Anesth Analg 2003;97:1016-1019
© 2003 International Anesthesia Research Society
AMBULATORY ANESTHESIA
The Effects of Preoperative Inflammation on the Analgesic Efficacy of Intraarticular Piroxicam for Outpatient Knee Arthroscopy
Seval Izdes, MD*,
Sibel Orhun, MD
,
Sacit Turanli, MD
,
Ezgi Erkilic, MD*, and
Orhan Kanbak, MD*
Departments of *Anesthesia,
Pathology, and
Orthopaedic Surgery, Emergency And Traumatology Hospital, Ankara, Turkey
Address correspondence and reprint requests to Seval Izdes, MD, 39 Sokak No:11/3 06500, Bahcelievler Ankara, Turkey. Address email to sevalizdes{at}yahoo.com
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Abstract
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We conducted a double-blinded study in 90 patients undergoing elective arthroscopic knee surgery to determine whether there is a role of inflammation in the analgesic efficacy of intraarticular piroxicam. Standardized general anesthetic techniques were used for all patients. At the end of the operation, after harvesting synovial biopsies, patients were randomized into three intraarticular groups equally. Group 1 received 25 mL saline, Group 2 received 25 mL 0.25% bupivacaine, and Group 3 received 25 mL 0.25% bupivacaine and piroxicam 20 mg. After microscopic examination of the synovial materials, the patients were divided into two subgroups, inflammation positive (I+) and inflammation negative (I-). Preoperatively and postoperatively at 1, 2, 4, and 6 h, pain levels, analgesic duration, and postoperative analgesic consumption were recorded. Analgesic duration was significantly longer in the I+ subgroup than the I- subgroup of Group 3 (P < 0.05). Pain scores at 1, 2, and 4 h postoperatively were significantly lower in the I+ subgroup than the I- subgroup of Group 3 (P < 0.05), whereas there were no significant differences among the subgroups of Group 1 and 2. We concluded that preoperative inflammation is one of the most important determinants of analgesic efficacy of intraarticular piroxicam.
IMPLICATIONS: Intraarticular administration of piroxicam along with bupivacaine improves postoperative analgesia in synovial inflammation before surgery.
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Introduction
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Arthroscopy of the knee joint is one of the most common operations performed on an ambulatory basis. The success of ambulatory surgery depends to some extent on effective control of postoperative pain. A variety of analgesic techniques have been used to manage postoperative pain after arthroscopic knee surgery. The ideal would be to provide adequate local analgesia of long duration without any side effects (1,2). Intraarticular drug use has become widespread, and thus local anesthetics, opioids, and nonsteroidal antiinflammatory drugs (NSAIDs) alone or in combined forms are used to enhance their effectiveness (2–4) in providing satisfactory analgesia after day-case knee arthroscopies. However, NSAIDs administered intraarticularly produce conflicting data with respect to their analgesic efficacy (3,5). These controversial results may be related to the presence of inflammation in the joint space structures before the operation. This clinical trial was therefore designed to determine whether preoperative inflammation has a role in analgesic efficacy of intraarticular piroxicam after arthroscopic knee surgery.
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Methods
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After obtaining local ethics committee approval and written informed consent, 90 unpremedicated ASA physical status I and II patients scheduled for outpatient arthroscopic knee surgery were enrolled in the study. Patients receiving analgesics preoperatively, having a contraindication to receive NSAIDs, or requiring knee drainage were excluded from the study. Before the operation all patients received instructions for using a 10-cm visual analog scale (VAS), with 0 = no pain to 10 = the worst imaginable pain, and baseline pain scores at rest were recorded. In all patients, anesthesia was induced with propofol 2.5 mg/kg IV and alfentanil 10 µg/kg IV and laryngeal masks (no: 3/4) were placed. Anesthesia was maintained with 1.5%–2% sevoflurane and 65% nitrous oxide in oxygen. No other supplementary analgesic medication was given during the operation after the first dose of alfentanil. Before surgical incision, a pneumatic tourniquet inflated to a pressure of 300 mm Hg was applied to all patients. The same surgeon performed all the surgical procedures using a standard surgical technique. At the end of the operation, after synovial biopsies from the inflammation-like synovial tissues were obtained, patients were randomized using a random number table into three equal groups consisting of 30 patients. Group 1 received 25 mL of normal saline, Group 2 received 25 mL of isobaric bupivacaine 0.25%, and Group 3 received 25 mL of isobaric bupivacaine 0.25% + 20 mg piroxicam intraarticularly through a 22-gauge needle after the closure of the knee joint and immediate application of a firm bandage around the knee. The pneumatic tourniquet was kept inflated for 10 min after the injection.
