Continous Intra-articular Tramadol/Bupivacaine Combination Infusion
Therapy Improves Postoperative Outcome of Total Knee Arthroplasty
Ehab Said MD, Ehab El-Shahat MD & Sayed Abdul Azeim MD
Department of Anesthesia, Faculty of Medicine, Benha University, Egypt
Abstract
Objectives: To evaluate postoperative (PO) analgesic yield of continuous intra-articular (IA) tramadol/bupivacaine infusion versus bupivacaine alone after total knee arthroplasty (TKA).
Patients & Methods: Sixty patients with arthrosis were randomly divided into three equal groups:
Bupivacaine group received continuous IA infusion of bupivacaine alone, combination group received continuous IA infusion of combination of bupivacaine with tramadol at rate of 6 ml/hr for 72-hours PO
(72-hr PO) and control group did not receive IA medications.
After release of the ischemic tourniquet and assurance of hemostasis, a vacuum drainage tube was applied. The IA infusion was delivered through a multi-pore No.8 neonatal feeding catheter for 45 minutes per hour for 72 hours.
Postoperative pain was assessed using 10-point visual analogue pain scale (VAS) and intravenous mepridine was given as rescue analgesia if VAS pain score was ≥4 or on patient's request. Total rescue analgesia consumption and angle of flexion of the knee joint and length of hospital stay were recorded.
Results: The ability to achieve better angle of flexion of knee joint was significantly higher in combination group compared to other groups with significant difference in favor of bupivacaine group compared to control group. At time of full recovery of anesthesia (0-hr PO) mean pain VAS scores were significantly lower with IA analgesia compared to control group and in combination group versus bupivacaine group. Number of requests and total dose of rescue analgesia consumed were significantly lower with IA analgesia with significant difference in favor of combination group. There was a positive significant correlation between pain VAS scores and angle of flexion of knee joint in IA groups.
Conclusion: Continuous IA bupivacaine/tramadol infusion safely reduced postoperative pain scores and spared rescue analgesics with significantly improved range of joint movement.
Keywords: Continuous, intra-articular, infusion, tramadol, total knee arthroplasty
Introduction
Arthroplastic surgeries carry multiple concerns for both surgeon and anesthetist. Firstly, patients need arthroplastic surgeries always geriatric patients acclimatized for their handicapping and immobilization or slow painful motion since years. Secondly, these patients mostly had additional morbidities which may delay their postoperative recovery
(1)
.
One of the utmost importance is the immediate postoperative pain which imposes both physical and mental burden preventing patients from trying to move their joints and so prolongs duration of postoperative care and delays rehabilitation
(2)
.
Multiple analgesic modalities were proposed for management of postoperative pain in patients undergoing arthroplastic surgery; Remeand et al.
(3)
reported that intravenous ketamine had a morphine-sparing effect after total hip arthroplasty, facilitated rehabilitation at 1 month and decreased postoperative chronic pain up to 6 months after surgery. Sundarathiti et al.
(4)
documented that continuous femoral nerve block represents the optimal analgesia with fewer side effects and greater patient, satisfaction. Andersen et al.
(5)
found total wound infiltration analgesia with ropivacaine in bilateral total knee arthroplasty is effective in early post-operative pain management.
Other studies tried various intra-articular medications for pain management after arthroplastic surgeries, Fu et al.
(6)
reported that intra-articular cocktail analgesic injection composed of bupivacaine, morphine and betamethasone, reduced the need for morphine and offered a better pain control, without apparent risks following TKA.
Garcia et al.
(7)
found postoperative intra-articular administration of morphine
- 1 -

promoted a longer period without rescue analgesics and reduced their consumption in the first 24 hours compared to placebo.
The current prospective comparative study aimed to evaluate the postoperative analgesic yield of intra-articular continuous tramadol/bupivacaine infusion versus bupivacaine alone after total knee arthroplasty.
Patients & Methods
The current prospective comparative study was conducted at Departments of
Anesthesia and Orthopedic Surgery, Benha University Hospital since Jan 2010 till
Sep 2011 after approval of the study protocol by the Local Ethical Committee and obtaining written fully informed patients' or near relative consent, 60 patients with primary knee arthrosis and assigned for TKA were enrolled in the study. Patients with neurological or psychological diseases that may interfere with assessment, patients had allergy or contraindication for the study drugs, patients with other orthopedic diseases than knee arthrosis were excluded from the study.
Patients were randomly, using sealed envelops, divided into three equal groups
(n=20): Bupivacaine group included patients received continuous intra-articular infusion of bupivacaine alone. Combination group included patients received continuous intra-articular infusion of combination of bupivacaine and tramadol.
Control group included patients did not receive intra-articular medications and were maintained on rescue analgesia.
