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Anesth Analg 1999;88:729
© 1999 International Anesthesia Research Society

AMBULATORY ANESTHESIA

Postoperative Analgesia for Outpatient Arthroscopic Knee Surgery with Intraarticular Clonidine

Scott S. Reuben, MD, and Neil Roy Connelly, MD

Department of Anesthesiology, Baystate Medical Center, Tufts University School of Medicine, Springfield, Massachusetts

Address correspondence and reprint requests to Scott S. Reuben, MD, Department of Anesthesiology, Baystate Medical Center, 759 Chestnut St., Springfield, MA 01199. Address e-mail to scott.reuben @bhs.org.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Intraarticular (IA) local anesthetics are often used for the management and prevention of pain after arthroscopic knee surgery. Clonidine prolongs the duration of local anesthetics. We designed this study to determine whether clonidine added to an IA injection would result in an analgesic benefit. Fifty patients were randomly assigned to one of five groups that received clonidine (either via the subcutaneous or IA route) or saline placebo with or without IA bupivacaine, as follows: Group 1 received 30 mL of 0.25% bupivacaine IA; Group 2 received 30 mL of 0.25% bupivacaine with clonidine (1 µg/kg) IA; Group 3 received 30 mL of 0.25% bupivacaine IA and subcutaneous clonidine (1 µg/kg); Group 4 received 30 mL of 0.25% bupivacaine with epinephrine (5 µg/mL) IA; and Group 5 received clonidine (1 µg/kg) in 30 mL of saline IA. The results of this study revealed a significant difference in analgesia from the IA administration of clonidine. The group who received a combination of IA bupivacaine and clonidine had a significantly decreased need for oral postoperative analgesics and an increased analgesic duration (P < 0.0001). We conclude that IA clonidine improved comfort in patients undergoing knee arthroscopy.

Implications: The intraarticular administration of clonidine along with bupivacaine results in a significant improvement in analgesia compared with either drug alone. There was an increased time to first analgesic request and a decreased need for postoperative analgesics.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
A variety of analgesic techniques have been used to manage postoperative pain after arthroscopic knee surgery. Lidocaine (1), prilocaine (2), and bupivacaine (3) have all been administered intraarticularly (IA) to provide intraoperative local anesthesia and postoperative analgesia. Bupivacaine is often chosen because of its longer duration of action. Clonidine has been shown to prolong the duration of action of local anesthetics in the laboratory setting (4). IA clonidine alone has recently been shown to provide effective postoperative analgesia (5). We hypothesized that IA clonidine and bupivacaine would provide more significant analgesia than clonidine alone. This study was performed in patients undergoing arthroscopic knee surgery to determine the analgesic effects of IA clonidine administered either alone or in combination with bupivacaine.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After institutional review board approval, informed written consent was obtained from 50 patients scheduled to undergo elective arthroscopic meniscal surgery by a single surgeon. Patients were eligible for participation if they spoke English, were older than 18 yr of age, and were ASA physical status I or II. Patients were excluded if they were being medicated with narcotics preoperatively or if they had a contraindication to the use of nonsteroidal antiinflammatory drugs (NSAIDs).

Patients were assigned to one of five treatment groups in a double-blinded, randomized manner: Group 1 received subcutaneous (SC) saline (S) (1 mL) and IA 0.25% bupivacaine (30 mL); Group 2 received SC S (1 mL) and IA 0.25 bupivacaine (30 mL) with clonidine (1 µg/kg); Group 3 received SC clonidine (1 µg/kg) and IA 0.25% bupivacaine (30 mL); Group 4 received SC S (1 mL) and IA 0.25% bupivacaine (30 mL) with epinephrine (5 µg/mL); and Group 5 received SC S (1 mL) and IA clonidine (1 µg/kg) with 30 mL of S.

After placement of routine monitors, patients received a similar general anesthetic. Induction of anesthesia was achieved with propofol (2 mg/kg) and fentanyl (2 µg/kg). No further opioid analgesics were administered during the intraoperative period. Endotracheal intubation was facilitated with succinylcholine (1 mg/kg). Anesthesia was maintained with nitrous oxide (67%) in oxygen and isoflurane (1.0%–2.0% inspired concentration).

When the surgical procedure was completed, the patient’s knee joint was injected through the arthroscope with the study drug. In addition, either 1 mL of saline or clonidine (1 µg/kg) was administered SC at this time according to the study protocol.