Pain levels were assessed using VAS at rest and at the point of the onset of the pain, and pain levels were assessed at 1, 2, 4, and 6 h postoperatively by another anesthesiologist blinded to the drug injected. A physician not related to the study managed analgesic therapy and meperidine 1 mg/kg IM was given for a pain VAS score >4. In addition, analgesic duration, defined as the time from completion of surgery until first requirement of supplemental analgesics, and postoperative analgesic consumption during the initial 6 h after surgery were also recorded.
In microscopic examination of the synovial materials by a blinded pathologist, presence of acute and/or chronic inflammatory cells (polymorphonuclear leukocytes, lymphocytes, plasma cells and macrophages) associated with tissue edema and vascular proliferation were accepted as evidence of inflammation. The inflammatory reaction, which had infiltrated more than 5% of synovial areas, was evaluated as positive. After microscopic examination, all the patients were divided into two subgroups, inflammation positive (I+) and inflammation negative (I-).
Data analysis was performed by the 
2 test, Kruskal-Wallis test or Mann-Whitney U-test as appropriate. In all cases, P < 0.05 was considered to be significant. All data are presented as mean ± SD.
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Results
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There were no significant differences among the subgroups of the three treatment groups with respect to age, sex, height, or weight. However among the three groups, I+ subgroups were found to have significantly longer operation and tourniquet times than I- subgroups (Table 1). When the groups were investigated without dividing into subgroups, analgesic duration was significantly longer in Groups 2 and 3 (mean, 60.8 ± 19.1 min; mean, 66.1 ± 13.1 min) than in Group 1 (mean, 24.5 ± 11 min) and VAS at the time to first pain and analgesic requirements over the 6-h study period were also significantly less (P < 0.05), but there were no significant differences among all variables between Groups 2 and 3. After dividing these groups into subgroups, we found that analgesic duration was significantly longer in the I+ subgroup than the I- subgroup of Group 3, and their requirements for meperidine over the 6-h study period was also significantly less (P < 0.05) (Table 2). VAS pain scores at 1, 2, and 4 h postoperatively were significantly lower in the I+ subgroup than the I- subgroup of Group 3 (P < 0.05), whereas there were no significant differences among the subgroups of Group 1 and 2 (Fig. 1).
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Figure 1. Preoperative and postoperative visual analog scores (VAS). Data expressed as mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001 compared with I- subgroup; #P < 0.05, ##P < 0.01, ###P < 0.001 compared with Group 1; !P < 0.05, !!P < 0.01, !!!P < 0.001 compared with Group 2.
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Discussion
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After arthroscopy of the knee joint, patients regularly suffer from severe pain. Although the degree of superficial trauma is less with these procedures, the internal surgical site of repair, including the synovial tissue, the anterior fat pad, and the joint capsule, have free nerve endings that are capable of transmitting painful stimuli and producing severe pain (6). A variety of treatment modalities have been applied for postoperative pain relief after arthroscopic knee surgery and many efforts have been made to maximize analgesia and minimize side effects (1,7). In recent years, intraarticular analgesia has been used for arthroscopy in an attempt to establish the smallest drug dose providing effective analgesia with minimum side effects. Local anesthetics were the first of such drugs to be given intraarticularly for purposes of postoperative analgesia, and they remain in wide use (2). However, in most cases observed reductions in postoperative pain are small to moderate and short lasting and patients may need supplementary analgesia, which delays their discharge (8). Intraarticular multimodal regimens after arthroscopic knee surgery may provide enhanced effects on postoperative pain. Many studies have focused on the benefits of the addition of different drugs such as bicarbonate, adrenaline, opioids, and NSAIDs to intraarticular local anesthetic (4,7,9,10).
