JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS
AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
A&A International Anesthesia Research Society
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (33)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Joshi, W.
Right arrow Articles by Maciolek, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Joshi, W.
Right arrow Articles by Maciolek, H.
Anesth Analg 2000;90:1102-1106
© 2000 International Anesthesia Research Society

AMBULATORY ANESTHESIA

Postoperative Analgesia for Outpatient Arthroscopic Knee Surgery with Intraarticular Clonidine and/or Morphine

Wanda Joshi, DO*, Scott S. Reuben, MD*, Prasad R. Kilaru, MD*, Joseph Sklar, MD{dagger}, and Holly Maciolek, RN*

* Departments of Anesthesiology and {dagger}Orthopedics, Baystate Medical Center and the 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{at}bhs.org


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Both clonidine, an {alpha}2 agonist, and morphine, an opioid agonist, provide enhanced patient analgesia after arthroscopic knee surgery when administered via the intraarticular (IA) route. Clonidine potentiates morphine analgesia in the animal model. We designed this study to determine whether clonidine or morphine results in better analgesia and whether their combination would provide superior analgesia to either drug alone. We evaluated 60 patients undergoing arthroscopic knee meniscus repair under local anesthesia with sedation. After surgery, patients were randomized into four IA groups: Group B received 30 mL 0.25% bupivacaine; Group BC received 30 mL 0.25% bupivacaine and clonidine 1 µg/kg; Group BM received 30 mL 0.25% bupivacaine and morphine 3 mg; and Group BCM received 30 mL 0.25% bupivacaine, clonidine 1 µg/kg, and morphine 3 mg. This study revealed a significant benefit from the individual IA administration of both clonidine and morphine. The combination of these drugs resulted in decreased postoperative pain and analgesic use, as well as an increased analgesic duration compared with either drug alone. We conclude that IA clonidine and morphine improved comfort compared with either drug alone in patients undergoing knee arthroscopy.

Implications: The intraarticular administration of both clonidine and morphine along with bupivacaine improves postoperative analgesia compared with either drug alone. There was an increased time to first analgesic request, decreased need for postoperative analgesics, and lower pain scores after arthroscopic knee surgery.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Intraarticular (IA) bupivacaine provides enhanced postoperative analgesia after arthroscopic knee surgery (1–3). The addition of either morphine (4,5) or clonidine (6) to IA bupivacaine improves postoperative analgesia compared with either drug alone. The antinociceptive activity of clonidine potentiates morphine analgesia in the animal model (7). However, Gentili et al. (8) were unable to detect an enhanced analgesic effect from the combination of IA morphine and clonidine. We investigated patients undergoing diagnostic arthroscopy in which they reported low postoperative pain scores and rescue medication was limited. We hypothesized that a more painful arthroscopic surgical procedure could have elicited a difference in analgesic efficacy between the two study drugs. We designed our study to determine whether IA morphine or clonidine results in better analgesia and whether the combination would provide superior analgesia to either drug alone after arthroscopic meniscectomy.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After institutional review board approval, informed written consent was obtained from 60 patients scheduled to undergo elective arthroscopic meniscal surgery by a single surgeon. Patients eligible for participation spoke English, were older than 18 yr, and were ASA physical status I or II. Patients excluded were being medicated with narcotics preoperatively or had a contraindication to the use of clonidine or morphine.

After placement of routine monitors, patients received 30 mL IA bupivacaine 0.25% for their anesthetic. IV sedation was achieved with propofol (10–100 µg · kg-1 · min-1) and midazolam (1–3 mg). Narcotics were not a component of the intraoperative sedation. After the surgical procedure, patients were assigned to one of four treatment groups in a double-blinded, randomized manner: Group B (IA bupivacaine) received 30 mL 0.25% bupivacaine; Group BC (IA clonidine) received 30 mL 0.25% bupivacaine and clonidine 1 µg/kg; Group BM (IA morphine) received 30 mL 0.25% bupivacaine and morphine 3 mg; and Group BCM (IA clonidine/morphine) received 30 mL 0.25% bupivacaine, clonidine 1 µg/kg, and morphine 3 mg.

