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Efficacy of Intra-Articular Bupivacaine, Ropivacaine, or a Combination of Ropivacaine, Morphine, and Ketorolac on Postoperative Pain Relief After Ambulatory Arthroscopic Knee Surgery: A Randomized Double-Blind Study
Efficacy of Intra-Articular Bupivacaine, Ropivacaine, or a Combination of Ropivacaine, Morphine, and Ketorolac on Postoperative Pain Relief After Ambulatory Arthroscopic Knee Surgery: A Randomized Double-Blind Study Huey-Ping Ng, M.D., Ulf Nordström, M.D., Kjell Axelsson, M.D., Ph.D., Andrea Davide Perniola, M.D., Ekbäck Gustav, M.D., Ph.D., Lars Ryttberg, M.D., and Anil Gupta, M.D., F.R.C.A., Ph.D. Background: Effective pain relief is important after diagnostic and therapeutic arthroscopic knee surgery to permit early discharge and improve comfort and mobility at home. The aim of this study was to assess the efficacy of bupivacaine, ropivacaine, or a combination of ropivacaine, morphine, and ketorolac injected intraarticularly for postoperative pain relief after arthroscopic knee surgery. Methods: Sixty-three healthy patients undergoing knee arthroscopy under local anesthesia (LA) were randomized to receive 1 of the following substances intra-articularly postoperatively: group B: 30 mL of bupivacaine (150 mg); group R: 30 mL of ropivacaine (150 mg); and group RMK: ropivacaine 150 mg, morphine 4 mg, and ketorolac 30 mg in normal saline (total volume 30 mL). Oral paracetamol 1g and tramadol 50 mg were used as rescue drugs. Postoperatively, pain was assessed at rest and movement, and side effects were recorded. The patients were asked to self-assess pain for 7 days and record analgesic consumption as well as activities of daily living (ADLs). Plasma concentration of LA was measured in another 8 patients. Results: All groups had excellent analgesia at 0 and 4 hours postoperatively. Group RMK had significantly lower visual analog pain score at rest at 8 hours and during movement at 8 and 24 hours compared with the other groups (P ⬍ .05). Group RMK required less paracetamol and tramadol on day 1 (P ⬍ .05), had less sleep disturbances because of pain, more patients were ready to work on days 1 and 2 (P ⬍ .05), and were more satisfied on days 1 and 4 to 7. Postoperatively, plasma concentrations of ropivacaine and lidocaine were far below known systemic toxic concentrations in all patients. Conclusion: Addition of morphine and ketolorac to ropivacaine intra-articularly enhances analgesic efficacy of LA, reduces postdischarge analgesic consumption, and improves ADLs without increasing side effects after ambulatory arthroscopic knee surgery. Reg Anesth Pain Med 2006;31:26-33. Key Words:
Anesthetics: Local, Surgery: Arthroscopy, Pain: Postoperative.
D
iagnostic and minor therapeutic knee arthroscopy is a common ambulatory procedure that can be performed under general, regional, or local anesthesia (LA). Knee arthroscopy performed using LA technique has been found to be safe, effective, and well accepted by patients.1,2
From the Departments of Anaesthesiology and Orthopaedics, University Hospital, Örebro, Sweden. Accepted for publication September 23, 2005. Reprint requests: Kjell Axelsson, Department of Anesthesiology, University Hospital, 702 21 Örebro, Sweden. E-mail: kjell. [email protected] © 2006 by the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/06/3101-0006$32.00/0 doi:10.1016/j.rapm.2005.09.009
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Effective postoperative pain relief with minimum associated side effects is important to permit sameday discharge from the surgery center and to improve the patient’s comfort, mobility, and rehabilitation at home. However, studies on intra-articular LA, morphine, and nonsteroidal anti-inflammatory drugs (NSAIDs) have found opposing results. Mohiniche et al.3 found that intra-articular LA alone may have only minor effects on postoperative pain relief of short duration (4 hours) compared with placebo. Gupta et al.4 found significant though minor pain reduction for up to 24 hours after intraarticular (IA) morphine. NSAIDs such as ketorolac have been shown to provide good postoperative pain relief when administered intra-articularly.5-7
Regional Anesthesia and Pain Medicine, Vol 31, No 1 (January–February), 2006: pp 26 –33
Arthroscopic Knee Surgery
Multimodal pain therapy (balanced analgesia) is recommended for treatment of postoperative pain.8 The rationale for this therapy is to achieve sufficient analgesia because of additive or synergistic effects between different analgesics, with concomitant reduction of side effects because of lower doses of analgesics used and differences in their side effect profiles. Therefore, a combination of IA ketorolac, morphine, and LA given postoperatively may prolong the duration of pain relief and minimize the side effects of each drug. The primary aim of this study was to investigate the efficacy of a combination of IA ropivacaine, morphine, and ketorolac compared with LA alone on postoperative pain intensity at 24 hours after knee arthroscopy. Morphine consumption and quality of life during 1 week were measured as secondary end points. Finally, the concentration of IA LA was measured in a pharmacokinetic study in 8 patients.
Methods The study protocol was approved by the hospital ethics committee, and written informed consent was obtained from all patients before their inclusion. Ninety-eight patients (American Society of Anesthesiologists I to II) in the age group 18 to 70 years old scheduled for ambulatory knee arthroscopy under local anesthesia were interviewed between October 15, 2002, and February 1, 2003. Exclusion criteria included allergy or contraindication to any of the drugs used in the study, history of substance abuse, and chronic opioid intake. The study was divided into 2 parts. In part 1, 69 patients were allocated to 1 of 3 groups (see later), and the analgesic efficacy of the different drugs was studied. Part 2 was a pharmacokinetic study of the plasma concentration of lidocaine and ropivacaine after their intra-articular injection in 10 patients. Part 1 Computer-generated random numbers were used and inserted into sealed envelopes by a nurse not involved in the study. Inside these envelopes was a number, which informed the nurse of the group to which the patient was allocated. The nurse mixed the drugs according to a protocol and gave 2 labelled syringes (total volume 30 mL) to the surgeon at the end of the procedure. All patients were permitted to eat and drink preoperatively, and all patients received paracetamol 1 g orally as premedication 1 hour before planned surgery. Intravenous access was obtained and the catheter heparinized. The patients were informed about the visual analog pain score (VAS) (0 ⫽ no
