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Continuous intra-articular infusion of bupivacaine for post-operative pain relief after total hip arthroplasty: A randomized, placebo-controlled, double-blind study
European Journal of Pain 14 (2010) 529–534
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Continuous intra-articular infusion of bupivacaine for post-operative pain relief after total hip arthroplasty: A randomized, placebo-controlled, double-blind study Dave W. Chen a,b, Pang-Hsin Hsieh a,b,*, Kuo-Chin Huang b,c, Chih-Chien Hu a, Yu-Han Chang a,b, Mel S. Lee a,b a
Department of Orthopedics, Chang Gung Memorial Hospital, Taoyuan, Taiwan College of Medicine, Chang Gung University, Taoyuan, Taiwan c Department of Orthopedics, Chang Gung Memorial Hospital, Chia-Yi, Taiwan b
a r t i c l e
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Article history: Received 6 May 2009 Received in revised form 20 August 2009 Accepted 30 August 2009 Available online 24 September 2009 Keywords: Pain-control infusion pumps (PCIP) Total hip arthroplasty (THA) Post-operative pain Bupivacaine Randomized controlled clinical trial (RCT)
a b s t r a c t Background: Instillation of local anesthetics into a surgical site has been gaining popularity in post-operative pain management. Aim: To determine whether continuous intra-articular infusion of bupivacaine via pain-control infusion pumps (PCIP) enhances and sustains analgesia after total hip arthroplasty (THA). Methods: Ninety-two patients undergoing THA were randomized to receive continuous intra-articular infusion of either 0.5% bupivacaine or 0.9% normal saline at a flow rate of 2 mL/h via a PCIP for 48 h. The primary outcome measure was pain intensity on Visual Analogue Scale (VAS) scores in the first 72 h. Other measures included time to first rescue dose of narcotics, amount of narcotic use, presence of adverse events, length of hospital stay, and hip function evaluated with the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index. Results: Despite a longer time to first narcotic rescue (56 versus 21 min, p < 0.0001) in patients receiving bupivacaine, the two groups did not differ significantly in overall pain relief (p = 0.54). A lower VAS score was found only at time 0 and 2 h; no difference in VAS score was noted at any other time point. Additionally, no difference was found in terms of amount of narcotic use, incidence of adverse events, hospitalization days, and the WOMAC score. Conclusion: Continuous intra-articular infusion of 0.5% bupivacaine at 2 mL/h via a PCIP does not provide sustained post-operative pain relief in patients undergoing THA. Ó 2009 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.
1. Introduction Orthopedic surgery is reportedly among the most painful surgical procedures (Chung et al., 1997; Rawal et al., 1997). Surgical damage following major orthopedic surgery often involves a large, deep incision with considerable tissue dissection and muscle, bone, and vascular exposure. Post-operative pain after such surgery is exacerbated on movement or by reflex spasms of the muscles, which may delay mobilization, reduce satisfaction, prolong hospitalization, and possibly increase medical costs (Strassels et al., 2002). The growing trend toward quicker recovery following orthopedic procedures has stimulated the development of a variety of techniques focused on improving post-operative pain management.
* Corresponding author. Address: Department of Orthopedic Surgery, Chang Gung Memorial Hospital, No. 5, Fu-Hsing Street 333, Kweishian, Taoyuan, Taiwan. Tel.: +886 3 3281200x2163; fax: +886 3 3278113. E-mail address: [email protected] (P.-H. Hsieh).
The use of nonsteroidal anti-inflammatory drugs is a common way to relieve post-operative pain but is not always effective following major orthopedic surgery. Systemic administration of narcotics helps to relieve the pain, but potentially has well-documented side effects such as nausea, vomiting, excessive sedation, and respiratory depression. Regional use of local anesthetics can provide analgesia and reduce the need for systemic medication (Kita et al., 2007), but often requires painful injections and carries a variable degree of technical difficulties and complications (Rathmell et al., 2005). Alternatively, application of local anesthetics at the surgical site can be an effective measure to alleviate pain (Singh et al., 2007). The pain-control infusion pump (PCIP) with a constant flow of local anesthetics over a period of time offers the benefit of prolonged analgesia with fewer adverse effects (Yamaguchi et al., 2002). Further, it is an easy and convenient method for surgeons and can be performed immediately after the index surgery. Infusion of local anesthetics into the wound has been shown to be effective as a post-operative pain-control technique in arthroscopic knee ligament reconstruction (Chew et al., 2003), iliac crest
1090-3801/$36.00 Ó 2009 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpain.2009.08.008
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bone grafting (Singh et al., 2007) and total joint replacement (Toftdahl et al., 2007; Andersen et al., 2007). However, techniques of delivering anesthetics into the surgical site differ among studies, including a single injection or infiltration on wound closure, regular intermittent injections, or continuous delivery through a catheter. To date, no study has evaluated the effects of delivering local anesthetics via an extended-release pump into the joint for postoperative pain management of patients undergoing THA. We therefore hypothesized that this technique would provide prolonged post-operative analgesia and attempted to determine the efficacy of a continuous intra-articular infusion of 0.5% bupivacaine (Abbott Laboratories, Abbott Park, Illinois, USA) with a PCIP after THA as an adjunct in post-operative pain management.
the capsule, the patients were randomized to receive a loading dose of a 12-mL intra-articular injection and a 12-mL subcutaneous injection of either 0.5% bupivacaine (treatment group) or 0.9% normal saline solution (control group) followed by continuous infusion of the designated solution at 2 mL/h for 48 h via the PCIP. A random-number generator was utilized to generate the treatment assignment. Group assignments were sealed in sequentially numbered identical envelopes. The bupivacaine and saline medications prepared by the hospital pharmacy appeared identical. Medication administration and data collection were performed in a double-blinded manner, such that neither the patients nor the health-care personnel were aware of the medication assignment. To ensure blinding, the randomization code was kept confidential until all data were available for analysis.
2. Methods
2.5. Post-operative pain management
2.1. Study design
The enrollment period was from August 2007 to March 2008. All patients undergoing unilateral THA during this period were evaluated for eligibility according to the following criteria: age range of 18–80 year, diagnosed for surgery of osteoarthritis or osteonecrosis, and ability to tolerate surgery under general anesthesia. Primary exclusion criteria included refusal or the lack of mental ability to provide informed consent, neuropathic pain or sensory disorders in the leg requiring surgery, previous surgery of the hip joint, coagulation abnormalities, severe renal or hepatic impairment, chronic opioid users and known history of intolerance to the drugs used in the study. Administration of anti-inflammatory drugs was suspended at least 1 week before the surgery. Secondary exclusion criteria were intra-operative fractures requiring additional fixation and reoperation or trauma to the hip within the study period.