Pain scores both at rest and with movement were recorded by a blinded observer in the postanesthesia care unit (PACU) at 1 and 2 h after injection of the study drug. A 10-cm linear visual analog scale (VAS) was used for this measurement with 0 = no pain and 10 = the worse imaginable pain. Patients received IV fentanyl (25 µg every 5 min as needed) in the PACU.

On discharge from the hospital, patients were instructed to take one acetaminophen 325 mg/oxycodone 5 mg (Percocet) 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 both at rest and with movement 24 h after surgery. Pain scores at 24 h were returned to the surgeon during their follow-up visit. 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 as 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 the Kruskal-Wallis test. When a significant result was obtained, Wilcoxon’s signed rank test was performed to determine significance between groups; a Bonferroni adjustment was made for multiple comparisons. Significance was determined at the P < 0.05 level. The following assumptions were made for the power analysis performed before the investigation: 1) for the pain scores, a 50% difference in pain scores; 2) for the analgesic consumption, a difference of two pills per 24 h; 3) for the time to first analgesic, a difference of 3 h. With these assumptions, a power of 90%, and an {alpha} of 0.05 of 6 (because there are six possible comparisons between the four groups), the pain score comparison required the largest number of patients. This figure was 15 patients per group. The power analysis performed at the conclusion of the study, by using an {alpha} of 0.05 of 6 and given 15 patients per group, revealed a power greater than 90%.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
There were no significant differences between the four treatment groups with respect to age, sex, height, weight, duration of surgery, or discharge time (Table 1). No patient experienced hypotension (mean arterial pressure <=20% baseline), hypoxemia (SpO2 <=90%), or bradycardia (heart rate <=60 bpm). No patient complained of sedation or other side effects.


View this table:
[in this window]
[in a new window]
  		Table 1. Patient Demographics and Surgical Data
 
There was a significant difference in the duration of analgesia between the groups (P < 0.0001) (Figure 1). Group BCM had a significantly longer time to first analgesic request than Group B (P < 0.0001), Group BC (P < 0.001), or Group BM (P < 0.001). Groups BC and BM had a significantly longer time to first analgesic request than Group B (P < 0.001). There was no significant difference in analgesic duration between Groups BC and BM.



View larger version (20K):
[in this window]
[in a new window]
  		Figure 1. The analgesic duration in minutes in the four groups. Group B received 30 mL intraarticular (IA) 0.25% bupivacaine; Group BC received 30 mL IA 0.25% bupivacaine and clonidine 1 µg/kg; Group BM received 30 mL IA 0.25% bupivacaine and morphine 3 mg; and Group BCM received 30 mL IA 0.25% bupivacaine, clonidine 1 µg/kg, and morphine 3 mg. The box represents the 25th to 75th percentiles, and the median is represented by the solid line. The extended bars represent the 10th to 90th percentiles. The solid circles (•) represent values outside this range. Group BCM had a significantly longer time to first analgesic request than Group B (P < 0.0001), Group BC (P < 0.001), or Group BM (P < 0.001). Groups BC and BM had a significantly longer time to first analgesic request than Group B (P < 0.001). There was no significant difference in analgesic duration between Groups BC and BM.

 
The 24 h consumption of Percocet was significantly different among the groups (P < 0.0001) (Figure 2). Group BCM consumed significantly fewer tablets than Group B (P < 0.0001), Group BC (P < 0.003), or Group BM (P < 0.02). Groups BC and BM consumed significantly fewer tablets than Group B (P < 0.0001). There was no significant difference in analgesic consumption between Groups BC and BM. No patients required IV fentanyl in the PACU.