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pain, 10 ⫽ worst imaginable pain), and VAS was measured preoperatively at rest and on movement of the knee to be operated. The surgeon then infiltrated a total of 40 mL lidocaine 1% with adrenaline 1:200,000 intra-articularly (20 mL) and along the port sites (20 mL) 30 minutes before planned surgery. No sedatives or analgesics were administered during the procedure. At the end of surgery, one of the following drugs was administered intraarticularly in a double-blind manner via the arthroscope: (1) group B: bupivacaine 0.5%, 150 mg (30 mL); (2) group R: ropivacaine 0.5%, 150 mg (30 mL); and (3) group RMK: ropivacaine 1% (150 mg), preservative-free morphine (4 mg), ketorolac (30 mg), and saline (0.9%) (total volume 30 mL). Neither the surgeon, the anesthesiologist, or the nurse looking after the patient postoperatively was aware of the randomization sequence. The portals were sealed carefully before the injection of the test drugs. At the end of the operation, VAS pain scores at rest and on movement (90° flexion of the knee) and side effects (nausea, vomiting, pruritus) were recorded. The patient was also asked to grade his/her satisfaction with the anesthesia technique on a 4-point scale (1 ⫽ poor, 2 ⫽ satisfactory, 3 ⫽ good, 4 ⫽ excellent), and if he/she would have a similar operation using the same anesthetic technique. The patients were discharged home about 10 to 15 minutes after the operation when they fulfilled the discharge criteria (normal blood pressure and pulse, adequate mobility with support, mild to no pain, and no nausea or vomiting). Rescue medication consisted of paracetamol 1 g (maximum 4 times a day) when pain was ⬎VAS 3 and, if the pain relief was insufficient after 30 minutes, tramadol 50 mg (maximum 4 times a day) orally. All patients were contacted by telephone the day after surgery and encouraged to complete their questionnaires. Self-assessment of VAS at rest and movement at 4, 8, and 24 hours and 2, 3, and 7 days was done postoperatively at home by all patients on a 10-cm–long vertical scale. During this self-assessment, the patients were also asked about any side effects (nausea, vomiting, pruritus), activities of daily living (ADLs; inability to sleep because of pain, appetite, concentration, need for assistance, ability to walk on flat ground with no pain, ability to go to work), and the numbers of analgesic tablets consumed over the 7-day period. The criteria for return to work were the following: no or minimal pain on movement and full mobilization. Part 2 Of the 10 patients who were interviewed, 2 were unable to stay in the postanesthesia care unit for 3
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Regional Anesthesia and Pain Medicine Vol. 31 No. 1 January–February 2006 Table 1. Patient Demographics and Surgical Data
Age (y) Height (cm) Weight (kg) ASA (I/II) Sex (M/F) Preop VAS (rest) Preop VAS (movement) Op time (min) Operating procedure Meniscectomy Shaving/synovectomy Diagnostic
Group B
Group R
Group RMK
47.7 ⫾ 13.5*† 173.2 ⫾ 7.8 78.8 ⫾ 12.6 15/6 10/11 1.6 ⫾ 2.0 5.9 ⫾ 2.0 25.6 ⫾ 10.5
37.6 ⫾ 12.4 175.6 ⫾ 7.6 79.7 ⫾ 12.2 19/2 13/8 1.5 ⫾ 1.9 5.8 ⫾ 1.8 24.0 ⫾ 9.6
37.9 ⫾ 12.3 177.9 ⫾ 6.8 81.0 ⫾ 13.0 20/1 13/8 1.2 ⫾ 1.4 5.4 ⫾ 2.1 24.2 ⫾ 10.4
8 12 1
7 14 0
10 9 2
Abbreviations: B, bupivacaine; R, ropivacaine; RMK, ropivacaine, morphine, and ketorolac; M, male; F, female. *P ⬍ .05 compared with group RMK. †P ⬍ .05 compared with group R.
hours for blood sampling. Plasma lidocaine and ropivacaine concentrations were measured in 8 patients undergoing arthroscopy. The LA technique was identical to that described earlier. At the end of surgery, all 8 patients received the drugs described in group RMK for postoperative pain management. Venous blood was sampled in heparinized tubes from a peripheral arm vein in the upper extremity 30, 60, 120, and 180 minutes after the study drug had been infused. The plasma concentration of lidocaine and ropivacaine was measured in the following way: the blood samples were centrifuged to separate the plasma, which was frozen to ⫺20°C. Free and bound fractions of the drugs were determined by ultrafiltration, essentially according to Arvidsson and Eklund.9 The chromatography was performed with a Zorbax SB-C18 column 75 ⫻ 4.6 mm, 3.5- particle diameter (Agilent Technologies Inc, Palo Alto, CA). The eluent consisted of 15 mmol/L sodium dihydrogen carbonate buffer, pH 3.0/acetonitrile, 4/1 and was pumped at 1.0 mL/ min. Detection was performed at 210 nm. Statistics We studied 6 patients who received only LA intra-articularly for minor arthroscopic surgery, which is a standard method in our hospital. The results showed that the mean VAS in the LA group after 24 hours was 6.0 ⫾ 2.5 on movement. We were interested in a VAS reduction of 40% or greater during 0 to 24 hours and calculated that we would need to study 18 patients/group to detect a statistically significant difference between the groups (P ⫽ 0.05, power ⫽ 80%). Twenty-three patients were recruited in each group to compensate for loss of data during follow-up. All results are presented as mean ⫾ standard deviation or median (range) as appropriate. The plasma concentration of
LA is presented as median and 25th to 75th percentiles (box and whisker plots). For nonparametric data, the Kruskal-Wallis test was used when appropriate followed by the Mann-Whitney U test when a significant difference was found. Categorical data were analyzed by using the chi-square test with Yate’s correction when appropriate. A P value ⬍.05 was considered to be statistically significant. The statistical program used was SPSS ps.exe (SPSS Inc, Chicago, IL).
Results Part 1 Of the 69 patients recruited, 2 patients in each group did not return the questionnaire, and, therefore, only results from 21 patients were analyzed in each group. Except for the age, the groups were comparable in respect to demographic data, operation time, and severity of knee pain preoperatively (Table 1). Intraoperatively, 2 patients in group B, none in group R, and 1 patient in group RMK felt mild pain during the operation but did not need any additional analgesia for completion of the operation. All patients were fit for discharge home immediately after surgery when the discharge criteria were attained, 15 minutes after the end of the operation. Postoperatively, pain intensity on a VAS 0 to 10 cm (rest, movement) over the 7 days is shown in Figures 1 and 2, respectively. All groups had excellent analgesia at 0 and 4 hours postoperatively. At 8 hours, groups B and R experienced moderate pain during movement. Group RMK had significantly lower pain score at rest compared with groups B and R at 8 hours and during movement at 8 and 24 hours. After 24 hours, no differences were found in VAS between the groups. The number of paraceta-
Visual Analogue Scale (VAS 0-10 cm), at rest
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Group B
10
Group R 9
Group RMK
8 7
**
6 5 4 3 2 1 0 pre-op
0
4
8
24
Hours after end of surgery
2
3
7
Days after end of surgery
Fig 1. Postoperative pain is shown as VAS at rest (median and IQR). Group B (bupivacaine), group R (ropivacaine), and group RMK (ropivacaine ⫹ morphine ⫹ ketorolac). *Groups B and R versus group RMK (P ⬍ .05).
mol and tramadol tablets taken over the week is shown in Table 2. Group RMK took less paracetamol and tramadol during the first 24 hours than groups B and R (P ⬍ .05). The results of the questionnaire are presented in Table 3. Significant differences were found between group RMK and groups B and R in the number of patients who had sleep disturbance during the first night and who were well enough to return to work during the first 2 postoperative
days. Group R had significantly less sleep disturbance than group B during the second postoperative night. Patients were more satisfied with the analgesia technique in group RMK compared with groups B and R on day 1 and days 4 to 7 (P ⫽ .05). The incidence of nausea, vomiting, and pruritus on day 1 were as follows: nausea: 66%, 31%, and 31%; vomiting: 11%, 0%, and 0%; and pruritus: 5%, 0%, and 0%, in groups B, R, and RMK, respectively. No significant differences
Fig 2. Postoperative pain is shown as VAS on movement (median and IQR). Group B (bupivacaine), group R (ropivacaine), and group RMK (ropivacaine ⫹ morphine ⫹ ketorolac). *Groups B and R versus group RMK (P ⬍ .05).