The patient was transferred to the recovery room after extubation in the operation theater. As per the protocol, patients were given meperidine (0.5 mg/kg) intravenously at 10-min intervals when they requested pain medication. The aim of post-operative pain relief was to maintain the pain intensity reported by the patients at rest of less than 40 mm on a 100-mm Visual Analogue Scale (VAS-100, where 0, no pain; 100, worst pain imaginable). After transfer to the ordinary ward, pain was treated with paracetamol tablets (500 mg every 6 h) during the entire post-operative period of observation. If patients still complained of pain with an intensity of more than 40 mm on the VAS-100, an additional dose of intramuscular meperidine (50 mg) was administered (and repeated if necessary) by the study nurse and registered at the study protocol. There were no restrictions on the frequency of drug administration or the overall daily dose in both groups. All patients received the same post-operative pain management. No other analgesic supplement was given during the study period. However, patients who had severe pain that was not adequately controlled by management in the study could withdraw from the study and receive other supplemental analgesia such as the patient-controlled analgesic (PCA) device. Patients in this category were still included in the trial and evaluated according to the intention-to-treat principle. The PCIP and catheter were removed 48 h after surgery. The patients were allowed to discharge home when no narcotic was required to relieve the pain, the wound was dry and they were able to walk with crutches or a walker.
2.3. Anesthesia
2.6. Outcome assessment
All enrolled patients received standardized general anesthesia with propofol (2 mg/kg) and fentanyl (2 lg/kg). Orotracheal intubation was facilitated with vecuronium (0.15 mg/kg). Anesthesia was maintained with isoflurane in a mixture of 70% nitrous oxide and 30% oxygen. Subsequent doses of 0.5–1 lg/kg fentanyl were added when necessary except during the last 30 min of surgery.
The primary outcome measure was pain intensity in the first 72 h after THA. All enrolled patients were instructed regarding how to assess pain using the VAS-100. Study participants were asked to rate the pain on arrival in the recovery room (time 0). Subsequent pain assessment was performed at 2, 4, 8, 12, 24, 36, 48, and 72 h after surgery. The time of the first rescue dose of narcotics, the amount of narcotic medication used at 24, 48, and 72 h after surgery and the length of stay in hospital were also documented. Evaluations of hip function were performed using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index 1 day before surgery and at 4, 6, and 12 weeks postoperatively (Bellamy et al., 1997). The WOMAC index was chosen because it is one of the most commonly used validated system to assess functional recovery after reconstructive hip surgery. The scores of the WOMAC index were normalized so that the most positive state of health was represented by 100 and the most negative state of health was represented by 0. The VAS and WOMAC scores were recorded by a specially trained study nurse who was also blinded to the treatment.
This study was approved as a randomized, double-blind, placebo-controlled trial by the Institutional Review Board before patient enrollment. Informed written consent was obtained from all participants prior to the intervention. THA was chosen as the surgical model because the intensity and duration of pain typically requires treatment with potent opioids for 48 h. 2.2. Participants
2.4. Operative procedure and randomization All surgical procedures were performed by the same orthopedic surgeon using standardized techniques through the anterolateral approach. A total hip prosthesis (Trilogy Acetabular Cup, VerSys Fiber Metal Taper Stem; Zimmer, Warsaw, IN) was implanted in all patients without using bone cement. No post-operative drainage was used in any patient. Before closure of the joint capsule, the catheter of the PCIP (Infusor System; Baxter, Chicago, IL) was placed percutaneously through a portal site 5 cm anterior and distal to the greater trochanter and positioned intra-articularly at the level of the femoral head under direct visualization. After closure of
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All pain evaluations were associated with the screening of side effects of the analgesic. Adverse events such as nausea or vomiting (yes/no), respiratory depression (respiratory rate <8 breaths/min; yes/no), hypotension (systolic blood pressure <80% of baseline or 80 mm Hg; yes/no), sedation (sleepy and not awakened by oral commands), urinary retention (inability to urinate, requiring a urinary catheter to empty the bladder; yes/no), pruritus (yes/no), and delayed wound healing (persistent discharge from incision wound 3 days after surgery; yes/no) were also documented.
the bupivacaine (treatment) group and 46 to the control (normal saline) group. Enrollment and outcomes are outlined in Fig. 1. The PCIP catheter had accidentally slipped in one patient on the evening after surgery. The results of this patient were included in the allocated group as the intention-to-treat analysis. One patient was excluded from the study due to intra-operative fracture requiring additional surgery for fixation with cable wires and plate. No patient was withdrawn because of severe pain requiring additional analgesic beyond the study protocol.