View larger version (26K):
[in this window]
[in a new window]
  		Figure 2. The 24-h consumption of oral analgesics in the four groups. Group B received 30 mL intraarticular (IA) 0.25% bupivacaine; Group BC received 30 mL IA 0.25% bupivacaine and clonidine 1 µg/kg; Group BM received 30 mL IA 0.25% bupivacaine and morphine 3 mg; and Group BCM received 30 mL IA 0.25% bupivacaine, clonidine 1 µg/kg, and morphine 3 mg. The box represents the 25th to 75th percentiles, and the median is represented by the solid line. The extended bars represent the 10th to 90th percentiles. The solid circles (•) represent values outside this range. Group BCM consumed significantly fewer tablets than Group B (P < 0.0001), Group BC (P < 0.003), or Group BCM (P < 0.02). Groups BC and BM consumed significantly fewer tablets than Group B (P < 0.0001). There was no significant difference in analgesic consumption between Groups BC and BM.

 
There was a significant difference with respect to pain scores both at rest and with movement at 2 and 24 h between the groups (Table 2). Both 2 and 24 h pain scores at rest were lower in Group BCM compared with Group B (P < 0.001) or Groups BC and BM (P < 0.01). Similarly, 2 and 24 h pain scores with movement were lower in Group BCM compared with Group B (P < 0.001) or Groups BC and BM (P < 0.03). There were no differences in pain scores between the four groups at 1 h postoperatively.


View this table:
[in this window]
[in a new window]
  		Table 2. Postoperative Pain Scores
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This study revealed a significant analgesic benefit from the individual IA administration of both clonidine and morphine. The analgesic effect of IA morphine has been well described in the literature (9,10). Most studies reveal a beneficial effect when morphine is administered via the IA route after arthroscopic knee surgery (9,10). More recently, clonidine has also been shown to possess an analgesic effect when injected into the knee joint after arthroscopic surgery (11). We recently demonstrated that the analgesic effect of bupivacaine was enhanced by the addition of IA clonidine (6). The current study not only confirmed this analgesic benefit, it further revealed that the addition of morphine to bupivacaine and clonidine provided even more effective analgesia. Patients in group IA clonidine/morphine had a longer analgesic duration and lower 24-hour analgesic use compared with either groups IA clonidine or IA morphine. Despite this improved pain relief in the early postoperative period, we were unable to demonstrate a difference in discharge times between the study groups. This finding was probably related to the fact that all patients underwent arthroscopy under local anesthesia, and postoperative pain scores were very low in all four treatment groups during the first two hours after surgery. In fact, no patients required opioid analgesics in the PACU before discharge home.

Several previous studies in the animal model have suggested a synergistic interaction between clonidine and morphine with respect to antinociception. Spaulding et al. (7) revealed that the antinociceptive activity of systemically administered clonidine was found to potentiate morphine analgesia in the rat tail flick assay. In this study, clonidine’s agonist activity was not reversed by naloxone, suggesting a mechanism of action independent of opioid receptor affinity. Murata et al. (12) also revealed that systemically administered clonidine and morphine have synergistic analgesic effects. These investigators demonstrated that subtherapeutic doses of clonidine and morphine by themselves were unable to elicit antinociceptive activity; however, their combination inhibited responses of wide dynamic-range neurons to thermal nociception. Ossipov et al. (13) and Wilcox et al. (14) reported the potentiation of clonidine and morphine when administered via the intrathecal route in the rat tail flick model. Drasner and Fields (15) demonstrated that systemic morphine and intrathecal clonidine also have synergistic antinociceptive activity in the same animal model. By using a more rigorous means to examine drug-drug interactions, Ossipov et al. (16) performed an isobolographic analysis of the dose-response curves of fixed ratios of morphine and clonidine. This study substantiated the reports that intrathecally administered morphine and clonidine act in a synergistic fashion. In addition, these authors revealed that the IV administration of these two drugs may be either additive or supraadditive, depending on the ratio of clonidine to morphine and the test used.

There have been no studies performed examining the antinociceptive effect of clonidine and morphine administered via the IA route in the animal model. Gentili et al (8). were the first investigators to study the analgesic effects of morphine and clonidine in humans when used alone and in combination after arthroscopic knee surgery. In this study, both clonidine 150 µg and morphine 2 mg resulted in equivocal analgesia, whereas the combination failed to demonstrate an enhanced analgesic effect. Similarly, we failed to demonstrate any significant difference in the analgesic efficacy between either IA morphine 3 mg or clonidine 1 µg/kg. However, at these doses, we revealed a significant analgesic benefit from the combination of these two drugs after arthroscopic meniscectomy. We used a smaller dose of clonidine in our study because when we previously administered IA clonidine doses <=2 µg/kg, many of the patients experienced excessive sedation and hypotension. Likewise, Gentili et al. (8) reported either hypotension or bradycardia in 20% of the patients who received 150 µg (approximately 2 µg/kg) of IA clonidine.