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Regional Anesthesia and Pain Medicine Vol. 31 No. 1 January–February 2006 Table 2. Analgesic Tablets Ingestion Group B
Group R
Paracetamol taken: no. of tablets (1 g) Day 1 3 (0-7)* 2 (0-6)* Day 2 2.5 (0-6) 1 (0-4) Day 3 1.5 (0-6) 1 (0-4) Day 4 2 (0-24) 0 (0-6) Tramadol taken: no. of tablets (50 mg) Day 1 3 (0-8) P ⬍ .001* 2 (0-4) ⫽ .005* Day 2 1 (0-8) 0 (0-6) Day 3 0 (0-8) 0 (0-4) Days 4-7 0 (0-16) 0 (0-5)
Group RMK
1 (0-3) 1 (0-4) 1 (0-4) 1 (0-10) 0 (0-3) 0 (0-4) 0 (0-3) 0 (0-6)
Abbreviations: B, bupivacaine, R, ropivacaine; RMK, ropivacaine, morphine, and ketorolac. *P ⬍ .01 compared with group RMK. Data presented as median (range).
were recorded between the groups in these side effects or in the ADLs such as appetite, difficulty in concentration, need for assistance, and ability to walk on flat ground without pain. Part 2 The total and free plasma concentrations of lidocaine and ropivacaine are shown in Figures 3 and 4, respectively. The total lidocaine venous plasma concentration (median [range]) was 630 (52-829) ng/mL at 30 minutes after surgery. The free plasma concentration was 142 (21-207) ng/mL. The median (range) total plasma concentration of ropivacaine was 583 (60-1175) ng/mL after 30 minutes, and the free plasma concentration of ropivacaine was 27 (9-62) ng/mL. The mean protein binding capacity of lidocaine and ropivacaine was 76% and 94%, respectively.
Discussion Our findings show that the combination of ropivacaine 150 mg with morphine 4 mg and ketorolac 30 mg injected intra-articularly at the end of ambulatory arthroscopic surgery enhances analgesic efficacy of LA, reduces postdischarge analgesic consumption, and improves some aspects of ADL without increasing side effects after ambulatory arthroscopic knee surgery. Postoperative Pain (0-7 Days) Pain after arthroscopic surgery varies considerably and depends, among other factors, on the type of procedure, with diagnostic procedures producing mild pain, whereas invasive procedures such as anterior cruciate ligament repair produce moderate to severe pain. Our patients underwent minor arthroscopic surgery and therefore the expected pain intensity could be considered to be mild. This was true
only during rest when the mean VAS pain scores were ⬍3 up to 8 hours postoperatively. In all groups, pain intensity increased from 4 hours postoperatively, peaking after 24 hours, both at rest and during mobilization. Thus, pain relief, specifically in the groups receiving only LA, was short-lasting, which is in agreement with the findings in a systematic review of the literature.3 The authors in that study found a reduction in pain score by 11 mm7-14 (mean and 95% confidence interval) during a 30- to 50-minute period. In contrast to the pain intensity at rest, pain during movement was moderate-severe in our study, specifically in the LA groups after 24 hours. Thus, LA may be adequate for attenuation of mild pain in the early postoperative period and at rest but is certainly inadequate when used alone during movement. The dose of LA is important because it was found that IA ropivacaine 150 mg resulted in lower pain scores compared with ropivacaine or bupivacaine 100 mg after knee arthroscopy. A higher dose of ropivacaine (⬎150 mg), however, did not further improve efficacy.10 Marchal et al.11 found that operative procedures associated with high inflammation (synovectomy, shaving, and so on) responded better to Table 3. Postdischarge Questionnaire and Patient Satisfaction Day Sleep disturbance from pain D1 D2 D3 D4 to D7 Well enough to return to work D1 D2 D3 D4 to D7 Choose the same anesthetic again Patient satisfaction D0 D1 D2 D3 D4 to D7
Group B (n)
Group R (n)
Group RMK (n)
15/21* 11/21† 5/21 3/21
16/21* 4/21 4/21 3/21
4/21 5/21 2/21 3/21
0/21* 0/21* 2/21 8/21 18/21
2/21 3/21 6/21 9/21 20/21
6/21 7/21 8/21 11/21 21/21
4 (3-4) 3 (1-4)*‡ 3 (1-4) 3 (1-4) 3 (1-4)*§储
4 (1-4) 4 (3-4) 3 (2-4)*ठ4 (2-4) 3 (1-4) 3 (2-4) 3 (2-4) 3.5 (2-4) 3 (2-4) 4 (2-4)
NOTE. The number of patients who had sleep disturbances, who could return to work, who would choose the same anesthetic again, and patient satisfaction (median/range) are shown. Abbreviations (Patient satisfaction score: 1 ⫽ poor, 2 ⫽ satisfactory, 3 ⫽ good, 4 ⫽ excellent) D0 ⫽ day of operation; D1 ⫽ postoperative day 1 and so on. B ⫽ bupivacaine, R ⫽ ropivacaine, RMK ⫽ ropivacaine, morphine, and ketorolac. *P ⬍ .05 versus group RMK. †P ⬍ .05 versus group R. ‡P ⫽ .017. §P ⫽ .022. 储P ⫽ .003.
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Fig 3. Total postoperative plasma concentration (ng/mL) of 400 mg lidocaine and 150 mg ropivacaine. Results are expressed as median and interquartile range (IQR).
morphine thus supporting the theory that inflammation is a prerequisite for the peripheral analgesic effect of opioids.12 Most of the patients in our study underwent meniscectomy and shaving or synovectomy which are also likely to be high-inflammatory procedures. Thus, patients who received IA morphine had better pain relief, specifically on movement, and lower analgesic consumption. Although the effects of IA morphine are rather controversial, in a quantitative systematic review, significant but mild effects were reported during 0 to 24 hours.4 These effects of morphine are even more marked when the pain intensity is ⬎5 on the VAS,13 as could be the case with moderately invasive arthroscopic procedures. In another study, the authors suggested an improved study design to include only those patients with moderate-severe pain when assessing the effects of IA drugs.14 Although the mean pain intensity in our patients was moderate-severe (VAS ⫽ 5-6 cm) 24 hours postoperatively in the LA groups, we included even patients with mild pain, which may be unfortunate. However, our patients are discharged home within 15 minutes after the operation and therefore a study design incorporating a postoperative observation period over 2 to 4 hours to include only those with moderate-severe pain was considered to be difficult. It is important here to reflect on the study by Toivonen et al.15
who found increased rescue analgesic consumption in patients treated with LA. They postulate that increased ambulation because of effective early pain relief in the IA LA group might have increased the swelling and pain later in the observation period. Since 2000, when we started with ropivacaine, morphine, and ketorolac IA administration postoperatively, all patients are clearly informed not to overexert themselves during the first 3 to 4 days because of the risk of developing swelling. NSAIDs have been found to reduce postoperative pain when injected intra-articularly in a number of studies. Both ketorolac as well as tenoxicam have been used, and most studies have found reduction in VAS pain scores and/or analgesic requirements postoperatively.5,6,16,17 In 1 study, LA combined with morphine and ketorolac for IA pain relief after minor arthroscopic procedures were found to give a synergistic effect.17 However, in another study, the authors found no benefit of combining ketorolac 60 mg with morphine 3 mg.18 These differences could be because Reuben and Connelly5 used a higher dose of IA ketorolac (60 mg), which we have previously found to provide good analgesia when used alone.17 In addition, the observation time postoperatively was only 24 hours, whereas we followed up the patients for 7 days postoperatively, which could be important. Our present study would confirm the
Fig 4. Total postoperative-free (unbound) plasma concentration (ng/mL) of 400 mg lidocaine and 150 mg ropivacaine. Results are expressed as median and interquartile range.