2.7. Statistics 3.2. Outcome analysis Sample size was calculated to achieve 80% power to detect a 15 mm difference in mean VAS scores at the 5% level (two-sided), assuming that the population mean VAS was 35 mm for the bupivacaine group and 50 mm for the saline group and the common within-population standard deviation was 25. Therefore, a minimum of 44 patients per treatment group were needed. To determine whether there were differences in either demographic variables or incidence of adverse events, chi-square analysis or Fisher’s exact test was used for categorical data, and two-tailed Student’s t-test or nonparametric Mann–Whitney U-test was applied for numerical data. The Kaplan–Meier survival method and the log rank test were used to evaluate the inter-group difference of the time to first narcotic rescue and the overall pain relief in the first 72 h, with VAS score censored at 550 (moderate pain intensity). Repeated measures analysis of variance (ANOVA) was used to determine the difference of WOMAC hip scores in both groups at the four designated time points (before surgery and at 4, 6, and 12 weeks postoperatively). A two-tailed Student’s t-test (a corrected by Bonferroni method) was applied to verify differences in VAS and WOMAC scores at each time point. Statistical significance was defined as p < 0.05. 3. Results 3.1. Enrollment of patients One hundred and eight consecutive patients were evaluated for eligibility. A total of 92 patients were randomized, 46 to
The randomization process provided two comparable cohorts of patient group as there was no significant difference between the groups in terms of demographic data, preoperative VAS scores, and surgical data (Table 1). Patients receiving bupivacaine had a longer mean time to first narcotic rescue (56 versus 21 min, p < 0.0001). However, overall pain relief in the first 72 h after THA to maintain VAS score 5 50, as assessed by the Kaplan–Meier survival method and the log rank test, was not different between patients receiving bupivacaine or placebo (p = 0.54). Further analysis of the VAS scores at each designated time point revealed that patients in the treatment group reported significantly lower scores only at time 0 (53 versus 86, p < 0.0001) and 2 h (65 versus 80, p = 0.0002) after surgery; no difference in VAS score was noted at any other time point (Fig. 2). Although there was a tendency for lower narcotic consumption in the form of systemic meperidine use at each 24-h period by patients in the treatment group than those in the control group (111 ± 44 mg versus 129 ± 49 mg, p = 0.21 on the first day; 54 ± 60 mg versus 61 ± 70 mg, p = 0.62 on the second day; 8 ± 21 mg versus 16 ± 26 mg, p = 0.12 on the third day; mean ± standard deviation), this difference did not reach statistical significance (Fig. 3). The length of hospital stay was similar in the two groups (bupivacaine group: 4.6 days, control group: 4.7 days; p = 0.8). Although significant improvement with time in the WOMAC scores was seen in both groups (p for trend <0.001), there was no between-group difference (p = 0.095) in the WOMAC scores at the
Assessed for eligibility (n = 108)
Excluded from analysis (n = 16) 1. Refused to participate (n = 7) Randomized (n = 92)
2. Previous hip surgery (n = 4) 3. Planned regional anesthesia (n = 5)
Allocated to the bupivacaine group (n = 46)
Allocated to the normal saline group (n = 46)
- Received allocated intervention (n = 46)
- Received allocated intervention (n = 45)
a
Analyzed (n = 45)
Analyzed (n = 46)
Excluded from analysis because of intraoperative fracture (n = 1)
Excluded from analysis (n = 0)
Fig. 1. Flow diagram of the patients. a The catheter of the pain-control infusion pump had accidentally slipped in one patient in the evening after surgery.
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Table 1 Baseline characteristics and surgical dataa.
Gender (male/female) Age (years)b Body weight (kg)b Body height (cm)b Diagnosis (OA/ ON) Left/ Right ASA status (I/ II/ III) Preoperative VAS scoreb Duration of surgery (minute)b Duration of anesthesia (minute)b Estimated blood loss (mL)b a b
Bupivacaine group (n = 45)
Control group (n = 46)
28/17 52 (12.6) 63 (8.6) 165 (5.8) 28/17 25/20 6/34/5 58 (18) 58 (11.2) 78 (13.7) 318 (68)
26/20 54 (13.7) 65 (7.9) 163 (6.2) 25/21 22/24 7/36/3 56 (23) 61 (9.5) 82 (10.1) 306 (81)
Table 2 Analysis of variance table of the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) scores in the two groups.
a b
Source
df
F
p Value
p For trend
Between Groupa Error
1 89
2.86
0.095
–
Within Timeb Time group Error (time) All
3 3 267 363
302.30 0.414
<0.001 0.743
<0.001 0.373
Group: 2 levels (bupivacaine group and normal saline group). Time: 4 levels (before surgery, 4 weeks, 6 weeks and 12 weeks after surgery).
No statistical difference was found between the two groups in these items. The values are given as the mean, with standard deviation in the parentheses.
four designated time points (Table 2). No difference was found between the groups in the incidence of adverse events (Table 3). 4. Discussion
Fig. 2. Kaplan–Meier survival analysis of overall pain relief in the first 72 h after THA to maintain moderate pain intensity (censoring at VAS score = 50). There was no difference between patients receiving bupivacaine or placebo (p = 0.54; log rank test).
Fig. 3. Box plots of meperidine consumption in the first 3 days after total hip arthroplasty. There was no statistical significance between the two groups in the designated periods.
We attempted to determine the sustained analgesic effect of a continuous intra-articular infusion of 0.5% bupivacaine via a PCIP after THA. Although infusion of 0.5% bupivacaine provided benefit in pain relief over the placebo in the early post-operative period, no difference in VAS scores between the groups was found at any time point after 2 h. Further, there was no inter-group difference regarding the amount of rescue narcotics, length of hospital stay, and WOMAC scores. The early pain-relief effect found in this study is most likely explained by the loading dose of 24-mL bupivacaine into the joint and subcutaneous tissues, which has a rapid onset within 4–7 min of administration, a duration of action ranging from 3 to 7 h, and a half life of elimination of 1.5–5.5 h in adults. The major strength of this study is its randomized, doubleblind, and placebo-controlled design. The randomization process was validated by statistical analysis and provided matched demographic data, preoperative VAS scores, and surgical data in both groups. Particularly, gender distribution was comparable, which is important because gender is known to be a significant confounding factor in pain studies. The double-blind and placebo-controlled nature ensured that patients in both groups were treated equally and evaluation was done with minimal bias. Although it is possible that we might not have controlled all potential variables, it is likely that these variables have been mitigated by the design of the study. Other strengths include uniformity, with all patients undergoing THA with a standardized surgical technique performed by one senior surgeon in a relatively short enrollment period. Furthermore, any patient with intra-operative complications, such as fracture requiring additional procedures, was excluded from analysis to ensure a uniform patient cohort. The limitation of the study included the lack of a negative-control patient cohort without the PCIP. Therefore, we were not aware of the psychological impact on perceived pain with use of the PCIP device. Alford and Fadale, in their evaluation of 49 patients with anterior cruciate ligament reconstruction, randomized the patients into three groups (Alford and Fadale, 2003). Group I received bupivacaine via a PCIP, Group II received normal saline solution through a PCIP, and Group III was not provided the device. The two groups that received a PCIP demonstrated decreased VAS scores and decreased narcotic use compared with controls. However, no difference was detected between the bupivacaine and normal saline-solution groups, which were supportive to our present study. This phenomenon might be explained simply by the placebo effect of using PCIP. Although there have been numerous reports on the use of intra-articular infusion of local anesthetics for post-operative pain
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D.W. Chen et al. / European Journal of Pain 14 (2010) 529–534 Table 3 Incidence of adverse events in the two groupsa.
