saline i.v. and dexmedetomidine intra-articularly, and the i.v. group received dexmedetomidine i.v. and saline intra-articularly. At the preoperative visit, a 10 cm visual analogue scale (VAS) (0, no pain, and 10, worst pain imaginable) was explained to each patient. Before operation, baseline heart rate (HR), mean arterial pressure (MAP), and VAS were recorded in each patient. Standard intraoperative monitoring includes 3-lead ECG, pulse oximeter, capnography, and non-invasive arterial pressure. The anaesthetic technique was standardized for all patients. After preoxygenation, anaesthesia was induced with fentanyl 2 mg kg 21 and propofol 2 2.5 mg kg 21. A laryngeal mask airway was inserted after loss of consciousness and the lungs were ventilated to maintain the end-tidal carbon dioxide partial pressure between 4.3 and 4.6 kpa. Anaesthesia was maintained in all groups with sevoflurane in oxygen and air. No further doses of opioid were given during the surgical procedure. At the end of the surgery when skin was closed and before tourniquet release, the test solution was injected. Syringes containing 20 ml aqueous solutions of either dexmedetomidine or saline were prepared in a double-blind fashion by a team member who was not involved in data recording. In the control group, patients received intra-articular saline 20 ml and i.v. saline 20 ml over 10 min. In the intra-articular group, the patients received intra-articular saline 20 ml containing 1 mg kg 21 dexmedetomidine (Precedex w, Abbott Laboratories) and i.v. saline 20 ml over 10 min. In the i.v. group, the patients received i.v. saline 20 ml containing 1 mg kg 21 dexmedetomidine over 10 min in addition to intra-articular saline 20 ml. The tourniquet was kept inflated for 10 min after the injection and no surgical drain was used in any patient. HR, MAP, pain VAS, and sedation scores were recorded at 1, 2, 4, 6, 8, 12, 18, and 24 h after discharging the patients from the operating theatre. The patients level of sedation was assessed using a modified Observer s Assessment of Alertness/Sedation (OAA/S) scale 10 (where 1, awake/alert to 5, asleep/unrousable). Diclofenac sodium (75 mg) was administered i.v. as an analgesic supplement if the recorded VAS pain score was 4 and was repeated every 8 h if required. Tramadol 50 mg i.v. was used as a rescue analgesic if the patients continued to have pain after diclofenac administration. The time to the first analgesic requirement and the total diclofenac use during the first 24 h after operation were also recorded. Side-effects such as nausea, vomiting, bradycardia (defined as HR,45 beats min 21 ), and hypotension (defined as reduction of MAP.25% of baseline) were recorded. All data were collected by an observer who was unaware of patients group assignment. Statistical analysis Sample size was estimated using pain scores as the primary variable. On the basis of a pilot study and assuming an SD of 1 cm, 17 patients were required in each group to have an 80% chance to detect a difference of 1 cm on the VAS at the 5% level of significance. Data were tested for normal distribution using the Kolmogorov Smirnov test. Gender and the incidence of complications were analysed using x 2 test. Two-way repeated measure analysis of variance was used for continuous variables as HR, MAP, and VAS and the differences were then calculated by post hoc testing (Newman Keuls test). Mann Whitney rank-sum test was used for the comparison between the groups for sedation score. A P-value of,0.05 was considered significant. Analysis was performed using Statistica software version 7.0 for windows (Statsoft, Inc.). Results There were no significant differences between the three groups with regard to age, weight, gender, and duration of surgery (Table 1). There were also no significant differences in the baseline VAS, HR, and MAP. No significant differences in HR between the three groups were recorded at any time (Fig. 1). However, in the i.v. group, the HR decreased significantly compared with the preoperative baseline value at 1 and 2 h after operation. MAP was significantly lower in the i.v. group compared with the control group at 1 h (P,0.05) (Fig. 1). Table 1 Patient characteristics (n¼20 in each group). Data are mean (range) or mean (SD) Control group Intra-articular group I.V. group Age (yr 38.2 (24 65) 40.2 (21 66) 41.2 (22 62) Weight (kg) 83.6 (9.1) 80.8 (7.4) 77.2 (10.3) Gender (male/female) 13/7 11/9 11/9 Duration of surgery (min) 39.6 (20.3) 42.0 (18.4) 36.3 (17.9) 396

