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Anesth Analg 2008; 107:300-308 © 2008 International Anesthesia Research Society doi: 10.1213/ane.0b013e3181732f21
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Abstract |
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 Top Abstract IntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION: With the increase in the number of total knee surgeries being performed, postoperative analgesic management remains a challenge. We used a new animal knee surgery model to characterize pain-related behavior in the rat, and its therapeutic modulation with systemic and intrathecal drug treatment.
METHODS: Rats were anesthetized with isoflurane and an incision was made over the left knee to expose the patella tendon. The tendon was reflected aside and a 1.4-mm diameter, 0.5 mm deep hole was drilled in both the femur and tibia at 2 mm above and below the knee joint, respectively. The holes were filled with dental cement and the wound was closed. Sham surgery animals only had a skin incision. Some animals had previously been implanted with a lumbar intrathecal catheter for drug injection. At 24 h after surgery, animals received the following drugs systemically: i.p. morphine sulfate 0.3–1 mg/kg, i.p. ketorolac 2.5–20 mg/kg, p.o. celecoxib 10–50 mg/kg, i.p. ketamine hydrochloride 2.5–10 mg/kg, i.p. clonidine hydrochloride 25 µg/kg, p.o. pregabablin 10–20 mg/kg, or drug vehicle; or intrathecally: morphine sulfate 0.3–1 µg, ketorolac 4–80 µg, L-745,337 80 µg, pregabalin 15 µg, neostigmine 0.5 µg, or saline vehicle. Pain-related behavior was then assessed by recording exploratory spontaneous activity, in which vertical and horizontal light beam interruptions were automatically recorded to measure rearing activity and ambulation for 60 min. Data were compared using analysis of variance with the Tukey-B post hoc test.
RESULTS: The model demonstrated deficits in rearing and ambulation compared with sham skin incision control animals on postsurgery days 1–3. Systemic and intrathecal morphine improved rearing and ambulation, with knee surgery/ morphine rats displaying as much activity as sham skin incision/vehicle animals, whereas knee surgery/vehicle rats showed decreased activity. Systemic ketorolac 20 mg/kg improved rearing and ambulation, with knee surgery/ketorolac rats showing increased activity compared with knee surgery/vehicle animals. Intrathecal ketorolac 4–40 µg did not increase rearing or ambulation, but the 80 µg dose was effective. Other drugs tested, systemically or intrathecally, did not restore activity to normal levels.
CONCLUSION: This study presents a new simple, reproducible rat model to assess function and discomfort after knee surgery, and one that responds to therapeutic interventions. In this knee surgery model, both systemic and intrathecal administration of either morphine or ketorolac caused reversal of the deficits in rearing and ambulatory behavior at 24 h postsurgery.
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Introduction |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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Total knee arthroplasty (TKA) has proved to be a successful surgical treatment for patients who have failed conservative medical management for osteoarthritis of the knee. In the United States, more than 400,000 TKAs are performed every year with reported success rates ranging from 85% to 90%.1 In an aging population, the number of annual TKA procedures is expected to reach 3.5 million by the year 2030.2 TKA is associated with considerable postoperative pain3 and unrelieved postoperative pain can result in increased risk for developing postoperative knee complications such as delay in strength recovery, prolonged stiffness, anterior knee pain, and chronic pain syndromes.4–6 In addition, it is very common to have patients who have undergone TKA to have minimal postsurgical pain at rest, but severe pain when they undergo physical therapy, demonstrating that postoperative pain has multifactorial determinants. Notably, the 2003 consensus statement by the National Institute of Health on TKA indicated agreement that aggressive postoperative pain management is important to TKA outcomes so that patients can undergo therapy1; however, it lacked data on the mode and analgesic drugs required to provide superior pain control.