Nausea/vomiting Respiratory depression Hypotension Sedation Urinary retention Pruritus Delayed wound healing a b
Bupivacaine group
Control group
Chi-squareb
P value
12 (26%) 0 4 (8.9%) 0 8 (17.8%) 1 (2.2%) 0
16 (34%) 1 (2.2%) 6 (13%) 0 6 (13%) 1 (2.2%) 0
0.703 0.989 0.401 1 0.392 0 1
0.497 1 0.739 1 0.531 1 1
The values are given as the number of events, with percentage in the parentheses. Degrees of freedom = 1.
control in orthopedic surgery, only few of them are regarding welldesigned randomized controlled trials and the results are mixed. A nonblinded trial by Andersen et al. (2007) evaluated the efficacy of pain control in 80 patients undergoing THA who were randomly assigned to receive either (1) continuous epidural infusion or (2) repeated periarticular injections with a mixture of ropivacaine, ketorolac, and epinephrine. The authors reported reduced hospital stay and narcotic consumption, and improved mobilization with local and intra-articular infiltration. Similarly, in a blinded study by Bianconi et al. (2003), 37 patients who underwent total hip or knee arthroplasty were randomized to receive subcutaneous infiltration with 0.2% ropivacaine at 5 mL/h followed by infusion for 55 h, or saline. Intensity of post-operative pain, consumption of rescue analgesics, and length of hospital stay were significantly reduced in the group that had received ropivacaine. Our findings are consistent with the results of two recent randomized, controlled studies in which continuous intra-articular infusion provided no adequate pain control following reconstructive surgery in the knee joint. Nechleba et al. (2005), in a study of 30 patients undergoing total knee arthroplasty, found that continuous infusion of 0.25% bupivacaine at 4.16 mL/h failed to improve either pain relief or medication use. With use of a suction drain, the authors also identified a significant loss of the local anesthetics (>25%) to the drainage. In a randomized, placebo-controlled, double-blinded trial, Parker and Streem (2007) concluded that, compared with either a normal saline placebo or a control group without a PCIP, continuous intra-articular infusion of bupivacaine (0.25%, 4 mL/h) via a PCIP cannot reduce post-operative pain or analgesic medication use after anterior cruciate ligament reconstruction. It seems likely that, in this trial, the absence of a sustained effect of 0.5% bupivacaine intra-articular infusion at 2 mL/h is attributable to one of three reasons. The first is the choice and dose of the local anesthetic. It is possible that the flow rate of 2 mL/h was inadequate for pain relief following a major orthopedic procedure such as THA, even though a high concentration (0.5%) of bupivacaine was selected and a drain was not used to maximize the analgesic effect. The concentration and flow rate were chosen to ensure patient safety, given that bupivacaine has well-known cardiotoxicity (Sztark et al., 1998). Alternatively, ropivacaine may be considered as it has fewer side effects than bupivacaine (Scott et al., 1989). The second reason is the location of the catheter placement. In this study, intra-articular placement was selected to block periosteum nociceptors under the fascia. It is likely that the poor pain control could be explained by the inability of bupivacaine to reach nociceptors outside the joint. However, little is known about the optimal catheter placement for total joint replacement procedures (Andersen et al., 2008). Finally, it may be argued that the systemic use of meperidine and paracetamol in all patients may have reduced pain effectively and eliminated the difference between the groups. This is the least likely reason as the VAS score often exceeded 40 mm in both groups and rescue medication was frequently requested by the patients.
The incidence of adverse effects was similar in both groups. Continuous intra-articular infusion of bupivacaine following THA seems to be a safe measure as we found low incidences of respiratory depression, hypotension, and sedation. However, we reported a high incidence of nausea and vomiting (26% and 34% for the bupivacaine and control groups, respectively). Such high incidences are frequently associated with opioid analgesia in the post-operative setting (Choinière et al., 1998). The similar incidence of side effects in the groups may be explained in part by the equal amounts of meperidine required for pain relief. In attempts to minimize these side effects, implementation of aggressive strategies to prevent opioid side effects (e.g., prophylactic antiemetic therapy) could be proposed (Tramer and Walder, 1999). The primary drawback of using a PCIP includes discontinuation of delivery by hardware breakage or dislodgement (Holmes et al., 2007). One patient in this study slipped out the catheter postoperatively, and the results of this patient were included in the allocated group as the intention-to-treat analysis. Another possible concern about this technique is the potential risk of delayed wound healing and infection. No such complication was found in any of the patients. However, the sample size does not allow us to draw definite conclusions regarding this problem. 5. Conclusion The data obtained via this clinical trial failed to prove significant advantages of using continuous intra-articular infusion of 5% bupivacaine at a flow rate of 2 mL/h via a PCIP for sustained post-operative pain management after THA. However, the possibility remains that different choices of local anesthetics, dose regimens, and locations of catheter placement may have a useful effect. References Alford JW, Fadale PD. Evaluation of postoperative bupivacaine infusion for pain management after anterior cruciate ligament reconstruction. Arthroscopy 2003;19:855–61. Andersen KV, Pfeiffer-Jensen M, Haraldsted V, Søballe K. Reduced hospital stay and narcotic consumption, and improved mobilization with local and intraarticular infiltration after hip arthroplasty: a randomized clinical trial of an intraarticular technique versus epidural infusion in 80 patients. Acta Orthop 2007;78:180–6. Andersen LØ, Kristensen BB, Husted H, Otte KS, Kehlet H. Local anesthetics after total knee arthroplasty: intraarticular or extraarticular administration? A randomized, double-blind, placebo-controlled study. Acta Orthop 2008;79:800–5. Bellamy N, Campbell J, Stevens J, Pilch L, Stewart C, Mahmood Z. Validation study of a computerized version of the Western Ontario and McMaster Universities VA3.0 Osteoarthritis Index. J Rheumatol 1997;24:2413–5. Bianconi M, Ferraro L, Traina GC, Zanoli G, Antonelli T, Guberti A, et al. Pharmacokinetics and efficacy of ropivacaine continuous wound instillation after joint replacement surgery. Br J Anaesth 2003;91:830–5. Chew HF, Evans NA, Stanish WD. Patient-controlled bupivacaine infusion into the infrapatelar fat pad after anterior cruciate ligament reconstruction. Arthroscopy 2003;19:500–5. Choinière M, Rittenhouse BE, Perreault S, Chartrand D, Rousseau P, Smith B, et al. Efficacy and costs of patient-controlled analgesia versus regularly administered intramuscular opioid therapy. Anesthesiology 1998;89:1377–88.