Opioids administered intraarticularly produce conflicting data with respect to their analgesic efficacy. Some reports showed intraarticular opioids to be ineffective (11,12); others reported a significant effect in reducing postoperative pain intensity and consumption of analgesics (4). Antinociceptive effects of opioids have been attributed primarily to an activation of receptors located in the central nervous system. However, experimental research indicated that locally administered opioid agonists could produce analgesic effects by binding with peripheral opioid receptors, which appeared to become especially active in the presence of inflammation (13). More recently, opioid receptors have been found in synovial biopsies from the knee (14). These experimental results were later confirmed in human clinical trials (15,16), and it is believed that the intraarticular analgesic effects of opioids are optimally found in the presence of preexisting inflammation, which may partly account for the discrepancy in the results between the studies.
As with the opioids, intraarticular administration of NSAIDs after knee arthroscopy has been found to provide variable results with respect to their analgesic efficacy. Different types of NSAIDs, such as ketorolac and tenoxicam, have been used alone or in combination with intraarticular local anesthetics or morphine in a number of clinical studies (3,17). Several clinical studies have reported effective analgesia and reduction in postoperative analgesic requirements and prolongation of analgesia provided by local anesthetics and morphine used alone (5,7,17). In contrast, other investigators have not demonstrated an analgesic effect or any benefit in terms of pain scores after the use of intraarticular NSAIDs over placebo (3,18,19). However, there is no clear explanation of the differences in findings among published studies. To resolve the controversy of intraarticular NSAIDs efficiency, this study was designed to determine whether preoperative inflammation has a role in analgesic efficacy of intraarticular piroxicam after arthroscopic knee surgery.
By evaluating the overall results obtained from our study we could not find any significant differences between bupivacaine alone and bupivacaine-piroxicam groups in terms of pain onset times and pain intensity at the onset. VAS pain scores in the group receiving both piroxicam and bupivacaine appear to be no better than bupivacaine alone irrespective of whether there was or was not preexisting inflammation. Conversely analgesic duration was found to be significantly longer in the bupivacaine-piroxicam synovial inflammation positive subgroup compared with the no inflammation subgroup. Significantly less pain intensity at 1, 2, and 4 h postoperatively and analgesic requirements were also observed in the same subgroup. However, there were no differences between the subgroups of the bupivacaine group and the control group. These results suggest that adding piroxicam to intraarticular local anesthetic can provide an additive synergic effect in the existence of synovial inflammation before surgery.
NSAIDs interrupt the activation of peripheral nociceptors by reducing the local concentration of arachidonic acid metabolites such as prostaglandins and thromboxanes, which mediate the inflammatory process. Some suggest a peripheral-central synergistic action that varies depending on the particular NSAID and on the presence or absence of an inflammatory process (20). Studies comparing intraarticular NSAIDs with systemic administration showed significant results in favor of the intraarticular administration, indicating a peripheral analgesic effect (5,7). It has been demonstrated that NSAIDs could cause a decrease in the secretion of inflammatory mediators when synovial membrane specimens were incubated locally with therapeutic doses of NSAIDs (21). The presence of inflammation in the joint spaces before operation may provide a source of postoperative sensory signals that can be prevented by NSAIDs, and these drugs would be more effective in controlling pain after surgery. In this respect, our findings may suggest why several studies have failed to demonstrate analgesic effects of intraarticular NSAIDs although a number of other studies have shown significant analgesic effects.
Conversely, there is a positive correlation between the severity of postoperative pain and the duration of surgery rather than the type of the surgery (5). In our study, although no significant differences were found in surgery times among the inflammation positive subgroups, pain intensity levels at 1, 2, and 4 h postoperatively were significantly less in the bupivacaine-piroxicam synovial inflammation positive subgroup. On the basis of these results, surgery time can be excluded as an important factor on postoperative pain in our study, and we have concluded that preoperative inflammation is one of the most important determinants on the analgesic efficacy of intraarticular NSAIDs.
Although there remains some question as to whether or not NSAIDs are safe for intraarticular administration, Elhakim (22) used intraarticular tenoxicam routinely with a much larger number of patients for years and did not address the possibility of adverse effects from the intraarticular administration of tenoxicam. Although more studies are needed before final recommendations can be made, by evaluating the results obtained from our study, widespread use of intraarticular NSAIDs cannot be recommended for day-case arthroscopic surgery. However, we strongly suggest adding NSAIDs to postoperative pain therapy if the existence of synovial inflammation has been considered before surgery.
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Footnotes
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Presented in part at the 10th ESA Anniversary Meeting and 24th EAA Annual Meeting Euroanaesthesia 2002, Nice, France, 6–9 April 2002.
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References
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Accepted for publication May 23, 2003.
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Abstract
Introduction