Pain and sedation scores were recorded by a blinded observer in the postanesthesia care unit (PACU) 1 and 2 h after injection of the study drug. Pain scores at rest and with movement were recorded during each of these evaluations. A 10-cm linear visual analog scale (VAS) was used for this measurement (0 = no pain and 10 = the worse imaginable pain). Sedation scores were measured on a numerical scale of 1–5 (1 = completely awake, 2 = awake but drowsy, 3 = asleep but responsive to verbal commands, 4 = asleep but responsive to tactile stimulus, 5 = asleep and not responsive to any stimulus).

Patients received IV fentanyl (25 µg every 5 min as needed) in the PACU if they experienced pain.

On discharge from the hospital, patients were instructed to take one Tylenol 3® (acetaminophen 300 mg/codeine 30 mg; McNeil Pharmaceuticals, Don Mills, Ontario, Canada) every 3 h as needed for pain. The first time they required additional opioid analgesia (either IV fentanyl or oral analgesics) and the total analgesic requirement during the initial 24 h after surgery were documented (patients were contacted by telephone the following day). In addition, patients recorded their VAS pain scores at rest and with movement 24 h after surgery.

Analgesic duration was considered as the time from IA injection of the study drug to the first requirement of supplemental opioid analgesics.

Patients were discharged when they were oriented to time and place, were able to void, had stable vital signs, and could ambulate with the assistance of crutches. Discharge time was classified s the time from the end of surgery until the patients met the discharge criteria.

Demographic data were analyzed by using analysis of variance. Duration of procedure, time to discharge, analgesic duration, pain scores, and amount of postoperative analgesics were analyzed by using Kruskal-Wallis. If a significant result was obtained, the Wilcoxon signed rank test was performed to determine between which groups there was significance; a Bonferroni adjustment was made for multiple comparisons. Significance was determined at the P < 0.05 level.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
There were no significant differences among the five treatment groups with respect to age, gender, height, weight, duration of surgery, or the time to discharge (Table 1). There was no significance with respect to the pain scores 1, 2, or 24 h postoperatively (Table 2). No patient experienced hypotension (mean arterial pressure <=20% baseline), hypoxemia (SpO2 <=90%), or bradycardia (heart rate <=60 bpm). There was no significant difference in sedation scores 1 and 2 h postoperatively (Table 2).


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  		Table 1. Demographic Data, Procedure, and Discharge Times
 

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  		Table 2. Pain and Sedation Scores
 
There was a significant difference in the duration of analgesia among the groups (P < 0.0001) (Figure 1). Group 2 had a significantly longer time to first analgesic request than Group 1 (P < 0.0001), Group 3 (P < 0.0001), Group 5 (P < 0.01), and Group 4 (P < 0.001). Group 5 had a significantly longer time to first analgesic request than Group 1 (P < 0.005), Group 3 (P <17;8>0.01), and Group 4 (P < 0.007).



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  		Figure 1. The analgesic duration in minutes in the five groups. Group B(IA) received subcutaneous (SC) saline (S) (1 mL) and intraarticular (IA) 0.25% bupivacaine (30 mL). Group BC(IA) received SC S (1 mL) and IA 0.25% bupivacaine (30 mL) with clonidine (1 µg/kg). Group B(IA)C(SC) received SC clonidine (1 µg/kg) and IA 0.25% bupivacaine (30 mL). Group BE(IA) received SC S (1 mL) and IA 0.25% bupivacaine (30 mL) with epinephrine (5 µg/mL). Group C(IA) received SC S (1 mL) and IA clonidine (1 µg/kg) with 30 mL of S. The box represents the 25th–75th percentiles, and the median is represented by the solid line. The extended bars represent the 10th–90th percentiles. The solid circles represent values outside this range. The BC(IA) group had a significantly longer time to first analgesic request than the B(IA) group (P < 0.0001), the B(IA)C(SC) group (P < 0.0001), the C(IA) group (P < 0.01), and the BE(IA) group (P < 0.001).

 
The 24-h consumption of Tylenol 3® was significantly different among the groups (P < 0.0001) (Figure 2). Group 2 consumed significantly fewer tablets than Group 1 (P < 0.0001), Group 3 (P < 0.0001), and Group 4 (P < 0.0001). Group 5 consumed significantly fewer tablets than Group 1 (P < 0.003), Group 3 (P < 0.005), and Group 4 (P < 0.001). There was no significant difference in analgesic consumption between Groups 5 and 2.