Dexmedetomidine and intra-articular analgesia HR (beats min 1 ) 90 85 80 75 70 Control group Intra-articular group I. V. group VAS 10 9 8 7 6 5 4 3 2 ## # # # Control group Intra-articular group I.V. group 65 60 1 0 Baseline 1 h 2 h 4 h 6 h 8 h 12 h 24 h Time MAP (mm Hg) 105 100 95 90 85 80 Fig 2 Changes in the VAS in the control, intra-articular, and i.v. dexmedetomidine groups. Measurements were recorded at baseline (preoperative), 1, 2, 4, 6, 8, 12, and 24 h after operation. Vertical bars denote 0.95 confidence intervals. There were no significant differences in comparison with baseline values; # significance difference in comparison with the control group. postoperative hour (P,0.05). Thereafter, the three groups were comparable regarding sedation. No differences were found between the groups in the incidence of nausea and vomiting. 75 Baseline 1 h 2 h 4 h 6 h 8 h 12 h 24 h Time Fig 1 Changes in HR and MAP in the control, intra-articular, and i.v. dexmedetomidine groups. Measurements were recorded at baseline (preoperative), 1, 2, 4, 6, 8, 12, and 24 h after operation. Vertical bars denote 0.95 confidence intervals. Significance difference in comparison with baseline values; there were no significance differences in comparison with the control group. No incidence of hypotension or bradycardia requiring intervention was reported in all groups. Compared with the control group, pain VAS was significantly lower in the first 6 h in the intra-articular group and only at the first hour after the end of surgery in the i.v. group (Fig. 2). The time to first postoperative analgesic request was longer in the intra-articular group [312.0 (120.7) min] compared with the control group [71.0 (50.1) min] and the i.v. group [102.1 (54.4) min] (P,0.001). Total diclofenac requirement was significantly lower in the intra-articular group [90.0 (46.2) mg] than in the control group [165.0 (52.2) mg] and in the i.v. group [129.3 (54.3) mg] (P,0.05). Moreover, total diclofenac use was significantly lower in the i.v. group than in the control group (P,0.05). None of the patients received tramadol. The sedation score (median, inter-quartile range) was higher in the i.v. group (3, 2 3) than in the control (1, 1 2) and intra-articular groups (2, 1 2.5) at the first Discussion The main finding in this study was that intra-articular dexmedetomidine in a dose of 1 mg kg 21 at the end of arthroscopic knee surgery enhanced postoperative pain relief. It also reduced the need for postoperative analgesia and prolonged the time to first request. These beneficial effects of dexmedetomidine were not as marked when the drug was given i.v. as it produced a limited improvement in postoperative pain VAS and less effect on postoperative analgesic requirement. Two recent studies have evaluated the systemic effects of dexmedetomidine on postoperative analgesia in arthroscopic knee surgery. Buccal rather than i.m. dexmedetomidine 2.5 mg kg 21 administration as premedication in patients undergoing arthroscopy with spinal anaesthesia attenuated postoperative pain and decreased diclofenac requirement. 8 In a randomized, double-blind, placebocontrolled clinical trial, patients received dexmedetomidine 1 mg kg 21 i.v. for 10 min followed by dexmedetomidine 0.3 mg kg 21 for 50 min before epidural anaesthesia. 9 The authors found that dexmedetomidine provided modest postoperative analgesia. However, in these studies, haemodynamic adverse effects such as hypotension, hypertension, bradycardia, or both were recorded. We are unaware of a previous study that evaluated the analgesic effects of intra-articular dexmedetomidine. The analgesic effects of a 2 -adrenergic agonists could be mediated through supraspinal, spinal, and peripheral 397

Al-Metwalli et al. actions. 11 In our study, the analgesic effect of intra-articular dexmedetomidine appears to be mainly due to a direct local action, as this effect was less pronounced after systemic administration of dexmedetomidine. However, a central analgesic effect resulting from systemic absorption cannot be excluded. The mechanism by which dexmedetomidine mediates intra-articular analgesia is not clearly defined. However, the mechanisms of analgesic effects for intra-articular dexmedetomidine might be similar to those suggested for intra-articular clonidine. Clonidine may act on a 2 -adrenergic presynaptic receptors and inhibit the release of norepinephrine at peripheral afferent nociceptors. 12 Clonidine has also been shown to provide local anaesthetic effects which inhibit the conduction of nerve signals through C and Ad fibres 13 and may stimulate the release of enkephalin-like substances at peripheral sites. 14 The analgesic effect of clonidine could be mediated via the modulation of the opioid-analgesic pathway. 15 Intra-articular clonidine attenuates arthritic pain-related behaviour in experimental animals 16 17 and provided postoperative analgesia when used either as a sole agent 212 or augmented the analgesia produced bupivacaine 4 18 and morphine. 3 Intra-articular apraclonidine, a clonidine derivative that has limited access to the central nervous system, provided effective analgesia after arthroscopy. 5 Intra-articular fadolmidine, a highly selective a 2 adrenoceptor agonist that has a restricted local effect after its peripheral administration, provided a suppression of arthritis pain-related behaviour in rats. 19 Arthroscopic surgery is associated with a variable amount of postoperative pain, but it may be quite considerable. The pain is caused by an irritation of free nerve endings of the synovial tissue, anterior fat pad, and joint capsule due to surgical excision and resection. 