All surgeries were conducted under general, spinal or epidural anesthesia according to requirement. All patients had undergone implantation with the cemented
Nex-Gen1 LPS with a patellar component (Zimmer, Inc, Warsaw, IN). After release of the ischemic tourniquet and assurance of hemostasis, a vacuum drainage tube was applied. Then, a multi-pore No.8 neonatal feeding catheter was inserted so as to assure equal distribution of infusion fluid throughout the joint cavity especially the areas where exposed tissues are present to assure effect of medication on exposed nerve endings. After airtight wound closure, the vacuum drainage system was activated till complete drainage of joint cavity was approached and the system was inactivated and analgesic infusion was started.
Dose calculation and preparation of infusions: in Bupivacaine group 5 ml of
0.5% bupivacaine were diluted with 5 ml saline to achieve a concentration of 2.5 mg/ml(0.25%) and 5 ml of this diluted bupivacaine(12.5 mg )was infused through 45 minutes by syringe pump during locking of the vacuum system which is activated for
15 minutes to withdraw the infused fluid and blood if present out of joint cavity and the procedure was repeated hourly for 72 hours. in Combination group each tramadol ampoule containing 100 mg/2 ml was diluted with normal saline to 20 ml so that each ml contains 5 mg tramadol. Infusion was prepared of 5 ml of diluted bupivacaine
(12.5 mg) and one ml of diluted tramadol (5 mg), these 6 ml were infused through 45 minutes by syringe pump during locking of the vacuum system as in bupivacaine group. The drainage catheter was removed 48 hours after surgery and thereafter the analgesic infusion was commenced by the same order for the 3 rd PO day.
Postoperative pain was assessed using 10-point visual analogue pain scale
(VAS) with 0 indicated no pain and 10 indicated the worst intolerable pain. Rescue analgesia in the form of intravenous mepridine given if VAS pain score was ≥4 or on patient's request. The daily consumption of rescue analgesia was determined. The frequency of side effects as nausea, vomiting, constipation, catheter site infection was recorded. The range of joint motion achieved daily was assessed as the angle of knee
- 2 -

flexion; i.e, the angle formed by the leg and the thigh. Length of hospital stay was also recorded.
Statistical analysis
Obtained data were presented as mean±SD and ranges. Results were analyzed using Wilcoxon ranked test for unrelated data (Z test) and Chi-square test (X
2
test).
Possible correlation was evaluated using Pearson's correlation coefficient (r).
Statistical analysis was conducted using the SPSS (Version 15, 2006) for Windows statistical package. P value <0.05 was considered statistically significant.
Results
The study included 60 patients with arthrosis; 33 had left and 27 had right arthrosis. Mean age of enrolled patients was 74.7±8.8; range: 56-91 years. Mean duration of symptoms was 12.9±3.4; range: 5-21 years. Patients' constitutional data are shown in table 1 showing non-significant (p>0.05) difference between studied groups.
Thirty patients received epidural anesthesia, 19 patients received spinal and 11 patients received general anesthesia. Mean duration of surgery was 67.6±12; 45-100 min. There was non-significant (p>0.05) difference between studied groups as regards type of anesthesia, duration of surgery, amount of daily drainage and duration of PO hospital stay. All patients showed progressive increase of range of motion throughout the first three PO days. However, the angle of knee joint movement was significantly
(p<0.05) better in combination group compared to other groups with significantly
(p<0.05) wider scale of motion in bupivacaine group compared to control group,
(Table 2).
Considering time of full recovery of anesthesia, irrespective its type, as the time zero (0-hr PO) for first evaluation of pain VAS score, at 0-hr PO, mean pain
VAS score was significantly (p<0.05) lower in patients received intra-articular analgesia compared to control group with significantly (p<0.05) lower scores in favor of combination group. At 0-hr time, 45 patients requested for rescue analgesia; 16 in bupivacaine, 20 in control and 9 in combination groups with significantly (p<0.05) lower frequency in combination group compared versus both other groups with nonsignificant (p>0.05) difference in favor of bupivacaine group. Thereafter, all studied patients showed progressive decline of pain VAS scores with significantly (p<0.05) lower scores in study groups compared to control group and non-significant (p>0.05) difference in favor of combination group till 12-hr PO. At 24-hr, 48-hr and 72-hr pain
VAS scores were significantly (p<0.05) lower scores in study groups compared to control group with significant (p<0.05) difference in favor of combination group,
(Table 3, Fig. 1).
Number of requests for rescue analgesia and total dose of mepridine consumed till 72-hr PO were significantly (p<0.05) lower in patients received intra-articular analgesia compared to control group with significantly (p<0.05) lower number of requests and total mepridine dose in combination group compared to bupivacaine group, (Table 3, Fig. 2).
There was a positive significant correlation (r=0.376, p=0.017) between pain
VAS scores and angle of knee joint flexion recorded at 72-hr PO in intra-articular groups. No catheter port site infection was reported and no complications related to the procedure or medications were reported.