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  		Figure 2. The 24-h consumption of oral analgesics in the five groups. Group B(IA) received subcutaneous (SC) saline (S) (1 mL) and intraarticular (IA) 0.25% bupivacaine (30 mL). Group BC(IA) received SC S (1 mL) and IA 0.25% bupivacaine (30 mL) with clonidine (1 µg/kg). Group B(IA)C(SC) received SC clonidine (1 µg/kg) and IA 0.25% bupivacaine (30 mL). Group BE(IA) received SC S (1 mL) and IA 0.25% bupivacaine (30 mL) with epinephrine (5 µg/mL). Group C(IA) received SC S (1 mL) and IA clonidine (1 µg/kg) with 30 mL of S. The box represents the 25th–75th percentiles, and the median is represented by the solid line. The extended bars represent the 10th–90th percentiles. The solid circles represent values outside this range. The BC(IA) group consumed significantly fewer tablets than the B(IA) group (P < 0.0001), the B(IA)C(SC) group (P < 0.0001), and the BE(IA) group (P < 0.0001).

 
No patients required IV fentanyl in the PACU.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In an attempt to improve the recovery from arthroscopic knee surgery, research has been directed at new techniques for postoperative analgesia. We have previously investigated IA local anesthetics, IA opioids, and NSAIDs (6,7).

The IA administration of clonidine has been shown to decrease postoperative pain (5). Because clonidine can enhance peripheral nerve block when added to local anesthetics (4), we were interested in determining whether it might provide additional analgesia when added to IA bupivacaine. The results of our study confirm the analgesic benefit of IA clonidine. In addition, this analgesia was enhanced by the addition of IA bupivacaine as evidenced by an increased analgesic duration and a decreased need for postoperative analgesics.

In contrast to the study by Gentili et al. (5), in which patients received 150 µg (approximately 2 µg/kg), we chose to administer a smaller dose of clonidine (1 µg/kg). We used this smaller dose because when we administered clonidine doses >=2 µg/kg in our pilot study, many of the patients experienced excessive sedation and hypotension, which required a prolonged recovery time in the PACU. Likewise, Gentili et al. (5) reported either hypotension or bradycardia in 20% of the patients who received 150 µg of IA clonidine. Patients in other studies of regional anesthesia that used clonidine doses >100 µg had side effects of sedation, decreased blood pressure, and decreased heart rate (8). Furthermore, doses >300 µg have resulted in transient oxhemoglobin desaturation.1

The mechanism of action of clonidine’s ability to enhance peripheral nerve block of local anesthetics is unknown. Clonidine can selectively block conduction of C an A {delta} fibers (9). It may also cause local vasoconstriction, thereby reducing the vascular uptake of local anesthetics (10). This last mechanism, however, is controversial. A previous study evaluating peak plasma concentrations of lidocaine revealed significantly higher levels when clonidine was used compared with epinephrine; the authors concluded that clonidine lacks a local vasoconstrictor effect (11). Furthermore, similar to previous studies (12), we could not demonstrate any prolonged analgesic benefit from the addition of epinephrine to IA bupivacaine. In addition to its local anesthetic effects, clonidine may produce analgesia by releasing enkephalin-like substances resulting in peripheral analgesia (13). Opioid receptors may have an important role in the analgesic effect of clonidine. Considerable evidence implicates opioid-noradrenergic interactions in the production of analgesia (14,15). This has been supported by previous investigations demonstrating a cross-tolerance in analgesia between morphine and clonidine (16,17). Furthermore, the antinociceptive effect of clonidine can be antagonized by the administration of small-dose naloxone (18,19). The precise mechanism of the antinociceptive interaction between {alpha}-adrenoceptor and opioid receptor agonism is unclear; it might be the result of receptor stimulation, modulation, or via a common final pathway.

The results of the present study provide some evidence that clonidine exhibits a significant portion of its effect at the periphery rather than through a central mechanism. Patients who were administered SC clonidine did not receive any additional analgesic benefit. In addition, we previously demonstrated that clonidine provides a peripheral analgesic effect when administered via IV regional anesthesia in patients with sympathetically maintained pain (20) and after ambulatory hand surgery (21).

In conclusion, we have shown that clonidine, when administered along with bupivacaine via the IA route, results in a significant improvement in analgesia. There was an increased time to first analgesic request and a decreased need for postoperative analgesics.