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Regional Anesthesia and Pain Medicine Vol. 31 No. 1 January–February 2006
beneficial effects of combining ketorolac and morphine because patients receiving this combination with LA had significantly lower VAS pain scores, specifically on movement up to 24 hours postoperatively compared with LA alone. Postoperative Questionnaire We followed-up our patients during the first 7 postoperative days by using a questionnaire to study the ADLs. This questionnaire included aspects of pain, sleep disturbances because of pain, appetite, difficulty in concentration, nausea and vomiting and the ability to dress without help, to walk without pain, and to return to work. Patients were also asked about their overall satisfaction with the analgesia and whether they would choose the same anesthetic again. We found that patients who received a combination of IA LA, morphine, and ketorolac had less sleep disturbances during the first 1 to 2 days, and more patients were willing to return to work on the first 2 days after the operation. It is likely that better pain relief resulted in decreased sleep disturbance as well as the wish to return to work earlier. Therefore, more patients in the combined analgesic regimen were satisfied with their analgesia compared with the LA groups. Better analgesia was also associated with greater patient satisfaction, specifically on day 1 and on days 4 to 7 in patients receiving combined analgesia regimen. This is an important aspect of outcome because patient-oriented parameters on quality of analgesia remain poorly studied. Side Effects and LA Toxicity All patients could be discharged within 15 minutes postoperatively, and none suffered from any significant complication. Patients at the 24-hour telephone follow-up reported no major side effects, and there was no evidence of LA toxicity in any patient. The total venous blood concentration of lidocaine was never above 0.830 g/mL in any of the 8 tested patients, which is far below 10 g/mL reported as a toxic plasma concentration in humans.19 The plasma concentration was also lower than the minimal plasma concentration considered to be therapeutic for cardiac arrhythmia (1-2 g/ mL).19 There was a marked variation in both total and free venous plasma concentration of ropivacaine. However, both total concentration (583 ng/ mL) and free concentration (27 ng/mL) were far below toxic concentrations of 1,000 to 2,000 ng/mL and 600 ng/mL, respectively, which are reported to give slight central nervous system toxic symptoms in volunteers.20 The peak concentrations of ropivacaine in our study corresponded well with that
found by Convery et al.10 Also, doses up to 200 mg of ropivacaine have been recognized to give low free plasma concentrations (61 ng/mL).10 Thus, in the doses used, LA appears to be completely safe when administered intra-articularly.
Limitations of the Study Patients in group B were on an average 10 years older than the other groups despite randomization. We could not have controlled this factor, but it is unlikely that pain perception in patients 37 years old differs from those who are 47 years old. We did not investigate the effect of IA versus intravenous ketorolac or morphine to differentiate between a systemic or local effect of the drugs because this has been done in previous studies.7,21 We did not measure the plasma concentration of morphine or ketorolac, which could have been an advantage. Although morphine is absorbed into the systemic circulation after IA injection, the concentrations have been below therapeutic levels and most authors are of the opinion that the effects of morphine are likely to be peripheral. A group of patients receiving only ketorolac may have given some idea of the advantage of the combination of morphine and ketorolac versus ketorolac alone. This has, however, been studied before,17,18 and we may not have added any new information to the existing literature. Finally, we have no long-term outcome data in this study, specifically on the effects of NSAIDs injected intra-articularly on side effects and mobilization. Since 2000, we have used the combination of ketorolac, morphine, and ropivacaine for pain relief postoperatively in 1,500 to 2,000 arthroscopies without any complications reported. Therefore, this is likely to be a minor problem in clinical practice. In conclusion, we found that the addition of morphine and ketorolac to ropivacaine intra-articularly enhances analgesic efficacy of LA, reduces postdischarge analgesic consumption, and improves some aspects of ADLs without increasing side effects after ambulatory arthroscopic knee surgery.
Acknowledgment The authors would like to thank Lennart Bodin, Unit of Biostatistics and Epidemiology, University Hospital, Örebro, for his kind assistance with the statistical calculations, and the nurses and doctors in the Ambulatory Surgical Unit, Department of Orthopedic Surgery, for their constant support during the process of patient recruitment.
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traarticular morphine and bupivacaine? A preliminary study. Clin J Pain 2003;19:240-246. Rosseland LA, Stubhaug A, Skoglund A, Breivik H. Intra-articular morphine for pain relief after knee arthroscopy. Acta Anaesthesiol Scand 1999;43:252-257. Kalso E, Smith L, McQuay HJ, Andrew Moore R. No pain, no gain: Clinical excellence and scientific rigour—Lessons learned from IA morphine. Pain 2002; 98:269-275. Rosseland LA, Stubhaug A, Sandberg L, Breivik H. Intra-articular (IA) catheter administration of postoperative analgesics. A new trial design allows evaluation of baseline pain, demonstrates large variation in need of analgesics, and finds no analgesic effect of IA ketamine compared with IA saline. Pain 2003;104: 25-34. Toivonen J, Pitko V-M, Rosenberg PH. Comparison between intra-articular bupivacaine with epinephrine and epinephrine alone on short-term and longterm pain after knee arthroscopic surgery under general anesthesia in day-surgery patients. Acta Anaesthesiol Scand 2002;46:435-440. Romsing J, Moiniche S, Ostergaard D, Dahl JB. Local infiltration with NSAIDs for postoperative analgesia: Evidence for a peripheral analgesic action. Acta Anaesthesiol Scand 2000;44:672-683. Gupta A, Axelsson K, Allvin R, Liszka-Hackzell J, Rawal N, Althoff B, Augustini BG. Postoperative pain following knee arthroscopy: The effects of intra-articular ketorolac and/or morphine. Reg Anesth Pain Med 1999;24:225-230. Reuben SS, Connelly NR. Postarthroscopic meniscus repair analgesia with intraarticular ketorolac or morphine. Anesth Analg 1996;82:1036-1039. Weiker GG, Kuivila TE, Pippinger CE. Serum lidocaine and bupivacaine levels in local technique knee arthroscopy. Am J Sports Med 1991;19:499-502. Knudsen K, Beckman Suurkula M, Blomberg S, Sjovall J, Edvardsson N. Central nervous and cardiovascular effects of i.v. infusions of ropivacaine, bupivacaine and placebo in volunteers. Br J Anaesth 1997; 78:507-514. Reuben SS, Steinberg RB, Kreitzer JM, Duprat KM. Intravenous regional anesthesia using lidocaine and ketorolac. Anesth Analg 1995;81:110-113.