The availability of an animal model will help in the understanding of the mechanisms of postoperative pain after knee surgery. The model should be simple to reproduce with direct clinical application. A suitable animal model for postoperative pain after knee surgery, with functional assessment, may aid in determining the optimal mode of analgesia after TKA. Earlier animal experimental models of postoperative pain used induction of cutaneous surgical hyperalgesia,7 which was very useful for assessment of postoperative pain. However, it is important to use multimodal and multistructure pain induction and assessment techniques, because a cutaneous incision model cannot describe the very complex and multifactorial aspects of postoperative pain management after various types of surgery. The laparotomy model described in rats,8,9 with the use of exploratory locomotor activity, is an attempt to link a basic animal model to clinical postoperative pain.
The current literature on the treatment of postoperative pain after TKA has not produced a consensus regarding which method is best. Many of the clinical trials use only one active drug, and in some studies the sample size is too small. A reproducible animal model is one of the ways to test multiple drugs and modalities to develop a consensus on which all anesthesiologists can depend. Moreover, the importance of the animal model is that once it is characterized and also shown to be responsive to some analgesics, then it can be used to test drugs that are not currently approved for human use. The present study seeks to develop an animal postoperative knee surgery pain model that will aid in the evaluation of innovative therapeutic interventions.
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METHODS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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Knee Surgery Model
Experiments were approved by the Institutional Animal Care and Use Committee. Male Sprague-Dawley rats (250–300 g; Charles River, Wilmington, MA) were anesthetized with 1.5% isoflurane in oxygen and placed in the supine position. The left knee was bent at 90° and firmly supported on either side by the blunt ends of stereotactic ear bars (Fig. 1A). Under sterile conditions, a 1-cm long skin incision was made over the patella tendon (Fig. 1B). The fascia over the muscle and tendon was scraped away with an elevator. The lateral side of the tendon was freed from underlying fascia with the tip of a #15 scalpel blade, and the tendon was moved laterally about 3 mm and held in place with a retractor (Fig. 1C). Using a diamond drill bur, a 1.4-mm diameter, 0.5-mm deep hole was drilled in both the femur and tibia, 2 mm above and below the knee joint respectively (Fig. 1D). The holes were immediately filled with cold-curing dental cement. The retractor was removed to allow the patella tendon to return to midline, and the skin closed with 4–0 nylon sutures.
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Sham surgery animals only had a skin incision. An additional group of control animals had the knee area shaved and prepped as with the other animals, but no incision was made. All animals had the same duration of exposure to isoflurane (about 5 min).
Animals were allowed to recover for 24 h before behavioral testing. Animals that were to receive intrathecal drugs after surgery had a polyethylene catheter (0.6-mm outer diameter) implanted via the cisterna magna,10,11 with the tip in the lumbar subarachnoid space (8 cm caudal), 7 days before knee surgery. Any animal showing neurological deficits after catheter implant was euthanized.
Behavioral Testing
After knee surgery, spontaneous exploratory activity was measured as a method to assess postoperative pain, similar to the evaluations in the rat laparotomy model8,9 and a rat thoracic muscle surgery model.12 Behavioral testing was performed between 8 am and 11 am in the morning, and the room was on a normal light/dark cycle. Animals were tested in clean, clear vivarium plastic cages (42 x 25 x 20 cm) enclosed in a cage rack Photobeam Activity System (San Diego Instruments, San Diego, CA) (Fig. 2A). Adjacent beams were 5 cm apart and beam interruptions were recorded automatically. One set of photobeams was set at foot level to measure ambulation (movement from one beam to another), and an upper set of photobeams was set 11 cm above ground to measure rearing (beam breaks in the vertical direction). The cage bedding was "1/4 in. corncob" and its starting height was about 8 mm to avoid blocking the lower photobeams over time. Activity was monitored in a low lit room for a 60-min period. As an additional measure of knee pain, mechanical hypersensitivity was subjectively evaluated by recording the response to squeezing the knee joint (also referred to as stifle joint in rats) in the medio-lateral direction,13 which is analogous to the widely used "Ritchie articular index" in patients.14 Briefly, the knee was held between the thumb and forefinger, and squeezed firmly (constant pressure applied for 3 sec). If excessive pressure is applied, the whole animal will struggle, and move both legs. With the same experienced tester, after a few practice trials each morning (with naïve rats from other studies), no excessive pressure was used during the experimental testing. The number of vocalizations (yes/no at each trial) in five trials was recorded (performed for both knees). Vocalizations are audible to the unaided ear. Data are displayed as number of nonvocalizations, for easier comparison with activity monitor graphs.
