Background
Arthroscopic knee surgery is one of the most common orthopedic procedures performed in the outpatient setting. Approximately 985,000 Americans underwent this surgery in 2006, according to national estimates [
1]. Although knee arthroscopy causes less trauma than open surgery, considerable postoperative pain can hinder a patient’s ability to participate in early rehabilitation and affect the patient’s activity level and satisfaction. Patients are usually discharged shortly after surgery and must be provided with analgesia that is both safe and effective. Single intra-articular (IA) administration of local anesthetic has been used to provide better analgesia after arthroscopic knee surgery and to reduce consumption and possible side effects of oral and intravenous anesthetics.
Bupivacaine is often used for IA analgesia because of its extended period of active effectiveness [
1]. The analgesic efficacy of IA bupivacaine, especially single-administration bupivacaine, has been studied because its effect on postoperative pain is conceptually simple. However, there are conflicting reports on the efficacy of single-administration IA bupivacaine. Despite reports supporting its use, the results of a number of studies on the efficacy of single-administration IA bupivacaine after arthroscopic knee surgery have been equivocal [
2,
3].
The active duration of analgesia provided by a single administration of IA bupivacaine is controversial as well. In a review by Moiniche
et al. [
4], the reduction in pain scores attributable to bupivacaine was short in duration, and some studies [
5,
6] have demonstrated bupivacaine to be superior to placebo for the first 2–4 h only. In contrast, other studies [
7,
8] showed bupivacaine to have a longer analgesic effect than placebo and to be more effective in the first 24 h. In other studies [
3,
9], bupivacaine dose and concentration were increased and augmented with epinephrine to obtain a longer analgesic effect. However, these findings were inconsistent, and a dose-dependent relationship with effectiveness could not be demonstrated [
4]. Because of the simplicity and apparent safety of the technique, it has gained widespread acceptance and use; nevertheless, the safety of IA bupivacaine has also been questioned [
10,
11].
A recent meta-analysis by Wei
et al. [
1] indicated that single-dose intra-articular bupivacaine is better than placebo at relieving pain after arthroscopic knee surgery. However, the data from several RCTs were not included in their analysis, and because VAS scores were acquired at different time points in different included studies, the results were pooled (i.e., VAS scores from 24 h postoperatively in one study and 48 h postoperatively in another were combined). A high degree of heterogeneity compromised the power of their findings, and the controversy surrounding active duration of analgesia provided by IA bupivacaine was ignored because of the lack of distinction among VAS scores at different follow-up time points. Finally, these researchers did not explore the effect of concentration, dose, and epinephrine use on the effectiveness of IA bupivacaine and were thus unable to determine whether the analgesic effect of IA bupivacaine was dose-dependent.
Therefore, considering the methodological deficiencies hindering exact interpretation in many studies, we conducted a meta-analysis with the following goals: 1) to assess the effectiveness and active duration of analgesia provided by single-administration IA bupivacaine for pain relief following arthroscopic knee surgery; 2) to evaluate the effects of factors such as bupivacaine concentration and supplemental epinephrine on the analgesic effect of IA bupivacaine; 3) to determine whether there is a dose–response relationship of IA bupivacaine and analgesic effect; and 4) to assess the safety of single-administration IA bupivacaine.
Discussion
The present meta-analysis of 28 RCTs [
2,
3,
5-
7,
9,
21-
43] evaluating the safety and efficacy of single-administration IA bupivacaine in the management of pain after arthroscopic knee surgery has clearly shown that a single administration of IA bupivacaine is significantly better than placebo and blank intervention at relieving pain. Moreover, it may decrease the number of patients requiring supplementary analgesia and prolong the time to first request for analgesia. The most important findings of the present study are that 1) the analgesic effect could be associated with concomitant epinephrine and with concentration of bupivacaine, 2) there was no dose–response relationship of single-administration IA bupivacaine on the analgesic effect, and 3) the use of single-administration IA may not increase the prevalence of side effects during short-term observation.