There were no cases of drug-related allergy or side effects, or port-site infection or complications.
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Table (1): Patients' constitutional data
Control group
Age (years)
(n=20)
74.1±9.9
(57-86)
Bupivacaine group (n=20)
74.4±9.7
(56-91)
Combination group (n=20)
75.4±7.7
(69-89)
Total (n=60)
74.7±8.8
(56-91)
Gender; M:F
Weight (kg)
Height (cm)
BMI (kg/m 2 )
8:12
86.6±3.3
(79-90)
167±3.9
(159-172)
31.1±2
(28-34.3)
12.2±3.8
7:13
86.3±4.8
(77-94)
167.4±5.5
(156-178)
30.9±2.3
(27-35.2)
13.2±3.4
Duration of symptoms
(years) (7-17) (8-21)
Data are presented as mean±SD & ratios; ranges are in parenthesis
Table (2): Patients' operative and postoperative data
Control group Bupivacaine group
6:14
87.2±4.6
(75-94)
167.1±4.9
(159-178)
31.3±2.5
(27.2-36)
12.9±3.3
(5-18)
21:39
86.7±4.4
(75-94)
167.2±4.8
(156-178)
31.1±2.3
(27-36)
12.9±3.4
(5-21)
Combination group
Type anesthesia of General
Spinal
4 (20%)
6 (30%)
3 (15%)
6 (30%)
4 (20%)
7 (35%)
Epidural 10 (50%) 11 (55%) 9 (45%)
Duration of surgery (min)
Amount of drainage (ml)
Scale of
Day-1
Day-2
Day-1
66±11.2 (50-90)
96±22.6 (80-150)
28.5±11.6 (10-40)
106±14.9 (90-135)
66.8±12.3 (45-100)
97±30.5 (70-200)
69.3±12.6 (50-100)
98±26.1 (70-180)
31.3±8.1 (20-50) 32±10.8 (15-60)
85±14.6 (60-110)* 71.5±14.2 (60-100)*† motion
(degrees)
Day-2
Day-3
92±14.8 (70-120)
78.5±12.2 (50-95)
74.9±14.7 (50-95)*
63.8±11.9 (45-80)*
66.6±12.8 (35-80)*†
53.5±12.5 (30-70)*†
Hospital stay (days) 6.6±1.2 (5-9) 6±1.7 (4-10) 6.7±0.9 (5-8)
Data are presented as mean±SD & numbers; ranges & percentages are in parenthesis
*: significant versus control group †: significant versus bupivacaine group
Table (3): Patients' postoperative pain data
Bupivacaine group
Pain scores
VAS 0-hr PO
4-hr PO
8-hr PO
12-hr PO
24-hr PO
Control group
6.7±1.3 (4-8)
4.2±1.5 (2-6)
3.3±2.2 (1-7)
4.1±1.5 (2-6)
3.8±1.6 (2-6)
4.35±1 (3-7)*
2.25±1.4 (1-6)*
2.8±1.1 (1-6)*
2.65±1.3 (1-6)*
2.9±1.3 (1-6)*
Combination group
3.5±0.9 (2-5)*†
2.75±1.4 (2-5)*
2.2±0.9 (1-4)*
1.9±1.1 (1-5)*
1.95±1.1 (1-5)*†
48-hr PO
72-hr PO
Number of requests of rescue analgesia (time)
Total dose of mepridine
4.4±1.6 (2-6)
3.3±1.5 (2-6)
5.3±1.16
(3-7)
265±58
2.5±1.1 (1-6)*
1.9±1 (1-4)*
3.4±0.8*
(2-5)
170±41*
1.65±0.7 (1-3)*†
1.4±0.5 (1-2)*†
1.85±0.67*†
(1-3)
92.5±33.5*† consumed till 72-hr PO (mg) (150-350) (100-250)
Data are presented as mean±SD & numbers; ranges & percentages are in parenthesis
*: significant versus control group
(50-150)
†: significant versus bupivacaine group
- 4 -

4
3
2
8
7
6
Control Bupivacaine Combination
5
4
3
2
1
0
6
0-hr PO 4-hr PO 8-hr PO 12-hr PO 24-hr PO 48-hr PO 72-hr PO
Fig. (1): Mean pain VAS scores determined throughout
72 hours PO in studied groups
300
No. of requests
Total dose
5 250
200
150
100
1 50
0 0
Control Bupivacaine Combination
Fig. (2): Mean number of requests of rescue analgesia and total dose of mepridine consumed till 72-hr PO
Discussion
Intra-articular analgesia proved effective for management of PO pain in TKA patients, irrespective of medication used, as manifested by the significantly lower pain
VAS scores recorded throughout 72 hours after surgery in comparison to patients who did not receive intra-articular analgesia (Control group). In support of the benefits of intra-articular analgesia, patients received intra-articular analgesia showed significantly wider scale of joint motion compared to control group with significantly wider scale of motion recorded in combination group versus bupivacaine alone. In hand with these results, Dobrydnjov et al.