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P = 0.013, compared with sham skin incision. Naïve rats are a different group of fresh animals. (D) Increased vocalizations (decreased nonvocalizations) after knee surgery (n = 12/group). 0 time is just before surgery on these rats. *P < 0.001 compared with sham skin incision.
Model Characterization
Twenty-four rats were used for evaluating spontaneous locomotor behavior (rearing and ambulation are recorded in parallel) over postoperative days 1–4, starting 24 h after surgery. Another 12 naïve rats were used for baseline assessment (we did not want to pretest any of the same animals that we were using postsurgically for behavioral testing, since there is a gradual adaptation of the rat to the surroundings over time8). Animals were randomly assigned to the two groups (knee surgery versus sham skin incision), and during any 60-min testing period, animals from both groups were included. An additional 24 rats were used for the knee squeeze test (including just before surgery).
Drug Treatment
For systemic drug administration experiments, at 24-h postsurgery, rats were gently restrained and given 0.5 mL drug solution either intraperitoneally (i.p.) or by oral gavage (p.o.). After a 20-min interval for i.p. treatment and a 60 min delay for p.o. drugs, activity was monitored for 60 min. For intrathecal drug administration, at 24 h postsurgery, rats were gently wrapped in a towel and 8 µL drug followed by 8 µL saline flush were injected. After a 20 min wait (60 min delay for pregabalin), activity was monitored for 60 min. These delays were based on previous drug studies with the plantar foot incision model, a laparotomy model, and nociceptive tests.8,9,11,15,16
We first evaluated each systemic and intrathecal drug used in this study in control rats (no previous surgery, other than those with intrathecal implants) to verify that they did not impair or enhance rearing or ambulation compared with drug vehicle. Drug doses were tested in sets of 24 rats that were evaluated for spontaneous locomotor behavior after drug injection: 8 rats received drug dose 1, 8 rats received drug dose 2, and 8 rats received vehicle injection. Animals were randomly assigned to the three groups (drug dose 1, drug dose 2, vehicle) and during any 60 min testing period, animals from all three groups were included. These same rats were tested at 3 day intervals, with another 2 drug doses (and vehicle) randomly assigned on those days. Each rat was tested a maximum of three times.
For the primary knee surgery study, each drug dose was tested in a new set of 24 rats that were randomly assigned to three groups (knee surgery/drug, knee surgery/vehicle, sham skin incision/vehicle) and at 24-h postsurgery evaluated for spontaneous locomotor behavior after drug injection: 8 rats had knee surgery and 24 h later received a drug injection, 8 rats had knee surgery and 24 h later received a vehicle injection, and 8 rats had sham skin incision and 24 h later received a vehicle injection. During any 60 min testing period in the activity monitor, animals from all three groups were included.
Drugs tested systemically were: the µ-opioid agonist morphine sulfate 0.3–1.0 mg/kg i.p.; cyclooxygenase (COX-1/COX-2) inhibitor ketorolac tromethamine 2.5–20.0 mg/kg i.p.; COX-2 selective inhibitor celecoxib 10.0–50.0 mg/kg p.o. (Pfizer Inc, Piscataway, NJ); the N-methyl-D-aspartate antagonist ketamine hydrochloride 2.5–10.0 mg/kg i.p.; the 
2-adrenergic agonist clonidine hydrochloride 25 µg/kg i.p.; the voltage-gated calcium blocker (at 2
subunit) pregabalin 10–20 mg/kg p.o. (Pfizer). The drug vehicle for i.p. delivery was saline (0.9% sodium chloride injection), and for p.o. administration a drug-suspending vehicle (Ora-Plus, Paddock Labs, Minneapolis, MN). Drugs tested intrathecally were: morphine sulfate 0.3, 1.0 µg; ketorolac tromethamine 4, 20, 40, 80 µg; the water-soluble COX-2 selective inhibitor L-745,337 80 µg (Merck Frosst, Kirkland, Quebec); pregabalin 15 µg; the anticholinesterase inhibitor neostigmine methylsulfate 0.5 µg.