Anesthetics: Local, Surgery: Arthroscopy, Pain: Postoperative.
D
iagnostic and minor therapeutic knee arthroscopy is a common ambulatory procedure that can be performed under general, regional, or local anesthesia (LA). Knee arthroscopy performed using LA technique has been found to be safe, effective, and well accepted by patients.1,2
From the Departments of Anaesthesiology and Orthopaedics, University Hospital, Örebro, Sweden. Accepted for publication September 23, 2005. Reprint requests: Kjell Axelsson, Department of Anesthesiology, University Hospital, 702 21 Örebro, Sweden. E-mail: kjell. [email protected] © 2006 by the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/06/3101-0006$32.00/0 doi:10.1016/j.rapm.2005.09.009
26
Effective postoperative pain relief with minimum associated side effects is important to permit sameday discharge from the surgery center and to improve the patient’s comfort, mobility, and rehabilitation at home. However, studies on intra-articular LA, morphine, and nonsteroidal anti-inflammatory drugs (NSAIDs) have found opposing results. Mohiniche et al.3 found that intra-articular LA alone may have only minor effects on postoperative pain relief of short duration (4 hours) compared with placebo. Gupta et al.4 found significant though minor pain reduction for up to 24 hours after intraarticular (IA) morphine. NSAIDs such as ketorolac have been shown to provide good postoperative pain relief when administered intra-articularly.5-7
Regional Anesthesia and Pain Medicine, Vol 31, No 1 (January–February), 2006: pp 26 –33
Arthroscopic Knee Surgery
Multimodal pain therapy (balanced analgesia) is recommended for treatment of postoperative pain.8 The rationale for this therapy is to achieve sufficient analgesia because of additive or synergistic effects between different analgesics, with concomitant reduction of side effects because of lower doses of analgesics used and differences in their side effect profiles. Therefore, a combination of IA ketorolac, morphine, and LA given postoperatively may prolong the duration of pain relief and minimize the side effects of each drug. The primary aim of this study was to investigate the efficacy of a combination of IA ropivacaine, morphine, and ketorolac compared with LA alone on postoperative pain intensity at 24 hours after knee arthroscopy. Morphine consumption and quality of life during 1 week were measured as secondary end points. Finally, the concentration of IA LA was measured in a pharmacokinetic study in 8 patients.
Methods The study protocol was approved by the hospital ethics committee, and written informed consent was obtained from all patients before their inclusion. Ninety-eight patients (American Society of Anesthesiologists I to II) in the age group 18 to 70 years old scheduled for ambulatory knee arthroscopy under local anesthesia were interviewed between October 15, 2002, and February 1, 2003. Exclusion criteria included allergy or contraindication to any of the drugs used in the study, history of substance abuse, and chronic opioid intake. The study was divided into 2 parts. In part 1, 69 patients were allocated to 1 of 3 groups (see later), and the analgesic efficacy of the different drugs was studied. Part 2 was a pharmacokinetic study of the plasma concentration of lidocaine and ropivacaine after their intra-articular injection in 10 patients. Part 1 Computer-generated random numbers were used and inserted into sealed envelopes by a nurse not involved in the study. Inside these envelopes was a number, which informed the nurse of the group to which the patient was allocated. The nurse mixed the drugs according to a protocol and gave 2 labelled syringes (total volume 30 mL) to the surgeon at the end of the procedure. All patients were permitted to eat and drink preoperatively, and all patients received paracetamol 1 g orally as premedication 1 hour before planned surgery. Intravenous access was obtained and the catheter heparinized. The patients were informed about the visual analog pain score (VAS) (0 ⫽ no
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pain, 10 ⫽ worst imaginable pain), and VAS was measured preoperatively at rest and on movement of the knee to be operated. The surgeon then infiltrated a total of 40 mL lidocaine 1% with adrenaline 1:200,000 intra-articularly (20 mL) and along the port sites (20 mL) 30 minutes before planned surgery. No sedatives or analgesics were administered during the procedure. At the end of surgery, one of the following drugs was administered intraarticularly in a double-blind manner via the arthroscope: (1) group B: bupivacaine 0.5%, 150 mg (30 mL); (2) group R: ropivacaine 0.5%, 150 mg (30 mL); and (3) group RMK: ropivacaine 1% (150 mg), preservative-free morphine (4 mg), ketorolac (30 mg), and saline (0.9%) (total volume 30 mL). Neither the surgeon, the anesthesiologist, or the nurse looking after the patient postoperatively was aware of the randomization sequence. The portals were sealed carefully before the injection of the test drugs. At the end of the operation, VAS pain scores at rest and on movement (90° flexion of the knee) and side effects (nausea, vomiting, pruritus) were recorded. The patient was also asked to grade his/her satisfaction with the anesthesia technique on a 4-point scale (1 ⫽ poor, 2 ⫽ satisfactory, 3 ⫽ good, 4 ⫽ excellent), and if he/she would have a similar operation using the same anesthetic technique. The patients were discharged home about 10 to 15 minutes after the operation when they fulfilled the discharge criteria (normal blood pressure and pulse, adequate mobility with support, mild to no pain, and no nausea or vomiting). Rescue medication consisted of paracetamol 1 g (maximum 4 times a day) when pain was ⬎VAS 3 and, if the pain relief was insufficient after 30 minutes, tramadol 50 mg (maximum 4 times a day) orally. All patients were contacted by telephone the day after surgery and encouraged to complete their questionnaires. Self-assessment of VAS at rest and movement at 4, 8, and 24 hours and 2, 3, and 7 days was done postoperatively at home by all patients on a 10-cm–long vertical scale. During this self-assessment, the patients were also asked about any side effects (nausea, vomiting, pruritus), activities of daily living (ADLs; inability to sleep because of pain, appetite, concentration, need for assistance, ability to walk on flat ground with no pain, ability to go to work), and the numbers of analgesic tablets consumed over the 7-day period. The criteria for return to work were the following: no or minimal pain on movement and full mobilization. Part 2 Of the 10 patients who were interviewed, 2 were unable to stay in the postanesthesia care unit for 3
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Regional Anesthesia and Pain Medicine Vol. 31 No. 1 January–February 2006 Table 1. Patient Demographics and Surgical Data
Age (y) Height (cm) Weight (kg) ASA (I/II) Sex (M/F) Preop VAS (rest) Preop VAS (movement) Op time (min) Operating procedure Meniscectomy Shaving/synovectomy Diagnostic
Group B
Group R
Group RMK
47.7 ⫾ 13.5*† 173.2 ⫾ 7.8 78.8 ⫾ 12.6 15/6 10/11 1.6 ⫾ 2.0 5.9 ⫾ 2.0 25.6 ⫾ 10.5
37.6 ⫾ 12.4 175.6 ⫾ 7.6 79.7 ⫾ 12.2 19/2 13/8 1.5 ⫾ 1.9 5.8 ⫾ 1.8 24.0 ⫾ 9.6
37.9 ⫾ 12.3 177.9 ⫾ 6.8 81.0 ⫾ 13.0 20/1 13/8 1.2 ⫾ 1.4 5.4 ⫾ 2.1 24.2 ⫾ 10.4
8 12 1
7 14 0
10 9 2
Abbreviations: B, bupivacaine; R, ropivacaine; RMK, ropivacaine, morphine, and ketorolac; M, male; F, female. *P ⬍ .05 compared with group RMK. †P ⬍ .05 compared with group R.