20 Postoperative pain scores were lower in the intra-articular dexmedetomidine group for 6 h, whereas it was lower in the i.v. group only for 1 h. This difference between the two groups may reflect a prolonged local analgesic effect of dexmedetomidine or slower absorption. In this study, transient sedation and reduction in MAP and HR were recorded exclusively in the i.v. group. The lack of systemic effects in the intra-articular group may be related to the relatively small dose used and the poorly vascular articular surface. Although our results demonstrated that intra-articular dexmedetomidine provided effective analgesia, probably due to peripheral effects, the safety concerns about its local adverse effects must be clarified before recommending its clinical use. Once this is established, further clinical studies can be performed to develop a more reliable and clinically efficient regime. This regime may be based on the use of multimodal analgesics by adding dexmedetomidine to other intra-articular agents such as local anaesthetics, morphine, or both, along with systemic or regional analgesia. Further studies are also required to define the optimal analgesic dose of intra-articular dexmedetomidine. A limitation of our study is that we did not measure the plasma concentration of dexmedetomidine to correlate it with the clinical findings, which may have confirmed the local effects. In conclusion, intra-articular dexmedetomidine enhanced postoperative analgesia after arthroscopic knee surgery. There was an increased time to first analgesic request and a decreased use of postoperative analgesia. References 1 Bondok RS, Abd El-Hady AM. Intra-articular magnesium is effective for postoperative analgesia in arthroscopic knee surgery. Br J Anaesth 2006; 97: 389 92 2 Gentili M, Houssel P, Osman M, Henel D, Juhel A, Bonnet F. Intra-articular morphine and clonidine produce comparable analgesia but the combination is not more effective. Br J Anaesth 1997; 79: 660 1 3 Buerkle H, Huge V, Wolfgart M, et al. Intra-articular clonidine analgesia after knee arthroscopy. Eur J Anaesthesiol 2000; 17: 295 9 4 Reuben SS, Connelly NR. Postoperative analgesia for outpatient arthroscopic knee surgery with intraarticular clonidine. Anesth Analg 1999; 88: 729 33 5 Tan PH, Buerkle H, Cheng JT, Shih HC, Chou WY, Yang LC. Double-blind parallel comparison of multiple doses of apraclonidine, clonidine, and placebo administered intra-articularly to patients undergoing arthroscopic knee surgery. Clin J Pain 2004; 20: 256 60 6 Gerlach AT, Dasta JF. Dexmedetomidine: an updated review. Ann Pharmacother 2007; 41: 245 52 7 Hayashi Y, Maze M. Alpha-2 adrenoceptor agonists and anaesthesia. Br J Anaesth 1993; 71: 108 18 8 Karaaslan D, Peker TT, Alaca A, et al. Comparison of buccal and intramuscular dexmedetomidine premedication for arthroscopic knee surgery. J Clin Anesth 2006; 18: 589 93 9 Gómez-Vázquez ME, Hernández-Salazar E, Hernández-Jiménez A, Pérez-Sánchez A, Zepeda-López VA, Salazar-Páramo M. Clinical analgesic efficacy and side effects of dexmedetomidine in the early postoperative period after arthroscopic knee surgery. J Clin Anesth 2007; 19: 576 82 10 Chernik DA, Gillings D, Laine H, et al. Validity and reliability of the Observer s Assessment of Alertness/Sedation Scale: study with intravenous midazolam. J Clin Psychopharmacol 1990; 10: 244 51 11 Ebert TJ, Hall JE, Barney JA, Ulrich TD, Colinco MD. The effects of increasing plasma concentrations of dexmedetomidine in humans. Anesthesiology 2000; 93: 382 94 12 Gentili M, Juhel A, Bonnet F. Peripheral analgesic effect of intra-articular clonidine. Pain 1996; 64: 593 6 13 Butterworth JFV, Strichartz GR. The alpha 2-adrenergic agonists clonidine and gunafacine produce tonic and phasic block of conduction in rat sciatic nerve fibers. Anesth Analg 1993; 76: 295 301 14 Nakamura M, Ferreira SH. Peripheral analgesic action of clonidine: mediation by release of endogenous enkephalin-like substances. Eur J Pharmacol 1988; 146: 223 8 398

Dexmedetomidine and intra-articular analgesia 15 Post C, Archer T, Minor BG. Evidence for cross tolerance to the analgesic effects between morphine and selective alpha 2- adrenergic agonists. J Neural Transm 1988; 72: 1 9 16 Buerkle H, Schäpsmeier M, Bantel C, Marcus MA, Wüsten R, Van Aken H. Thermal and mechanical antinociceptive action of spinal vs peripherally administered clonidine in the rat inflamed knee joint model. Br J Anaesth 1999; 83: 436 41 17 Khasar SG, Green PG, Chou B, Levine JD. Peripheral nociceptive effects of alpha 2-adrenergic receptor agonists in the rat. Neuroscience 1995; 66: 427 32 18 Joshi W, Reuben SS, Kilaru PR, Sklar J, Maciolek H. Postoperative analgesia for outpatient arthroscopic knee surgery with intraarticular clonidine and/or morphine. Anesth Analg 2000; 90: 1102 6 19 Ansah OB, Pertovaara A. Peripheral suppression of arthritic pain by intraarticular fadolmidine, an alpha 2-adrenoceptor agonist, in the rat. Anesth Analg 2007; 105: 245 50 20 Dye SF, Vaupel GL, Dye CC. Conscious neurosensory mapping of the internal structures of the human knee without intraarticular anesthesia. Am J Sports Med 1998; 26: 773 7 399