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European Journal of Pain journal homepage: www.EuropeanJournalPain.com
Continuous intra-articular infusion of bupivacaine for post-operative pain relief after total hip arthroplasty: A randomized, placebo-controlled, double-blind study Dave W. Chen a,b, Pang-Hsin Hsieh a,b,*, Kuo-Chin Huang b,c, Chih-Chien Hu a, Yu-Han Chang a,b, Mel S. Lee a,b a
Department of Orthopedics, Chang Gung Memorial Hospital, Taoyuan, Taiwan College of Medicine, Chang Gung University, Taoyuan, Taiwan c Department of Orthopedics, Chang Gung Memorial Hospital, Chia-Yi, Taiwan b
a r t i c l e
i n f o
Article history: Received 6 May 2009 Received in revised form 20 August 2009 Accepted 30 August 2009 Available online 24 September 2009 Keywords: Pain-control infusion pumps (PCIP) Total hip arthroplasty (THA) Post-operative pain Bupivacaine Randomized controlled clinical trial (RCT)
a b s t r a c t Background: Instillation of local anesthetics into a surgical site has been gaining popularity in post-operative pain management. Aim: To determine whether continuous intra-articular infusion of bupivacaine via pain-control infusion pumps (PCIP) enhances and sustains analgesia after total hip arthroplasty (THA). Methods: Ninety-two patients undergoing THA were randomized to receive continuous intra-articular infusion of either 0.5% bupivacaine or 0.9% normal saline at a flow rate of 2 mL/h via a PCIP for 48 h. The primary outcome measure was pain intensity on Visual Analogue Scale (VAS) scores in the first 72 h. Other measures included time to first rescue dose of narcotics, amount of narcotic use, presence of adverse events, length of hospital stay, and hip function evaluated with the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index. Results: Despite a longer time to first narcotic rescue (56 versus 21 min, p < 0.0001) in patients receiving bupivacaine, the two groups did not differ significantly in overall pain relief (p = 0.54). A lower VAS score was found only at time 0 and 2 h; no difference in VAS score was noted at any other time point. Additionally, no difference was found in terms of amount of narcotic use, incidence of adverse events, hospitalization days, and the WOMAC score. Conclusion: Continuous intra-articular infusion of 0.5% bupivacaine at 2 mL/h via a PCIP does not provide sustained post-operative pain relief in patients undergoing THA. Ó 2009 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.
1. Introduction Orthopedic surgery is reportedly among the most painful surgical procedures (Chung et al., 1997; Rawal et al., 1997). Surgical damage following major orthopedic surgery often involves a large, deep incision with considerable tissue dissection and muscle, bone, and vascular exposure. Post-operative pain after such surgery is exacerbated on movement or by reflex spasms of the muscles, which may delay mobilization, reduce satisfaction, prolong hospitalization, and possibly increase medical costs (Strassels et al., 2002). The growing trend toward quicker recovery following orthopedic procedures has stimulated the development of a variety of techniques focused on improving post-operative pain management.
* Corresponding author. Address: Department of Orthopedic Surgery, Chang Gung Memorial Hospital, No. 5, Fu-Hsing Street 333, Kweishian, Taoyuan, Taiwan. Tel.: +886 3 3281200x2163; fax: +886 3 3278113. E-mail address: [email protected] (P.-H. Hsieh).
The use of nonsteroidal anti-inflammatory drugs is a common way to relieve post-operative pain but is not always effective following major orthopedic surgery. Systemic administration of narcotics helps to relieve the pain, but potentially has well-documented side effects such as nausea, vomiting, excessive sedation, and respiratory depression. Regional use of local anesthetics can provide analgesia and reduce the need for systemic medication (Kita et al., 2007), but often requires painful injections and carries a variable degree of technical difficulties and complications (Rathmell et al., 2005). Alternatively, application of local anesthetics at the surgical site can be an effective measure to alleviate pain (Singh et al., 2007). The pain-control infusion pump (PCIP) with a constant flow of local anesthetics over a period of time offers the benefit of prolonged analgesia with fewer adverse effects (Yamaguchi et al., 2002). Further, it is an easy and convenient method for surgeons and can be performed immediately after the index surgery. Infusion of local anesthetics into the wound has been shown to be effective as a post-operative pain-control technique in arthroscopic knee ligament reconstruction (Chew et al., 2003), iliac crest
1090-3801/$36.00 Ó 2009 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpain.2009.08.008
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bone grafting (Singh et al., 2007) and total joint replacement (Toftdahl et al., 2007; Andersen et al., 2007). However, techniques of delivering anesthetics into the surgical site differ among studies, including a single injection or infiltration on wound closure, regular intermittent injections, or continuous delivery through a catheter. To date, no study has evaluated the effects of delivering local anesthetics via an extended-release pump into the joint for postoperative pain management of patients undergoing THA. We therefore hypothesized that this technique would provide prolonged post-operative analgesia and attempted to determine the efficacy of a continuous intra-articular infusion of 0.5% bupivacaine (Abbott Laboratories, Abbott Park, Illinois, USA) with a PCIP after THA as an adjunct in post-operative pain management.
the capsule, the patients were randomized to receive a loading dose of a 12-mL intra-articular injection and a 12-mL subcutaneous injection of either 0.5% bupivacaine (treatment group) or 0.9% normal saline solution (control group) followed by continuous infusion of the designated solution at 2 mL/h for 48 h via the PCIP. A random-number generator was utilized to generate the treatment assignment. Group assignments were sealed in sequentially numbered identical envelopes. The bupivacaine and saline medications prepared by the hospital pharmacy appeared identical. Medication administration and data collection were performed in a double-blinded manner, such that neither the patients nor the health-care personnel were aware of the medication assignment. To ensure blinding, the randomization code was kept confidential until all data were available for analysis.
2. Methods
2.5. Post-operative pain management
2.1. Study design
The enrollment period was from August 2007 to March 2008. All patients undergoing unilateral THA during this period were evaluated for eligibility according to the following criteria: age range of 18–80 year, diagnosed for surgery of osteoarthritis or osteonecrosis, and ability to tolerate surgery under general anesthesia. Primary exclusion criteria included refusal or the lack of mental ability to provide informed consent, neuropathic pain or sensory disorders in the leg requiring surgery, previous surgery of the hip joint, coagulation abnormalities, severe renal or hepatic impairment, chronic opioid users and known history of intolerance to the drugs used in the study. Administration of anti-inflammatory drugs was suspended at least 1 week before the surgery. Secondary exclusion criteria were intra-operative fractures requiring additional fixation and reoperation or trauma to the hip within the study period.