Statistical Analysis
Behavioral data comparing exploratory activity or mechanical hyperalgesia in the knee surgery model to a sham skin incision over postoperative days 1–4 were analyzed using a mixed 2-factor ANOVA, where time is the repeated factor and group is the independent factor, with an autoregressive covariance structure (SAS 8.2, SAS, Cary, NC). Sham skin incision behavior at 24-h postsurgery was compared with shave-and-scrub controls using t-test. Rearing or ambulation counts among the three groups of animals in each drug administration experiment were compared by analysis of variance with post hoc Tukey-B testing. Tables of postsurgery drug effect on rearing and ambulation show %reversal = 100 x (knee surgery with drug - knee surgery with vehicle)/(sham skin incision with vehicle – knee surgery with vehicle). A 100% reversal means that the drug had restored knee surgery animals back to control (sham skin incision with vehicle). An asterisk showing a significant %reversal in the tables means that there was a difference in counts among the three groups (ANOVA) and knee surgery with drug was greater than knee surgery with vehicle (post hoc test). Tables of drug effects in normal rats on rearing and ambulation show %change = 100 x (drug dose – vehicle)/vehicle. If %change is positive, then the drug increased spontaneous activity; if the %change is negative, then the drug decreased activity.
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RESULTS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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Knee Surgery Model
Knee surgery in rats resulted in a decrease in rearing compared with sham incision animals over postoperative days 1–4 (F = 55.1, df = 1,22, P < 0.0001), with significant differences on postsurgery days 1–3 (Fig. 2B). By day 4, rearing had decreased three-fold in sham skin incision rats, so the comparison between knee surgery versus sham skin incison on day 4 was confounded by adaptation to the environment. Knee surgery also reduced ambulation compared with sham incision animals over postoperative days 1–4 (F = 22.8, df = 1,22, P < 0.0001), with significant differences on postsurgery days 1–3 (Fig. 2C). By day 4, ambulation had decreased two-fold in sham skin incision rats, again showing adaptation to the plastic cages. There was also an increase in vocalization (decrease in non-vocalization) when pressure was applied to the knee with femur/tibia injury compared with sham skin incision animals over postoperative days 1–4 (F = 43.3, df = 1,22, P < 0.0001), with significant differences on postsurgery days 1–3, but not day 4 (Fig. 2D). Before surgery, and in the contralateral knee at all times, there were no vocalizations in any animal. To confirm that the behavioral pattern in this deep tissue/bone surgery model would not occur with a knee skin incision alone, we compared the exploratory behavior of sham skin incision with control animals that were only prepped for surgery. No difference in rearing or ambulation was seen at 24 h postsurgery (Figs. 3A and B).
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Drug Treatment
Systemic morphine 1 mg/kg (i.p.) improved rearing (F = 7.31, df = 2,21, P = 0.001), with post hoc testing showing that the knee surgery/vehicle group had reduced rearing behavior compared with the knee surgery/drug or sham skin incision/vehicle groups (Fig. 4A). Morphine 1 mg/kg also improved ambulation (F = 7.15, df = 2,21, P = 0.002), with the knee surgery/vehicle group being less active than the knee surgery/drug or sham skin incision/vehicle groups (Fig. 4B). However, smaller doses of morphine 0.5 mg/kg or 0.3 mg/kg did not improve rearing or ambulation (post hoc testing showed no difference between the knee surgery/drug and the knee surgery/vehicle groups, both being less active than the sham skin incision/vehicle group) (Table 1). Systemic morphine did not significantly change rearing or ambulation compared with saline in unoperated control rats (Table 2).