   Footnotes
 
1 Macaire P, Bernard JM, Le Roux D, et al. Dose-ranging study of clonidine added to lidocaine for axillary plexus block in outpatients [abstract]. Anesthesiology 1995;83:A774. Back


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Dahl MR, Dasta JF, Zuelzer W, McSweeney TD. Lidocaine local anesthesia for arthroscopic knee surgery. Analg 1990;71:670–4.[Abstract/Free Full Text]
  2. Eriksson E, Haggmark T, Saarto KT, Ortengren B. Knee arthroscopy with local anesthesia in ambulatory patients: methods, results, and compliance. Orthopedics 1986;9:186–91.[Web of Science][Medline]
  3. Chirwa SS, MacLeod BA, Day B. Intraarticular bupivacaine after arthroscopic meniscectomy: a randomized double-blind controlled study. Arthroscopy 1989;5:33–5.[Medline]
  4. Gaumann DM, Brunet PC, Jirounek P. Clonidine enhances the effects of lidocaine on C-fiber action potential. Anesth Analg 1992;74:719–25.[Abstract/Free Full Text]
  5. Gentili M, Juhel A, Bonnett F. Peripheral analgesic effect of intra-articular clonidine. Pain 1996;64:593–6.[Web of Science][Medline]
  6. Reuben SS, Connelly NR. Postoperative analgesia for outpatient arthroscopic knee surgery with intraarticular bupivacaine and ketorolac. Anesth Analg 1995;80:1154–7.[Abstract]
  7. Reuben SS, Connelly NR. Postarthroscopic meniscus repair analgesia with intraarticular ketorolac or morphine. Anesth Analg 1996;82:1036–9.[Abstract]
  8. Eisenach JC, DeKlock M, Klimscha W. {alpha}2-Adrenergic agonists for regional anesthesia: a clinical review of clonidine. Anesthesiology 1996;85:655–74.[Web of Science][Medline]
  9. Butterworth JF, Strichartz GR. The {alpha}2-adrenergic agonists clonidine and guanfacine produce tonic and phasic block of conduction in rat sciatic nerve fibers. Anesth Analg 1993;76:295–301.[Web of Science][Medline]
  10. Langer SZ, Duval N, Masingham R. Pharmacologic and therapeutic significance of alpha-adrenoceptor subtypes. J Cardiovasc Pharmacol 1985;7:1–8.[Web of Science][Medline]
  11. Gaumann D, Forster A, Griessen M, et al. Comparison between clonidine and epinephrine admixture to lidocaine in brachial plexus block. Anesth Analg 1992;75:69–74.[Abstract/Free Full Text]
  12. Osborne D, Keene G. Pain relief after arthroscopic surgery of the knee: a prospective, randomized, and blinded assessment of bupivacaine and bupivacaine with adrenaline. Arthroscopy 1993;9:177–80.[Web of Science][Medline]
  13. Nakamura M, Ferreira SH. Peripheral analgesic action of clonidine: mediation by release of endogenous enkephalin-like substances. J Pharmacol 1988;146:223–8.
  14. Spaulding TC, Fielding S, Venafro JJ, Lal H. Antinociceptive activity of clonidine and its potentiation of morphine analgesia. Eur J Pharmacol 1979;58:19–25.[Web of Science][Medline]
  15. Camarata PJ, Yaksh TL. Characterization of the spinal adrenergic receptors mediating the spinal effects produced by microinjection of morphine into the periaqueductal gray. Brain Res 1985;336:133–42.[Web of Science][Medline]
  16. Post C, Archer T, Minor BG. Evidence for cross-tolerance to the analgesic effects between morphine and selective {alpha}2-adrenoceptor agonists. J Neural Trans 1988;72:1–9.
  17. Paul D, Tran JG. Differential cross-tolerance between analgesia produced by {alpha}2-adrenoceptor agonists and receptor subtype selective opioid treatments. Eur J Pharmacol 1995;272:11–4.
  18. Kumar A, Raghubir R, Dhawan BN. Analgesic effect of morphine, clonidine and serotonin microinjected into the PTN of rats. Neuroreport 1993;4:944–6.[Web of Science][Medline]
  19. Sierralta F, Naquira D, Pinardi G, Miranda HF. {alpha}-Adrenoceptor and opioid receptor modulation of clonidine-induced antinociception. Br J Pharmacol 1996;119:551–4.[Web of Science][Medline]
  20. Reuben SS, Steinberg RB, Madabhushi L, Rosenthal E. Intravenous regional clonidine in the management of sympathetically mediated pain. Anesthesiology 1998;89:527–30.[Web of Science][Medline]
  21. Reuben SS, Klatt ML, Klatt JL, et al. Intravenous regional anesthesia with lidocaine and clonidine [abstract]. Anesthesiology 1998;89:A857.
Accepted for publication January 7, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press