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* From the Department of Anesthesiology and Intensive Care, Chaim Sheba Medical Center, Tel Hashomer, Israel; and
the Anaesthetic Department, Kings College Hospital, London, UK.
Address correspondence to: Dr. M. Plaza, Anaesthetic Department, Kings College Hospital, Denmark Hill, London SE5 9RS, UK. Phone: 020-7346-3154; Fax: 020-7346-4106; E-mail: plaza{at}londoc.com
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Abstract |
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Methods: Twenty-five studies were reviewed using specific inclusion criteria and, accordingly, included in the final assessment. These studies were assessed for pain scores, total analgesic consumption and time to first analgesic request to determine a possible peripheral effect, as opposed to possible systemic effects of an adjuvant administered intra-articularly.
Results: A total of 16 studies, met the inclusion criteria. These studies considered the use of non-steroidal anti-inflammatory drugs, steroids, neostigmine and clonidine. Ketorolac was used in four studies (for a total of 230 patients) and showed a significant improvement in analgesia. Clonidine has shown considerable analgesic effect, with minimal adverse effects. All seven studies assessed in this review were supportive (a total of 424 patients). Furthermore the addition of clonidine to bupivacaine or morphine was found to increase duration and quality of postoperative analgesia.
Conclusions: Current evidence indicates that a variety of agents have synergistic effects when added to local anesthetics and there is evidence that the improvement in analgesia is, at least partially, through a local rather than a central mechanism. The results of this review suggest that clonidine and ketorolac, when administered intra-articulary after arthroscopic knee surgery, may reduce postoperative pain.
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Introduction |
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IA bupivacaine produces transient analgesia,1–4 and there are conflicting reports about the effectiveness of IA morphine.5
The purpose of this article is to review the current evidence for the IA addition of clonidine, neostigmine, steroids and non-steroidal anti-inflammatory agents intra-articularly as adjuvants to LA drugs after arthroscopic knee surgery. Recently, IA morphine has been reviewed in detail5 and thus it was not considered in this analysis.
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Methods |
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Relevant studies included all those that analyzed the effect of non-narcotic analgesic adjuncts with or without LAs for IA administration after arthroscopic knee surgery. Of the 25 studies identified, only those that were prospective and double-blinded were considered for further analysis. Each report, which could be described as a randomized control study (RCT) was read independently by each of the authors and scored using a three-item quality scale (Jadad 1996).6 The scale takes into consideration randomization, double-blinding and reporting of dropouts and withdrawals. Spinal or epidural anesthesia was not included in this review because of the possible continued effect in the immediate postoperative period, which would render studies insensitive.
For studies meeting the inclusion criteria, the following data were collected: measure of postoperative pain, time to first analgesic, and total analgesic consumption. In addition, for each study the anesthetic technique, concentration and volume of LA, type and dose of adjuncts and type of surgery were recorded. We independently reviewed each study using the above criteria. Detailed results of the review process are presented in Tables I, II and III (available as Additional Material at www.cja-jca.org).
Each study was assessed for appropriate recording, and interpretation of adverse effects.
Effectiveness was defined as a significant difference (P < 0.05) in pain intensity (early and late) between the group with an adjunct agent and the control group and total consumption of rescue analgesia.
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Results |
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Seven studies evaluated clonidine,15–22 one in combination with LAs.18 One further study considered the combined use of neostigmine and clonidine.21 Only one study investigated neostigmine in combination with LAs22 (Tables I, II and III available as Additional Material at www.cja-jca.org).
NSAIDS
Of seven studies examining the effect of NSAIDS, four used ketorolac7–10 and three used tenoxicam.11–13 Five of these studies evaluated the addition of LAs7–10,13 and two of them the addition of morphine.8,9 Only three studies9,11,13 had a systemic control.
All studies using ketorolac showed additional analgesic effects. There was a statistically significant reduction in pain scores in the first and second hour, increased duration of analgesia and decreased 24-hr consumption of analgesics in the IA ketorolac group. Convery10 found that a small dose of IA ketorolac had a similar effect to a larger dose given iv. The results from the addition of morphine in two studies8,9 were conflicting with regards to the additive effect of morphine and ketorolac.
Nausea,8 accompanied by itching and tiredness9 was reported in two studies, but the increased incidence was not statistically significant. Only one study10 postulated a statistically significant chondrotoxic effect of ketorolac at high doses based on animal studies.