It is possible that the different ratio of clonidine to morphine we used may have accounted for the observed difference in analgesic efficacy, as suggested by Ossipov et al. (16). We believe the more likely explanation is the result of including a more painful surgical procedure (meniscectomy) in our study group rather than a less painful procedure (diagnostic arthroscopy). In the study by Gentili et al. (8), patients reported very low postoperative pain scores (mean VAS <=3) at all time intervals. In addition, >50% of the patients required no postoperative analgesics for the entire study period. Under these circumstances, sufficient analgesia was already achieved with either drug alone, thus making it difficult to detect a difference in analgesic efficacy from the combination. In contrast, we studied a more painful surgical procedure in which all patients required postoperative analgesics during the 24 h study period. In addition, we evaluated pain both at rest and with movement, which is a more sensitive measurement of analgesic efficacy.

In conclusion, we have shown that the IA administration of both clonidine and morphine, along with bupivacaine, improves postoperative analgesia compared with either drug alone. There was an increased time to first analgesic request, decreased need for postoperative analgesics, and lower pain scores after arthroscopic knee surgery.


   Footnotes
 
Presented in part at the annual meeting of the American Society of Anesthesiologists, Dallas, TX, October, 1999.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Chirwa SS, MacLeod BA, Day B. Intraarticular bupivacaine after arthroscopic meniscectomy: a randomized double-blind controlled study. Arthroscopy 1989;5:3–5.
  2. Henderson RC, Campion ER, Demasi RA, Taft TN. Postarthroscopy analgesia with bupivacaine: a prospective, randomized blinded evaluation. Am J Sports Med 1990;18:614–7.[Abstract/Free Full Text]
  3. Allen GC, St. Amand MA, Lui ACP, et al. Postarthroscopy analgesia with intraarticular bupivacaine/morphine. Anesthesiology 1993;79:475–80.[Web of Science][Medline]
  4. Stein C, Haimerl E, Yassouridis A, et al. Analgesic effect of intraarticular morphine after arthroscopic knee surgery. Engl J Med 1991;325:1123–6.[Abstract]
  5. Khoury GF, Chen ACN, Garland DE, Stein C. Intraarticular morphine, bupivacaine and morphine/bupivacaine for pain control after knee videoarthroscopy. Anesthesiology 1992;77:263–6.[Web of Science][Medline]
  6. Reuben SS, Connelly NR. Postoperative analgesia for outpatient arthroscopic knee surgery with intraarticular clonidine. Anesth Analg 1999;88:729–33.[Abstract/Free Full Text]
  7. 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]
  8. Gentili M, Houssel P, Osman M, et al. Intra-articular morphine and clonidine produce comparable analgesia but the combination is not more effective. Br J Anaesth 1997;79:660–1.[Abstract/Free Full Text]
  9. Kalso E, Tramer MR, Carroll D, et al. Pain relief from intra-articular morphine after knee surgery: a qualitative review. Pain 1997;71:127–34.[Web of Science][Medline]
  10. Stein CS, Schafer M. Peripheral opioid analgesia: basic and clinical aspects. Semin Anesth 1997;16:112–6.
  11. Gentili M, Jubel A, Bonnet F. Peripheral analgesic effects of intraarticular clonidine. Pain 1996;64:593–6.[Web of Science][Medline]
  12. Murata K, Nakagawa I, Kumeta Y, et al. Intrathecal clonidine suppresses noxiously evoked activity of spinal wide dynamic range neurons in cats. Anesth Analg 1989;69:185–91.[Abstract/Free Full Text]
  13. Ossipov MH, Suarez LJ, Spaulding TC. Antinociceptive interactions between alpha-2 adrenergic and opiate agonists at the spinal level in rodents. Anesth Analg 1989;68:194–200.[Abstract/Free Full Text]
  14. Wilcox GL, Carlsson KH, Johim A, Jurna I. Mutual potentiation of antinociceptive effects of morphine and clonidine on motor and sensory responses in rat spinal cord. Brain Res 1987;405:84–93.[Web of Science][Medline]
  15. Drasner K, Fields HL. Synergy between the antinociceptive effects of intrathecal clonidine and systemic morphine in rats. Pain 1988;32:309–12.[Web of Science][Medline]
  16. Ossipov MH, Harris S, Lloyd P, Messineo E. An isobolographic analysis of the antinociceptive effect of systemically and intrathecally administered combinations of clonidine and opiates. J Pharmacol Exp Ther 1990;225:1107–16.
Accepted for publication January 26, 2000.