The patient was transferred to the recovery room after extubation in the operation theater. As per the protocol, patients were given meperidine (0.5 mg/kg) intravenously at 10-min intervals when they requested pain medication. The aim of post-operative pain relief was to maintain the pain intensity reported by the patients at rest of less than 40 mm on a 100-mm Visual Analogue Scale (VAS-100, where 0, no pain; 100, worst pain imaginable). After transfer to the ordinary ward, pain was treated with paracetamol tablets (500 mg every 6 h) during the entire post-operative period of observation. If patients still complained of pain with an intensity of more than 40 mm on the VAS-100, an additional dose of intramuscular meperidine (50 mg) was administered (and repeated if necessary) by the study nurse and registered at the study protocol. There were no restrictions on the frequency of drug administration or the overall daily dose in both groups. All patients received the same post-operative pain management. No other analgesic supplement was given during the study period. However, patients who had severe pain that was not adequately controlled by management in the study could withdraw from the study and receive other supplemental analgesia such as the patient-controlled analgesic (PCA) device. Patients in this category were still included in the trial and evaluated according to the intention-to-treat principle. The PCIP and catheter were removed 48 h after surgery. The patients were allowed to discharge home when no narcotic was required to relieve the pain, the wound was dry and they were able to walk with crutches or a walker.
2.3. Anesthesia
2.6. Outcome assessment
All enrolled patients received standardized general anesthesia with propofol (2 mg/kg) and fentanyl (2 lg/kg). Orotracheal intubation was facilitated with vecuronium (0.15 mg/kg). Anesthesia was maintained with isoflurane in a mixture of 70% nitrous oxide and 30% oxygen. Subsequent doses of 0.5–1 lg/kg fentanyl were added when necessary except during the last 30 min of surgery.
The primary outcome measure was pain intensity in the first 72 h after THA. All enrolled patients were instructed regarding how to assess pain using the VAS-100. Study participants were asked to rate the pain on arrival in the recovery room (time 0). Subsequent pain assessment was performed at 2, 4, 8, 12, 24, 36, 48, and 72 h after surgery. The time of the first rescue dose of narcotics, the amount of narcotic medication used at 24, 48, and 72 h after surgery and the length of stay in hospital were also documented. Evaluations of hip function were performed using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index 1 day before surgery and at 4, 6, and 12 weeks postoperatively (Bellamy et al., 1997). The WOMAC index was chosen because it is one of the most commonly used validated system to assess functional recovery after reconstructive hip surgery. The scores of the WOMAC index were normalized so that the most positive state of health was represented by 100 and the most negative state of health was represented by 0. The VAS and WOMAC scores were recorded by a specially trained study nurse who was also blinded to the treatment.
This study was approved as a randomized, double-blind, placebo-controlled trial by the Institutional Review Board before patient enrollment. Informed written consent was obtained from all participants prior to the intervention. THA was chosen as the surgical model because the intensity and duration of pain typically requires treatment with potent opioids for 48 h. 2.2. Participants
2.4. Operative procedure and randomization All surgical procedures were performed by the same orthopedic surgeon using standardized techniques through the anterolateral approach. A total hip prosthesis (Trilogy Acetabular Cup, VerSys Fiber Metal Taper Stem; Zimmer, Warsaw, IN) was implanted in all patients without using bone cement. No post-operative drainage was used in any patient. Before closure of the joint capsule, the catheter of the PCIP (Infusor System; Baxter, Chicago, IL) was placed percutaneously through a portal site 5 cm anterior and distal to the greater trochanter and positioned intra-articularly at the level of the femoral head under direct visualization. After closure of
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All pain evaluations were associated with the screening of side effects of the analgesic. Adverse events such as nausea or vomiting (yes/no), respiratory depression (respiratory rate <8 breaths/min; yes/no), hypotension (systolic blood pressure <80% of baseline or 80 mm Hg; yes/no), sedation (sleepy and not awakened by oral commands), urinary retention (inability to urinate, requiring a urinary catheter to empty the bladder; yes/no), pruritus (yes/no), and delayed wound healing (persistent discharge from incision wound 3 days after surgery; yes/no) were also documented.
the bupivacaine (treatment) group and 46 to the control (normal saline) group. Enrollment and outcomes are outlined in Fig. 1. The PCIP catheter had accidentally slipped in one patient on the evening after surgery. The results of this patient were included in the allocated group as the intention-to-treat analysis. One patient was excluded from the study due to intra-operative fracture requiring additional surgery for fixation with cable wires and plate. No patient was withdrawn because of severe pain requiring additional analgesic beyond the study protocol.