The three studies examining tenoxicam11–13 showed additional analgesic effects although one11 found only a decrease in analgesic requirements. All these studies postulated a chondroprotective effect based on a review of animal studies.
Steroids
One article reviewed the addition of methylprednisolone to bupivacaine and morphine.14 This combination resulted in a significant improvement in pain scores, both at rest and on movement, in part due to the anti-inflammatory effect of steroids (clinical reduction of swelling and a decrease in the level of inflammatory markers such as interleukin-6, bradykinin and plasma orosomucoid).
There were no side effects when correctly placed by a single injection.
Clonidine
Seven articles reviewed the use of clonidine,15–21 two in combination with LAs,17,18 six with morphine,14–16,18–20 and one with neostigmine.21 Only one did not include a systemic control.17
All the articles comparing clonidine to morphine found their analgesic effect similar and unrelated to vascular uptake, with the exception of Iqbal et al.20 who found clonidine superior to morphine. As for the synergistic effect of both drugs, two articles found a positive additive effect18,19 while one of them did not.16
The addition of clonidine to bupivacaine was found to increase postoperative analgesia with both drugs having an additive effect.17
Clonidine and neostigmine were found to have similar analgesic properties postoperatively, with no additive effect when used in combination;21 only Gentili21 reported statistically significant hypotension and bradycardia with these drugs although no treatment was required.
Neostigmine
Two articles examined the use of neostigmine, one in comparison with clonidine21 and one with morphine.22 Yang et al. found neostigmine IA and sc superior for postoperative analgesia to IA morphine. There was no significant difference between neostigmine given intra-articularly or subcutaneously. The incidence of nausea with the use of neostigmine was not increased when compared to control groups.
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Discussion |
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Various factors have been recognized as influencing post-arthroscopy pain and the effectiveness of IA analgesia. These include preoperative pain scores, duration and type of surgery, seniority of surgeon, use of general or regional anesthesia, premedication, volume of the analgesic agent injected and timing of IA injection. It is important to mention that clonidine, neostigmine and NSAIDS are not approved for IA use, however neither is morphine.
Clonidine has shown good analgesic effect, with minimal adverse effects at a dose of 150 µg. All seven studies assessed in this review were supportive (for a total of 424 patients) with six using a control. Furthermore the addition of clonidine to bupivacaine or morphine was found to increase the duration and quality of postoperative analgesia. Analgesia was unrelated to vascular uptake. Inhibition of norepinephrine release by stimulation of presynaptic receptors in 
2 nerve endings may explain the peripheral analgesic effect of clonidine. Furthermore clonidine blocks the conduction of nerve fibres and has also been demonstrated to induce encephalin-like substance release at peripheral sites.
NSAIDS were used in seven studies in 531 patients. Several NSAIDS have deleterious effects on human cartilage (reducing chondrocyte biosynthesis) with resulting cartilage destruction in vivo and, particularly in patients with osteoarthritis. The difference in analgesia provided by matched doses of iv or IA NSAIDS has not been well determined. NSAIDS may act locally via inhibition of prostaglandin synthesis that is responsible for inflammatory changes following trauma.
Ketorolac was used in four studies (for a total of 280 patients) and showed a significant improvement in analgesia, with some evidence that the effect was exerted at the periphery rather than through a central mechanism.
Tenoxicam reduced total consumption of rescue analgesia but did not alter patients’ perception of pain in comparison to bupivacaine; however it had a better analgesic effect than when administered parenterally. Tenoxicam is an aqueous formulation suitable for IA administration. In contrast to other NSAIDS it has a chondroprotective effect on human cartilage.
Neostigmine is an acetylcholinesterase inhibitor which, when administered intra-articularly, produces a moderate and dose-dependent analgesic effect. Several mechanisms such as the hyperpolarization of neurons, reduction in the release of pronociceptive neurotransmitters, or activation of the nitric oxide-cyclic guanosine monophosphate pathway might mediate this peripheral cholinergic antinociception by elevating endogenous acetylcholine.
Steroids were used in one study (60 patients). Methylprednisolone may reduce pain when administered in a multimodal analgesic regime.
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Conclusions |
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TOPAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
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Current evidence indicates that a variety of agents have synergistic effects when added to LAs and there is evidence that the improvement in analgesia is, at least partially, through a local rather than a central mechanism.