This article has been cited by other articles:


Home page
 Br J AnaesthHome page
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
Effect of intra-articular dexmedetomidine on postoperative analgesia after arthroscopic knee surgery
Br. J. Anaesth., September 1, 2008; 101(3): 395 - 399.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
N. M. Elsharnouby, H. E. Eid, N. F. Abou Elezz, and A. N. Moharram
Intraarticular Injection of Magnesium Sulphate and/or Bupivacaine for Postoperative Analgesia After Arthroscopic Knee Surgery
Anesth. Analg., May 1, 2008; 106(5): 1548 - 1552.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
O. B. Ansah and A. Pertovaara
Peripheral Suppression of Arthritic Pain by Intraarticular Fadolmidine, an {alpha}2-Adrenoceptor Agonist, in the Rat
Anesth. Analg., July 1, 2007; 105(1): 245 - 250.
[Abstract] [Full Text] [PDF]

Home page
 JBJSHome page
S. S. Reuben and A. Buvanendran
Preventing the Development of Chronic Pain After Orthopaedic Surgery with Preventive Multimodal Analgesic Techniques
J. Bone Joint Surg. Am., June 1, 2007; 89(6): 1343 - 1358.
[Abstract] [Full Text] [PDF]

Home page
 Br J AnaesthHome page
R. S. Bondok and A. M. Abd El-Hady
Intra-articular magnesium is effective for postoperative analgesia in arthroscopic knee surgery
Br. J. Anaesth., September 1, 2006; 97(3): 389 - 392.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
K. M. Tran, T. J. Ganley, L. Wells, A. Ganesh, K. I. Minger, and G. Cucchiaro
Intraarticular Bupivacaine-Clonidine-Morphine Versus Femoral-Sciatic Nerve Block in Pediatric Patients Undergoing Anterior Cruciate Ligament Reconstruction
Anesth. Analg., November 1, 2005; 101(5): 1304 - 1310.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
P. F. White
The Changing Role of Non-Opioid Analgesic Techniques in the Management of Postoperative Pain
Anesth. Analg., November 1, 2005; 101(5S_Suppl): S5 - 22.
[Abstract] [Full Text] [PDF]

Home page
 Pharmacol. Rev.Home page
J. Sawynok
Topical and Peripherally Acting Analgesics
Pharmacol. Rev., March 1, 2003; 55(1): 1 - 20.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
S. S. Reuben, J. Sklar, and M. El-Mansouri
The Preemptive Analgesic Effect of Intraarticular Bupivacaine and Morphine After Ambulatory Arthroscopic Knee Surgery
Anesth. Analg., April 1, 2001; 92(4): 923 - 926.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
S. S. Reuben and M. F. Mulroy
Ambulatory Anesthesia for Knee Arthroscopy
Anesth. Analg., February 1, 2001; 92(2): 556 - 556.
[Full Text] [PDF]

Home page
 JBJSHome page
S. S. Reuben and J. Sklar
Pain Management in Patients Who Undergo Outpatient Arthroscopic Surgery of the Knee
J. Bone Joint Surg. Am., December 1, 2000; 82(12): 1754 - 1754.
[Full Text]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (33)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Joshi, W.
Right arrow Articles by Maciolek, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Joshi, W.
Right arrow Articles by Maciolek, H.

Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press