hours for blood sampling. Plasma lidocaine and ropivacaine concentrations were measured in 8 patients undergoing arthroscopy. The LA technique was identical to that described earlier. At the end of surgery, all 8 patients received the drugs described in group RMK for postoperative pain management. Venous blood was sampled in heparinized tubes from a peripheral arm vein in the upper extremity 30, 60, 120, and 180 minutes after the study drug had been infused. The plasma concentration of lidocaine and ropivacaine was measured in the following way: the blood samples were centrifuged to separate the plasma, which was frozen to ⫺20°C. Free and bound fractions of the drugs were determined by ultrafiltration, essentially according to Arvidsson and Eklund.9 The chromatography was performed with a Zorbax SB-C18 column 75 ⫻ 4.6 mm, 3.5- particle diameter (Agilent Technologies Inc, Palo Alto, CA). The eluent consisted of 15 mmol/L sodium dihydrogen carbonate buffer, pH 3.0/acetonitrile, 4/1 and was pumped at 1.0 mL/ min. Detection was performed at 210 nm. Statistics We studied 6 patients who received only LA intra-articularly for minor arthroscopic surgery, which is a standard method in our hospital. The results showed that the mean VAS in the LA group after 24 hours was 6.0 ⫾ 2.5 on movement. We were interested in a VAS reduction of 40% or greater during 0 to 24 hours and calculated that we would need to study 18 patients/group to detect a statistically significant difference between the groups (P ⫽ 0.05, power ⫽ 80%). Twenty-three patients were recruited in each group to compensate for loss of data during follow-up. All results are presented as mean ⫾ standard deviation or median (range) as appropriate. The plasma concentration of
LA is presented as median and 25th to 75th percentiles (box and whisker plots). For nonparametric data, the Kruskal-Wallis test was used when appropriate followed by the Mann-Whitney U test when a significant difference was found. Categorical data were analyzed by using the chi-square test with Yate’s correction when appropriate. A P value ⬍.05 was considered to be statistically significant. The statistical program used was SPSS ps.exe (SPSS Inc, Chicago, IL).
Results Part 1 Of the 69 patients recruited, 2 patients in each group did not return the questionnaire, and, therefore, only results from 21 patients were analyzed in each group. Except for the age, the groups were comparable in respect to demographic data, operation time, and severity of knee pain preoperatively (Table 1). Intraoperatively, 2 patients in group B, none in group R, and 1 patient in group RMK felt mild pain during the operation but did not need any additional analgesia for completion of the operation. All patients were fit for discharge home immediately after surgery when the discharge criteria were attained, 15 minutes after the end of the operation. Postoperatively, pain intensity on a VAS 0 to 10 cm (rest, movement) over the 7 days is shown in Figures 1 and 2, respectively. All groups had excellent analgesia at 0 and 4 hours postoperatively. At 8 hours, groups B and R experienced moderate pain during movement. Group RMK had significantly lower pain score at rest compared with groups B and R at 8 hours and during movement at 8 and 24 hours. After 24 hours, no differences were found in VAS between the groups. The number of paraceta-
Visual Analogue Scale (VAS 0-10 cm), at rest
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Group B
10
Group R 9
Group RMK
8 7
**
6 5 4 3 2 1 0 pre-op
0
4
8
24
Hours after end of surgery
2
3
7
Days after end of surgery
Fig 1. Postoperative pain is shown as VAS at rest (median and IQR). Group B (bupivacaine), group R (ropivacaine), and group RMK (ropivacaine ⫹ morphine ⫹ ketorolac). *Groups B and R versus group RMK (P ⬍ .05).
mol and tramadol tablets taken over the week is shown in Table 2. Group RMK took less paracetamol and tramadol during the first 24 hours than groups B and R (P ⬍ .05). The results of the questionnaire are presented in Table 3. Significant differences were found between group RMK and groups B and R in the number of patients who had sleep disturbance during the first night and who were well enough to return to work during the first 2 postoperative
days. Group R had significantly less sleep disturbance than group B during the second postoperative night. Patients were more satisfied with the analgesia technique in group RMK compared with groups B and R on day 1 and days 4 to 7 (P ⫽ .05). The incidence of nausea, vomiting, and pruritus on day 1 were as follows: nausea: 66%, 31%, and 31%; vomiting: 11%, 0%, and 0%; and pruritus: 5%, 0%, and 0%, in groups B, R, and RMK, respectively. No significant differences
Fig 2. Postoperative pain is shown as VAS on movement (median and IQR). Group B (bupivacaine), group R (ropivacaine), and group RMK (ropivacaine ⫹ morphine ⫹ ketorolac). *Groups B and R versus group RMK (P ⬍ .05).
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Regional Anesthesia and Pain Medicine Vol. 31 No. 1 January–February 2006 Table 2. Analgesic Tablets Ingestion Group B
Group R
Paracetamol taken: no. of tablets (1 g) Day 1 3 (0-7)* 2 (0-6)* Day 2 2.5 (0-6) 1 (0-4) Day 3 1.5 (0-6) 1 (0-4) Day 4 2 (0-24) 0 (0-6) Tramadol taken: no. of tablets (50 mg) Day 1 3 (0-8) P ⬍ .001* 2 (0-4) ⫽ .005* Day 2 1 (0-8) 0 (0-6) Day 3 0 (0-8) 0 (0-4) Days 4-7 0 (0-16) 0 (0-5)
Group RMK
1 (0-3) 1 (0-4) 1 (0-4) 1 (0-10) 0 (0-3) 0 (0-4) 0 (0-3) 0 (0-6)
Abbreviations: B, bupivacaine, R, ropivacaine; RMK, ropivacaine, morphine, and ketorolac. *P ⬍ .01 compared with group RMK. Data presented as median (range).
were recorded between the groups in these side effects or in the ADLs such as appetite, difficulty in concentration, need for assistance, and ability to walk on flat ground without pain. Part 2 The total and free plasma concentrations of lidocaine and ropivacaine are shown in Figures 3 and 4, respectively. The total lidocaine venous plasma concentration (median [range]) was 630 (52-829) ng/mL at 30 minutes after surgery. The free plasma concentration was 142 (21-207) ng/mL. The median (range) total plasma concentration of ropivacaine was 583 (60-1175) ng/mL after 30 minutes, and the free plasma concentration of ropivacaine was 27 (9-62) ng/mL. The mean protein binding capacity of lidocaine and ropivacaine was 76% and 94%, respectively.