With regard to duration of analgesic effect, our meta-analysis showed that single-administration IA bupivacaine is effective for pain management for approximately 24 h following arthroscopic knee surgery, which is consistent with some previous studies [
22,
25,
32,
42]. However, most of the RCTs [
3,
5,
7,
9,
21,
23,
24,
26-
28,
30,
31,
33,
36-
38,
40,
41] included in this analysis reported either no effect or only a very short (less than 12-hour) effect duration of single-administration IA bupivacaine compared with placebo. Various factors may have been responsible for the conflicting results regarding the use of IA bupivacaine for pain control after arthroscopic knee surgery. Various acute or chronic comorbidities might have had led to different levels of pain tolerance [
3], and the type of anesthetic (general and/or spinal anesthetic) patients received [
29] might have affected the results because different amounts of intraoperative opioids were used. The use of pre- and/or perioperative opioids might also have influenced postoperative analgesia [
21]; for example, augmentation with epinephrine might have slowed the release of analgesia into the vascular system. In addition, postoperative hemarthrosis may have increased the level of pain and decreased the concentration of anesthetic within the knee joint [
43]. Concerns about the concentration and duration of action of bupivacaine have also been reported [
41]. However, despite all these confounders, the overall results of our meta-analysis suggest that the patients receiving IA bupivacaine had an analgesic effect for 24 h postoperatively, and analysis of postoperative time points revealed a positive correlation. (An additional file shows that in more detail [see Additional file
3: Figure S1]). In other words, the absolute difference of VAS pain score (SMD) between the bupivacaine group and the placebo group decreased as time progressed postoperatively. Decreasing pain intensity over the follow-up period could also explain this result.
In the present meta-analysis, we assessed the effects of various pre-specified treatment factors on the treatment efficacy of IA bupivacaine. According to our results, the analgesic effect of IA bupivacaine appears to be associated with epinephrine use and concentration of bupivacaine, findings that may be applicable to clinical practice. These findings are supported by some early research [
5,
9,
29]. As a concomitant treatment, epinephrine is considered to improve the efficacy of a local anesthetic by slowing its release into the vascular system, and local presence of epinephrine may alter the inflammatory process, thereby interfering with the activation of the opiate receptors [
5]. Epinephrine may also protect from systemic toxicity [
44]. The concentration of bupivacaine also affected the results. A higher concentration of bupivacaine traverses the synovium more rapidly to reach the joint capsule, which is perforated by articular vessels and nerve endings [
3]; indeed, in the present analysis a 0.5% concentration of bupivacaine was associated with a better analgesic effect than 0.25%, which supports the use of a higher concentration of bupivacaine. In general, the administration of IA 0.5% bupivacaine augmented by epinephrine in clinical practice may be advisable.
The present meta-analysis investigated whether the effectiveness of IA bupivacaine after arthroscopic knee surgery was dose-dependent. Our results suggest that there was no association between the reduction in number of patients requiring supplementary analgesia and bupivacaine dose, a potentially valuable finding given that high doses of IA bupivacaine may be associated with adverse side effects. Recent studies have demonstrated dose dependent chondrotoxic effects of bupivacaine
in vitro as well as
in vivo [
45,
46], suggesting that low-dose IA bupivacaine is potentially the least harmful strategy [
47]. Despite quite strong evidence for chondrotoxicity, the incidence of chondrolysis following IA administration of bupivacaine in clinical practice seems to be low or possibly underreported [
48]. Given equal efficacy for pain control after arthroscopic knee surgery across doses and a dose–response relationship for chondrotoxic effects, a clinical decision leaning toward low-dose (50-mg) bupivacaine appears to be supported, although the lowest effective bupivacaine dose has not yet been identified.
Our meta-analysis revealed no significant difference in the rate of side effects between the IA-bupivacaine group and the placebo group. Consistent with a previous review [
1], this important finding establishes the safety of IA bupivacaine during very short term observation. Moreover, compared with continuous IA infusion of analgesics, which is associated with large effusion of the surgical wound and direct access for infectious agents with catheter placement, single-administration IA bupivacaine maximizes the safety of postoperative pain relief in the early postoperative period. Nevertheless, it should be recognized that the follow-up period in the majority of studies was not long enough to detect signs and symptoms of infection. Although plasma levels were all below reported toxic plasma bupivacaine concentrations [
49], data on cardiac and central nervous system toxicity of megadose bupivacaine for assessment of long-term safety are lacking. Further investigation of the long-term safety of IA bupivacaine is therefore required.
The present study has some limitations that should be taken into account. First, we acknowledge that the individual studies included relatively small numbers of patients (n < 30 in three studies [
30,
37,
40]) and that overestimation of the treatment effect is more likely in smaller trials. Second, there was considerable heterogeneity among the included trials. Lack of standardization of IA-bupivacaine administration (e.g., with respect to injection time) and differing study designs may have led to heterogeneity and potentially affected our results. Furthermore, side effects require some time to become apparent, but none of our included studies had long enough observation periods to accomplish this.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
QBS conceived and designed and coordinated the experiments and participated in drafting the manuscript. SDL performed the experiments. QJM participated in the acquisition of data. HZQ participated in data analysis and interpretation. ZZ participated in the criteria for authorship read and met. All authors read and approved the final manuscript.