(8)
found continuous intra-articular ropivacaine infusion reduced the incidence of high pain intensity during first exercises than ropivacaine extra-articular infusion, and could therefore be expected to improve mobilization up to 24 h after TKA.
- 5 -

However, the obtained results of continuous bupivacaine infusion were superior to that reported by Chen et al.
(9)
who found continuous intra-articular infusion of 0.5% bupivacaine at 2 ml/h does not provide sustained post-operative pain relief in patients undergoing THA. This difference could be attributed to the following: firstly the use of catheter with multiple pore allowed homogenous distribution of the fluid through the joint cavity, secondly, the larger volume used allowed filling of the joint cavity so that no parts with exposed nerves were missed and the higher dose used in the current study; 12.5 mg vs 10 mg provide additional explanation for the difference.
The provided postoperative pain control allowed rapid movement of patients with progressively increasing range of motion thus inducing alleviation of patients' apprehension and release of emotional upset with subsequent uneventful postoperative course and easy rehabilitation. In line with data, Koltka et al.
(10) tried intra-articular injection of magnesium sulphate, levobupivacaine or lornoxicam versus placebo and found administration of all the drugs provided better analgesia than placebo and allowed early rehabilitation after knee arthroscopic surgery. Liu et al.
(11) reported that in patients undergoing total hip arthroplasty, a cocktail composed of morphine, bupivacaine; betamethasone and epinephrine reduced postoperative systemic opioid use and offer better pain control and earlier rehabilitation, without observable risks compared to placebo.
Combination therapy provided enhanced analgesic effect compared to bupivacaine alone as manifested by the significantly lower pain VAS scores, lower total consumption of rescue analgesia and wider range of movement. In hand with the use of combined intra-articular therapy; Senthilkumaran et al.
(12)
reported that simple addition of morphine to the intra-articular injection of bupivacaine gives a significant reduction in opiate analgesic requirement after anterior cruciate ligament reconstruction. Eroglu et al.
(13)
found administration of morphine and bupivacaine intra-articularly provided better pain relief and shorter discharge time without increasing the side effects than placebo for arthroscopic knee surgery. Ayoglu et al.
(14) also, found administration of intra-articular tramadol-ketamine combination to be more effective in decreasing postoperative daily analgesic consumption compared to either alone or to local anesthetic.
In support of the advantageous effect of tramadol as adjuvant to local anesthetic, Cekic et al.
(15)
found the addition of tramadol as an adjuvant to local anesthetics for bilateral infraorbital block is safe and significantly reduced pain score and consumption of rescue analgesics with significant prolongation of duration of analgesia compared to levobupivacaine alone and placebo.
These beneficial effects of intra-articular analgesia could be attributed to direct target effect of analgesic used, but considering bupivacaine is a fixed medication provided for both groups, enhanced analgesic effect of the use of combination of bupivacaine and tramadol could be attributed to the effect of tramadol. Moreover, considering the weak absorption occurring through the tissues of the joint cavity, the effect of tramadol could not be attributed to systemic effect but mostly to a local effect.
Multiple studies tried to investigate the mechanisms underlying such local effect of tramadol; Bianchi et al.
(16)
reported significant decrease of synovial fluid concentrations of substance P and non-significant decrease in concentration of IL-6 and proposed that the activity of tramadol may involve the modulation of inflammatory mediators. Altunkaya et al.
(17)(18)
, studied the local anesthetic effect of tramadol for minor surgical procedures when injected subcutaneously versus
- 6 -

lidocaine and proposed that tramadol can be used as an alternative drug to lidocaine for minor surgeries. Alagol et al.
(19)
reported that tramadol provides analgesia with a peripheral mechanism when administered intraarticularly.
Moreover, tramadol due to the previously mentioned mechanisms of actions other than being opiate analgesic appears to be superior and more beneficial than other opiates for such route of administration; such data was dependent on the previous work of Gutierez et al.
(20)
who found adding intra-articular fentanyl to the combination of epinephrine plus bupivacaine did not decrease pain, and did not increase neither the analgesia time nor the range of motion in patients undergoing knee arthroscopy. As an explanation for varied effect of opiates, Liu & Wang
(21) found the A118G polymorphism of the mu-opioid receptor gene resulting in the substitution of an amino acid, has been found to be associated with functional effects and response to opioid treatment.
The obtained results and review of literature allowed to conclude that continuous intra-articular tramadol/bupivacaine infusion safely reduced postoperative pain scores and spared rescue analgesics with significantly improved range of joint movement.
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