The results of this review suggest that clonidine and ketorolac when administered intra-articulary after arthroscopic knee surgery may reduce postoperative pain.
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Footnotes |
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References |
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2 Smith I, Van Hemelrijck J, White PF, Shively R. Effects of local anesthesia on recovery after outpatient arthroscopy. Anesth Analg 1991; 73: 536–9.
3 Allen GC, St Amand MA, Lui AC, Johnson DH, Lindsay MP. Postarthroscopy analgesia with intraarticular bupivacaine/morphine. A randomized clinical trial. Anesthesiology 1993; 79: 475–80.[Medline]
4 Geutjens G, Hambidge JE. Analgesic effects of intraarticular bupivacaine after day-case arthroscopy. Arthroscopy 1994; 10: 299–300.[Medline]
5 Kalso E, Tramer MR, Carroll D, McQuay HJ, Moore RA. Pain relief from intra-articular morphine after knee surgery: a qualitative systematic review. Pain 1997; 71: 127–34.[Medline]
6 Jadad AR, Carroll D, Moore A, McQuay H. Developing a database of published reports of randomised clinical trials in pain research. Pain 1996; 66: 239–46.[Medline]
7 Reuben SS, Connelly NR. Postoperative analgesia for outpatient arthroscopic knee surgery with intraarticular bupivacaine and ketorolac. Anesth Analg 1995; 80: 1154–7.[Abstract]
8 Reuben SS, Connelly NR. Postarthroscopic meniscus repair analgesia with intraarticular ketorolac or morphine. Anesth Analg 1996; 82: 1036–9.[Abstract]
9 Gupta A, Axelsson K, Allvin R, et al. Postoperative pain following knee arthroscopy: the effects of intra-articular ketorolac and/or morphine. Reg Anesth Pain Med 1999; 24: 225–30.[Medline]
10 Convery PN, Milligan KR, Quinn P, Scott K, Clarke RC. Low-dose intra-articular ketorolac for pain relief following arthroscopy of the knee joint. Anaesthesia 1998; 53: 1117–29.[Medline]
11 Cook TM, Tuckey JP, Nolan JP. Analgesia after day-case knee arthroscopy: double–blind study of intra-articular tenoxicam, intra-articular bupivacaine and placebo. Br J Anaesth 1997; 78: 163–8.
12 Colbert ST, Curran E, O’Hanlon DM, Moran R, McCarroll M. Intra-articular tenoxicam improves postoperative analgesia in knee arthroscopy. Can J Anesth 1999; 46: 653–7.
13 Elhakim M, Nafie M, Eid A, Hassin M. Combination of intra-articular tenoxicam, lidocaine, and pethidine for outpatient knee arthroscopy. Acta Anaesthesiol Scand 1999; 43: 803–8.[Medline]
14 Rasmussen S, Larsen AS, Thomsen ST, Kehlet H. Intra-articular glucocorticoid, bupivacaine and morphine reduces pain. Inflammatory response and convalescence after arthroscopic meniscectomy. Pain 1998; 78: 131–4.[Medline]
15 Gentili M, Juhel A, Bonnet F. Peripheral analgesic effect of intra-articular clonidine. Pain 1996; 64: 593–6.[Medline]
16 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.
17 Reuben SS, Connelly NR. Postoperative analgesia for outpatient arthroscopic knee surgery with intraarticular clonidine. Anesth Analg 1999; 88: 729–33.
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 Buerkle H, Huge V, Wolfgart M, et al. Intra-articular clonidine analgesia after knee arthroscopy. Eur J Anaesthesiol 2000; 17: 295–9.[Medline]
20 Iqbal J, Wig J, Bhardwaj N, Dhillon MS. Intra-articular clonidine vs. morphine for post-operative analgesia following arthroscopic knee surgery (a comparative evaluation). The Knee 2000; 7: 109–13.[Medline]
21 Gentili M, Enel D, Szymskiewicz O, Mansour F, Bonnet F. Postoperative analgesia by intraarticular clonidine and neostigmine in patients undergoing knee arthroscopy. Reg Anesth Pain Med 2001; 26: 342–7.[Medline]
22 Yang LC, Chen LM, Wang CJ, Buerkle H. Postoperative analgesia by intra-articular neostigmine in patients undergoing knee arthroscopy. Anesthesiology 1998; 88: 334–9.[Medline]
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