Discussion Our findings show that the combination of ropivacaine 150 mg with morphine 4 mg and ketorolac 30 mg injected intra-articularly at the end of ambulatory arthroscopic surgery enhances analgesic efficacy of LA, reduces postdischarge analgesic consumption, and improves some aspects of ADL without increasing side effects after ambulatory arthroscopic knee surgery. Postoperative Pain (0-7 Days) Pain after arthroscopic surgery varies considerably and depends, among other factors, on the type of procedure, with diagnostic procedures producing mild pain, whereas invasive procedures such as anterior cruciate ligament repair produce moderate to severe pain. Our patients underwent minor arthroscopic surgery and therefore the expected pain intensity could be considered to be mild. This was true
only during rest when the mean VAS pain scores were ⬍3 up to 8 hours postoperatively. In all groups, pain intensity increased from 4 hours postoperatively, peaking after 24 hours, both at rest and during mobilization. Thus, pain relief, specifically in the groups receiving only LA, was short-lasting, which is in agreement with the findings in a systematic review of the literature.3 The authors in that study found a reduction in pain score by 11 mm7-14 (mean and 95% confidence interval) during a 30- to 50-minute period. In contrast to the pain intensity at rest, pain during movement was moderate-severe in our study, specifically in the LA groups after 24 hours. Thus, LA may be adequate for attenuation of mild pain in the early postoperative period and at rest but is certainly inadequate when used alone during movement. The dose of LA is important because it was found that IA ropivacaine 150 mg resulted in lower pain scores compared with ropivacaine or bupivacaine 100 mg after knee arthroscopy. A higher dose of ropivacaine (⬎150 mg), however, did not further improve efficacy.10 Marchal et al.11 found that operative procedures associated with high inflammation (synovectomy, shaving, and so on) responded better to Table 3. Postdischarge Questionnaire and Patient Satisfaction Day Sleep disturbance from pain D1 D2 D3 D4 to D7 Well enough to return to work D1 D2 D3 D4 to D7 Choose the same anesthetic again Patient satisfaction D0 D1 D2 D3 D4 to D7
Group B (n)
Group R (n)
Group RMK (n)
15/21* 11/21† 5/21 3/21
16/21* 4/21 4/21 3/21
4/21 5/21 2/21 3/21
0/21* 0/21* 2/21 8/21 18/21
2/21 3/21 6/21 9/21 20/21
6/21 7/21 8/21 11/21 21/21
4 (3-4) 3 (1-4)*‡ 3 (1-4) 3 (1-4) 3 (1-4)*§储
4 (1-4) 4 (3-4) 3 (2-4)*ठ4 (2-4) 3 (1-4) 3 (2-4) 3 (2-4) 3.5 (2-4) 3 (2-4) 4 (2-4)
NOTE. The number of patients who had sleep disturbances, who could return to work, who would choose the same anesthetic again, and patient satisfaction (median/range) are shown. Abbreviations (Patient satisfaction score: 1 ⫽ poor, 2 ⫽ satisfactory, 3 ⫽ good, 4 ⫽ excellent) D0 ⫽ day of operation; D1 ⫽ postoperative day 1 and so on. B ⫽ bupivacaine, R ⫽ ropivacaine, RMK ⫽ ropivacaine, morphine, and ketorolac. *P ⬍ .05 versus group RMK. †P ⬍ .05 versus group R. ‡P ⫽ .017. §P ⫽ .022. 储P ⫽ .003.
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Fig 3. Total postoperative plasma concentration (ng/mL) of 400 mg lidocaine and 150 mg ropivacaine. Results are expressed as median and interquartile range (IQR).
morphine thus supporting the theory that inflammation is a prerequisite for the peripheral analgesic effect of opioids.12 Most of the patients in our study underwent meniscectomy and shaving or synovectomy which are also likely to be high-inflammatory procedures. Thus, patients who received IA morphine had better pain relief, specifically on movement, and lower analgesic consumption. Although the effects of IA morphine are rather controversial, in a quantitative systematic review, significant but mild effects were reported during 0 to 24 hours.4 These effects of morphine are even more marked when the pain intensity is ⬎5 on the VAS,13 as could be the case with moderately invasive arthroscopic procedures. In another study, the authors suggested an improved study design to include only those patients with moderate-severe pain when assessing the effects of IA drugs.14 Although the mean pain intensity in our patients was moderate-severe (VAS ⫽ 5-6 cm) 24 hours postoperatively in the LA groups, we included even patients with mild pain, which may be unfortunate. However, our patients are discharged home within 15 minutes after the operation and therefore a study design incorporating a postoperative observation period over 2 to 4 hours to include only those with moderate-severe pain was considered to be difficult. It is important here to reflect on the study by Toivonen et al.15
who found increased rescue analgesic consumption in patients treated with LA. They postulate that increased ambulation because of effective early pain relief in the IA LA group might have increased the swelling and pain later in the observation period. Since 2000, when we started with ropivacaine, morphine, and ketorolac IA administration postoperatively, all patients are clearly informed not to overexert themselves during the first 3 to 4 days because of the risk of developing swelling. NSAIDs have been found to reduce postoperative pain when injected intra-articularly in a number of studies. Both ketorolac as well as tenoxicam have been used, and most studies have found reduction in VAS pain scores and/or analgesic requirements postoperatively.5,6,16,17 In 1 study, LA combined with morphine and ketorolac for IA pain relief after minor arthroscopic procedures were found to give a synergistic effect.17 However, in another study, the authors found no benefit of combining ketorolac 60 mg with morphine 3 mg.18 These differences could be because Reuben and Connelly5 used a higher dose of IA ketorolac (60 mg), which we have previously found to provide good analgesia when used alone.17 In addition, the observation time postoperatively was only 24 hours, whereas we followed up the patients for 7 days postoperatively, which could be important. Our present study would confirm the
Fig 4. Total postoperative-free (unbound) plasma concentration (ng/mL) of 400 mg lidocaine and 150 mg ropivacaine. Results are expressed as median and interquartile range.
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Regional Anesthesia and Pain Medicine Vol. 31 No. 1 January–February 2006
beneficial effects of combining ketorolac and morphine because patients receiving this combination with LA had significantly lower VAS pain scores, specifically on movement up to 24 hours postoperatively compared with LA alone. Postoperative Questionnaire We followed-up our patients during the first 7 postoperative days by using a questionnaire to study the ADLs. This questionnaire included aspects of pain, sleep disturbances because of pain, appetite, difficulty in concentration, nausea and vomiting and the ability to dress without help, to walk without pain, and to return to work. Patients were also asked about their overall satisfaction with the analgesia and whether they would choose the same anesthetic again. We found that patients who received a combination of IA LA, morphine, and ketorolac had less sleep disturbances during the first 1 to 2 days, and more patients were willing to return to work on the first 2 days after the operation. It is likely that better pain relief resulted in decreased sleep disturbance as well as the wish to return to work earlier. Therefore, more patients in the combined analgesic regimen were satisfied with their analgesia compared with the LA groups. Better analgesia was also associated with greater patient satisfaction, specifically on day 1 and on days 4 to 7 in patients receiving combined analgesia regimen. This is an important aspect of outcome because patient-oriented parameters on quality of analgesia remain poorly studied. Side Effects and LA Toxicity All patients could be discharged within 15 minutes postoperatively, and none suffered from any significant complication. Patients at the 24-hour telephone follow-up reported no major side effects, and there was no evidence of LA toxicity in any patient. The total venous blood concentration of lidocaine was never above 0.830 g/mL in any of the 8 tested patients, which is far below 10 g/mL reported as a toxic plasma concentration in humans.19 The plasma concentration was also lower than the minimal plasma concentration considered to be therapeutic for cardiac arrhythmia (1-2 g/ mL).19 There was a marked variation in both total and free venous plasma concentration of ropivacaine. However, both total concentration (583 ng/ mL) and free concentration (27 ng/mL) were far below toxic concentrations of 1,000 to 2,000 ng/mL and 600 ng/mL, respectively, which are reported to give slight central nervous system toxic symptoms in volunteers.20 The peak concentrations of ropivacaine in our study corresponded well with that
found by Convery et al.10 Also, doses up to 200 mg of ropivacaine have been recognized to give low free plasma concentrations (61 ng/mL).10 Thus, in the doses used, LA appears to be completely safe when administered intra-articularly.