2.7. Statistics 3.2. Outcome analysis Sample size was calculated to achieve 80% power to detect a 15 mm difference in mean VAS scores at the 5% level (two-sided), assuming that the population mean VAS was 35 mm for the bupivacaine group and 50 mm for the saline group and the common within-population standard deviation was 25. Therefore, a minimum of 44 patients per treatment group were needed. To determine whether there were differences in either demographic variables or incidence of adverse events, chi-square analysis or Fisher’s exact test was used for categorical data, and two-tailed Student’s t-test or nonparametric Mann–Whitney U-test was applied for numerical data. The Kaplan–Meier survival method and the log rank test were used to evaluate the inter-group difference of the time to first narcotic rescue and the overall pain relief in the first 72 h, with VAS score censored at 550 (moderate pain intensity). Repeated measures analysis of variance (ANOVA) was used to determine the difference of WOMAC hip scores in both groups at the four designated time points (before surgery and at 4, 6, and 12 weeks postoperatively). A two-tailed Student’s t-test (a corrected by Bonferroni method) was applied to verify differences in VAS and WOMAC scores at each time point. Statistical significance was defined as p < 0.05. 3. Results 3.1. Enrollment of patients One hundred and eight consecutive patients were evaluated for eligibility. A total of 92 patients were randomized, 46 to
The randomization process provided two comparable cohorts of patient group as there was no significant difference between the groups in terms of demographic data, preoperative VAS scores, and surgical data (Table 1). Patients receiving bupivacaine had a longer mean time to first narcotic rescue (56 versus 21 min, p < 0.0001). However, overall pain relief in the first 72 h after THA to maintain VAS score 5 50, as assessed by the Kaplan–Meier survival method and the log rank test, was not different between patients receiving bupivacaine or placebo (p = 0.54). Further analysis of the VAS scores at each designated time point revealed that patients in the treatment group reported significantly lower scores only at time 0 (53 versus 86, p < 0.0001) and 2 h (65 versus 80, p = 0.0002) after surgery; no difference in VAS score was noted at any other time point (Fig. 2). Although there was a tendency for lower narcotic consumption in the form of systemic meperidine use at each 24-h period by patients in the treatment group than those in the control group (111 ± 44 mg versus 129 ± 49 mg, p = 0.21 on the first day; 54 ± 60 mg versus 61 ± 70 mg, p = 0.62 on the second day; 8 ± 21 mg versus 16 ± 26 mg, p = 0.12 on the third day; mean ± standard deviation), this difference did not reach statistical significance (Fig. 3). The length of hospital stay was similar in the two groups (bupivacaine group: 4.6 days, control group: 4.7 days; p = 0.8). Although significant improvement with time in the WOMAC scores was seen in both groups (p for trend <0.001), there was no between-group difference (p = 0.095) in the WOMAC scores at the
Assessed for eligibility (n = 108)
Excluded from analysis (n = 16) 1. Refused to participate (n = 7) Randomized (n = 92)
2. Previous hip surgery (n = 4) 3. Planned regional anesthesia (n = 5)
Allocated to the bupivacaine group (n = 46)
Allocated to the normal saline group (n = 46)
- Received allocated intervention (n = 46)
- Received allocated intervention (n = 45)
a
Analyzed (n = 45)
Analyzed (n = 46)
Excluded from analysis because of intraoperative fracture (n = 1)
Excluded from analysis (n = 0)
Fig. 1. Flow diagram of the patients. a The catheter of the pain-control infusion pump had accidentally slipped in one patient in the evening after surgery.
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Table 1 Baseline characteristics and surgical dataa.
Gender (male/female) Age (years)b Body weight (kg)b Body height (cm)b Diagnosis (OA/ ON) Left/ Right ASA status (I/ II/ III) Preoperative VAS scoreb Duration of surgery (minute)b Duration of anesthesia (minute)b Estimated blood loss (mL)b a b
Bupivacaine group (n = 45)
Control group (n = 46)
28/17 52 (12.6) 63 (8.6) 165 (5.8) 28/17 25/20 6/34/5 58 (18) 58 (11.2) 78 (13.7) 318 (68)
26/20 54 (13.7) 65 (7.9) 163 (6.2) 25/21 22/24 7/36/3 56 (23) 61 (9.5) 82 (10.1) 306 (81)
Table 2 Analysis of variance table of the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) scores in the two groups.
a b
Source
df
F
p Value
p For trend
Between Groupa Error
1 89
2.86
0.095
–
Within Timeb Time group Error (time) All
3 3 267 363
302.30 0.414
<0.001 0.743
<0.001 0.373
Group: 2 levels (bupivacaine group and normal saline group). Time: 4 levels (before surgery, 4 weeks, 6 weeks and 12 weeks after surgery).
No statistical difference was found between the two groups in these items. The values are given as the mean, with standard deviation in the parentheses.
four designated time points (Table 2). No difference was found between the groups in the incidence of adverse events (Table 3). 4. Discussion
Fig. 2. Kaplan–Meier survival analysis of overall pain relief in the first 72 h after THA to maintain moderate pain intensity (censoring at VAS score = 50). There was no difference between patients receiving bupivacaine or placebo (p = 0.54; log rank test).
Fig. 3. Box plots of meperidine consumption in the first 3 days after total hip arthroplasty. There was no statistical significance between the two groups in the designated periods.
We attempted to determine the sustained analgesic effect of a continuous intra-articular infusion of 0.5% bupivacaine via a PCIP after THA. Although infusion of 0.5% bupivacaine provided benefit in pain relief over the placebo in the early post-operative period, no difference in VAS scores between the groups was found at any time point after 2 h. Further, there was no inter-group difference regarding the amount of rescue narcotics, length of hospital stay, and WOMAC scores. The early pain-relief effect found in this study is most likely explained by the loading dose of 24-mL bupivacaine into the joint and subcutaneous tissues, which has a rapid onset within 4–7 min of administration, a duration of action ranging from 3 to 7 h, and a half life of elimination of 1.5–5.5 h in adults. The major strength of this study is its randomized, doubleblind, and placebo-controlled design. The randomization process was validated by statistical analysis and provided matched demographic data, preoperative VAS scores, and surgical data in both groups. Particularly, gender distribution was comparable, which is important because gender is known to be a significant confounding factor in pain studies. The double-blind and placebo-controlled nature ensured that patients in both groups were treated equally and evaluation was done with minimal bias. Although it is possible that we might not have controlled all potential variables, it is likely that these variables have been mitigated by the design of the study. Other strengths include uniformity, with all patients undergoing THA with a standardized surgical technique performed by one senior surgeon in a relatively short enrollment period. Furthermore, any patient with intra-operative complications, such as fracture requiring additional procedures, was excluded from analysis to ensure a uniform patient cohort. The limitation of the study included the lack of a negative-control patient cohort without the PCIP. Therefore, we were not aware of the psychological impact on perceived pain with use of the PCIP device. Alford and Fadale, in their evaluation of 49 patients with anterior cruciate ligament reconstruction, randomized the patients into three groups (Alford and Fadale, 2003). Group I received bupivacaine via a PCIP, Group II received normal saline solution through a PCIP, and Group III was not provided the device. The two groups that received a PCIP demonstrated decreased VAS scores and decreased narcotic use compared with controls. However, no difference was detected between the bupivacaine and normal saline-solution groups, which were supportive to our present study. This phenomenon might be explained simply by the placebo effect of using PCIP. Although there have been numerous reports on the use of intra-articular infusion of local anesthetics for post-operative pain
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D.W. Chen et al. / European Journal of Pain 14 (2010) 529–534 Table 3 Incidence of adverse events in the two groupsa.