Limitations of the Study Patients in group B were on an average 10 years older than the other groups despite randomization. We could not have controlled this factor, but it is unlikely that pain perception in patients 37 years old differs from those who are 47 years old. We did not investigate the effect of IA versus intravenous ketorolac or morphine to differentiate between a systemic or local effect of the drugs because this has been done in previous studies.7,21 We did not measure the plasma concentration of morphine or ketorolac, which could have been an advantage. Although morphine is absorbed into the systemic circulation after IA injection, the concentrations have been below therapeutic levels and most authors are of the opinion that the effects of morphine are likely to be peripheral. A group of patients receiving only ketorolac may have given some idea of the advantage of the combination of morphine and ketorolac versus ketorolac alone. This has, however, been studied before,17,18 and we may not have added any new information to the existing literature. Finally, we have no long-term outcome data in this study, specifically on the effects of NSAIDs injected intra-articularly on side effects and mobilization. Since 2000, we have used the combination of ketorolac, morphine, and ropivacaine for pain relief postoperatively in 1,500 to 2,000 arthroscopies without any complications reported. Therefore, this is likely to be a minor problem in clinical practice. In conclusion, we found that the addition of morphine and ketorolac to ropivacaine intra-articularly enhances analgesic efficacy of LA, reduces postdischarge analgesic consumption, and improves some aspects of ADLs without increasing side effects after ambulatory arthroscopic knee surgery.
Acknowledgment The authors would like to thank Lennart Bodin, Unit of Biostatistics and Epidemiology, University Hospital, Örebro, for his kind assistance with the statistical calculations, and the nurses and doctors in the Ambulatory Surgical Unit, Department of Orthopedic Surgery, for their constant support during the process of patient recruitment.
Arthroscopic Knee Surgery
References 1. Jacobson E, Forssblad M, Weidenhielm L, Renstrom P. Knee arthroscopy with the use of local anesthesia—An increased risk for repeat arthroscopy? A prospective, randomized study with a six-month followup. Am J Sports Med 2002;30:61-65. 2. Lintner S, Shawen S, Lohnes J, Levy A, Garrett W. Local anesthesia in outpatient knee arthroscopy: A comparison of efficacy and cost. Arthroscopy 1996;12: 482-488. 3. Moiniche S, Mikkelsen S, Wetterslev J, Dahl JB. A systematic review of intra-articular local anesthesia for postoperative pain relief after arthroscopic knee surgery. Reg Anesth Pain Med 1999;24:430-437. 4. Gupta A, Bodin L, Holmstrom B, Berggren L. A systematic review of the peripheral analgesic effects of intraarticular morphine. Anesth Analg 2001;93:761770. 5. Reuben SS, Connelly NR. Postoperative analgesia for outpatient arthroscopic knee sugery with intraarticular bupivacaine and ketorolac. Anesth Analg 1995; 80:1154-1157. 6. Calmet J, Esteve C, Boada S, Gine J. Analgesic effect of intra-articular ketorolac in knee arthroscopy: Comparison of morphine and bupivacaine. Knee Surg Sports Traumatol Arthrosc 2004;12:552-555. 7. Convery PN, Milligan KR, Quinn P, Scott K, Clarke RC. Low-dose intra-articular ketorolac for pain relief following arthroscopy of the knee joint. Anaesthesia 1998;53:1125-1129. 8. Kehlet H, Dahl JB. The value of “multimodal” or “balanced analgesia” in postoperative pain treatment. Anesth Analg 1993;77:1048-1056. 9. Arvidsson T, Eklund E. Determination of free concentration of ropivacaine and bupivacaine in blood plasma by ultrafiltration and coupled-column liquid chromatography. J Chromatogr B Biomed Appl 1995; 668:91-98. 10. Convery PN, Milligan KR, Quinn P, Sjovall J, Gustafsson U. Efficacy and uptake of ropivacaine and bupivacaine after single intra-articular injection in the knee joint. Br J Anaesth 2001;87:570-576. 11. Marchal JM, Delgado-Martinez AD, Poncela M, Valenzuela J, de Dios Luna J. Does the type of arthroscopic surgery modify the analgesic effect of in-
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traarticular morphine and bupivacaine? A preliminary study. Clin J Pain 2003;19:240-246. Rosseland LA, Stubhaug A, Skoglund A, Breivik H. Intra-articular morphine for pain relief after knee arthroscopy. Acta Anaesthesiol Scand 1999;43:252-257. Kalso E, Smith L, McQuay HJ, Andrew Moore R. No pain, no gain: Clinical excellence and scientific rigour—Lessons learned from IA morphine. Pain 2002; 98:269-275. Rosseland LA, Stubhaug A, Sandberg L, Breivik H. Intra-articular (IA) catheter administration of postoperative analgesics. A new trial design allows evaluation of baseline pain, demonstrates large variation in need of analgesics, and finds no analgesic effect of IA ketamine compared with IA saline. Pain 2003;104: 25-34. Toivonen J, Pitko V-M, Rosenberg PH. Comparison between intra-articular bupivacaine with epinephrine and epinephrine alone on short-term and longterm pain after knee arthroscopic surgery under general anesthesia in day-surgery patients. Acta Anaesthesiol Scand 2002;46:435-440. Romsing J, Moiniche S, Ostergaard D, Dahl JB. Local infiltration with NSAIDs for postoperative analgesia: Evidence for a peripheral analgesic action. Acta Anaesthesiol Scand 2000;44:672-683. Gupta A, Axelsson K, Allvin R, Liszka-Hackzell J, Rawal N, Althoff B, Augustini BG. Postoperative pain following knee arthroscopy: The effects of intra-articular ketorolac and/or morphine. Reg Anesth Pain Med 1999;24:225-230. Reuben SS, Connelly NR. Postarthroscopic meniscus repair analgesia with intraarticular ketorolac or morphine. Anesth Analg 1996;82:1036-1039. Weiker GG, Kuivila TE, Pippinger CE. Serum lidocaine and bupivacaine levels in local technique knee arthroscopy. Am J Sports Med 1991;19:499-502. Knudsen K, Beckman Suurkula M, Blomberg S, Sjovall J, Edvardsson N. Central nervous and cardiovascular effects of i.v. infusions of ropivacaine, bupivacaine and placebo in volunteers. Br J Anaesth 1997; 78:507-514. Reuben SS, Steinberg RB, Kreitzer JM, Duprat KM. Intravenous regional anesthesia using lidocaine and ketorolac. Anesth Analg 1995;81:110-113.