Nausea/vomiting Respiratory depression Hypotension Sedation Urinary retention Pruritus Delayed wound healing a b
Bupivacaine group
Control group
Chi-squareb
P value
12 (26%) 0 4 (8.9%) 0 8 (17.8%) 1 (2.2%) 0
16 (34%) 1 (2.2%) 6 (13%) 0 6 (13%) 1 (2.2%) 0
0.703 0.989 0.401 1 0.392 0 1
0.497 1 0.739 1 0.531 1 1
The values are given as the number of events, with percentage in the parentheses. Degrees of freedom = 1.
control in orthopedic surgery, only few of them are regarding welldesigned randomized controlled trials and the results are mixed. A nonblinded trial by Andersen et al. (2007) evaluated the efficacy of pain control in 80 patients undergoing THA who were randomly assigned to receive either (1) continuous epidural infusion or (2) repeated periarticular injections with a mixture of ropivacaine, ketorolac, and epinephrine. The authors reported reduced hospital stay and narcotic consumption, and improved mobilization with local and intra-articular infiltration. Similarly, in a blinded study by Bianconi et al. (2003), 37 patients who underwent total hip or knee arthroplasty were randomized to receive subcutaneous infiltration with 0.2% ropivacaine at 5 mL/h followed by infusion for 55 h, or saline. Intensity of post-operative pain, consumption of rescue analgesics, and length of hospital stay were significantly reduced in the group that had received ropivacaine. Our findings are consistent with the results of two recent randomized, controlled studies in which continuous intra-articular infusion provided no adequate pain control following reconstructive surgery in the knee joint. Nechleba et al. (2005), in a study of 30 patients undergoing total knee arthroplasty, found that continuous infusion of 0.25% bupivacaine at 4.16 mL/h failed to improve either pain relief or medication use. With use of a suction drain, the authors also identified a significant loss of the local anesthetics (>25%) to the drainage. In a randomized, placebo-controlled, double-blinded trial, Parker and Streem (2007) concluded that, compared with either a normal saline placebo or a control group without a PCIP, continuous intra-articular infusion of bupivacaine (0.25%, 4 mL/h) via a PCIP cannot reduce post-operative pain or analgesic medication use after anterior cruciate ligament reconstruction. It seems likely that, in this trial, the absence of a sustained effect of 0.5% bupivacaine intra-articular infusion at 2 mL/h is attributable to one of three reasons. The first is the choice and dose of the local anesthetic. It is possible that the flow rate of 2 mL/h was inadequate for pain relief following a major orthopedic procedure such as THA, even though a high concentration (0.5%) of bupivacaine was selected and a drain was not used to maximize the analgesic effect. The concentration and flow rate were chosen to ensure patient safety, given that bupivacaine has well-known cardiotoxicity (Sztark et al., 1998). Alternatively, ropivacaine may be considered as it has fewer side effects than bupivacaine (Scott et al., 1989). The second reason is the location of the catheter placement. In this study, intra-articular placement was selected to block periosteum nociceptors under the fascia. It is likely that the poor pain control could be explained by the inability of bupivacaine to reach nociceptors outside the joint. However, little is known about the optimal catheter placement for total joint replacement procedures (Andersen et al., 2008). Finally, it may be argued that the systemic use of meperidine and paracetamol in all patients may have reduced pain effectively and eliminated the difference between the groups. This is the least likely reason as the VAS score often exceeded 40 mm in both groups and rescue medication was frequently requested by the patients.
The incidence of adverse effects was similar in both groups. Continuous intra-articular infusion of bupivacaine following THA seems to be a safe measure as we found low incidences of respiratory depression, hypotension, and sedation. However, we reported a high incidence of nausea and vomiting (26% and 34% for the bupivacaine and control groups, respectively). Such high incidences are frequently associated with opioid analgesia in the post-operative setting (Choinière et al., 1998). The similar incidence of side effects in the groups may be explained in part by the equal amounts of meperidine required for pain relief. In attempts to minimize these side effects, implementation of aggressive strategies to prevent opioid side effects (e.g., prophylactic antiemetic therapy) could be proposed (Tramer and Walder, 1999). The primary drawback of using a PCIP includes discontinuation of delivery by hardware breakage or dislodgement (Holmes et al., 2007). One patient in this study slipped out the catheter postoperatively, and the results of this patient were included in the allocated group as the intention-to-treat analysis. Another possible concern about this technique is the potential risk of delayed wound healing and infection. No such complication was found in any of the patients. However, the sample size does not allow us to draw definite conclusions regarding this problem. 5. Conclusion The data obtained via this clinical trial failed to prove significant advantages of using continuous intra-articular infusion of 5% bupivacaine at a flow rate of 2 mL/h via a PCIP for sustained post-operative pain management after THA. However, the possibility remains that different choices of local anesthetics, dose regimens, and locations of catheter placement may have a useful effect. References Alford JW, Fadale PD. Evaluation of postoperative bupivacaine infusion for pain management after anterior cruciate ligament reconstruction. Arthroscopy 2003;19:855–61. Andersen KV, Pfeiffer-Jensen M, Haraldsted V, Søballe K. Reduced hospital stay and narcotic consumption, and improved mobilization with local and intraarticular infiltration after hip arthroplasty: a randomized clinical trial of an intraarticular technique versus epidural infusion in 80 patients. Acta Orthop 2007;78:180–6. Andersen LØ, Kristensen BB, Husted H, Otte KS, Kehlet H. Local anesthetics after total knee arthroplasty: intraarticular or extraarticular administration? A randomized, double-blind, placebo-controlled study. Acta Orthop 2008;79:800–5. Bellamy N, Campbell J, Stevens J, Pilch L, Stewart C, Mahmood Z. Validation study of a computerized version of the Western Ontario and McMaster Universities VA3.0 Osteoarthritis Index. J Rheumatol 1997;24:2413–5. Bianconi M, Ferraro L, Traina GC, Zanoli G, Antonelli T, Guberti A, et al. Pharmacokinetics and efficacy of ropivacaine continuous wound instillation after joint replacement surgery. Br J Anaesth 2003;91:830–5. Chew HF, Evans NA, Stanish WD. Patient-controlled bupivacaine infusion into the infrapatelar fat pad after anterior cruciate ligament reconstruction. Arthroscopy 2003;19:500–5. Choinière M, Rittenhouse BE, Perreault S, Chartrand D, Rousseau P, Smith B, et al. Efficacy and costs of patient-controlled analgesia versus regularly administered intramuscular opioid therapy. Anesthesiology 1998;89:1377–88.
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