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Systemic ketorolac 20 mg/kg (i.p.) improved rearing (F = 7.35, df = 2,21, P = 0.004), with post hoc testing showing that the knee surgery/vehicle group had reduced rearing behavior compared with the knee surgery/drug or sham skin incision/vehicle groups (Fig. 5A). Ketorolac 20 mg/kg also improved ambulation (F = 5.39, df = 2,21, P = 0.013), with the knee surgery/vehicle group being less active than the knee surgery/drug or sham skin incision/vehicle groups (Fig. 5B). At the 5 mg/kg dose, rearing deficits were completely reversed as with the 20 mg/kg dose (Table 1), but ambulation was only partially reversed with post hoc testing showing knee surgery/vehicle < knee surgery/drug < sham skin incision/vehicle. At the 2.5 mg/kg dose, there was no improvement in rearing or ambulation (Table 1). Systemic ketorolac did not significantly change rearing or ambulation compared with saline in unoperated control rats (Table 2).
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To evaluate the opioid-sparing effects of ketorolac on morphine in this model, an ineffective dose of i.p. ketorolac, 2.5 mg/kg, was co-administered with an ineffective dose of i.p. morphine, 0.3 mg/kg. The drug combination improved rearing (F = 8.08, df = 2,21, P = 0.002), with post hoc testing showing that the knee surgery/vehicle group had reduced rearing behavior compared with the knee surgery/drug or sham skin incision/vehicle groups (surgery/vehicle 81 ± 11, surgery/drugs 187 ± 26, sham/vehicle 208 ± 30 counts). Ambulation (F = 6.38, df = 2,21, P = 0.007) was also improved, with the knee surgery/vehicle group being less active than the knee surgery/drug or sham skin incision/vehicle groups (Table 1). This i.p. drug combination did not significantly change rearing or ambulation compared with saline in unoperated control rats (Table 2).
Systemic celecoxib at 10, 20, or 50 mg/kg (p.o.) did not improve rearing or ambulation (Table 1). Ketamine at 2.5, 5, 10 mg/kg (i.p.) did not reverse deficits in rearing or ambulation (Table 1); larger doses could not be tested due to the anesthetic effect. Pregabalin at 10 mg/kg or 20 mg/kg (p.o.) also did not reverse deficits in rearing or ambulation, whereas the 30 mg/kg dose could not be tested due to its reduction of ambulation in naïve rats. Clonidine at the largest non-sedating dose, 25 µg/kg, was also ineffective in restoring spontaneous exploratory activity (Table 1).
The effect of intrathecal morphine 1 µg on rearing was significant (F = 6.48, df = 2,21, P = 0.001), with post hoc testing showing that the knee surgery/vehicle group had reduced rearing behavior compared with the knee surgery/drug or sham skin incision/vehicle groups (Fig. 6A). Morphine 1 µg also improved ambulation (F = 6.55, df = 2,21, P = 0.003), with the surgery/vehicle group being less active than the knee surgery/drug or sham skin incision/vehicle groups (Fig. 6B). A smaller dose of morphine, 0.3 µg, did not improve rearing or ambulation (Table 3). Intrathecal morphine did not significantly change rearing or ambulation compared with saline in control rats (Table 4).
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Intrathecal ketorolac at 80 µg improved rearing (F = 5.60, df = 2,21, P = 0.007), with post hoc testing showing that the knee surgery/vehicle group had reduced rearing behavior compared with the knee surgery/drug or sham skin incision/vehicle groups (knee surgery/vehicle 52 ± 8, knee surgery/drug 87 ± 10, sham skin incision/vehicle 98 ± 11 counts). Ketorolac 80 µg also improved ambulation (F = 4.50, df = 2,21, P = 0.017), with the knee surgery/vehicle group being less active than the knee surgery/drug or sham skin incision/vehicle groups (Table 3). However, smaller doses of intrathecal ketorolac (4, 20, 40 µg) did not improve rearing or ambulation (Table 3). A combination of ineffective doses of intrathecal ketorolac (40 µg) and morphine (0.3 µg), to evaluate the opioid-sparing effect, was unsuccessful in restoring activity (Table 3). Intrathecal ketorolac did not significantly change rearing or ambulation compared with saline in control rats (Table 4).
Intrathecal injection of a water soluble COX-2 inhibitor, L745,337,11,17 at 80 µg (largest water soluble dose in 8 µL) did not improve rearing or ambulation (Table 3). Pregabalin 15 µg, a dose that did not impair rearing or ambulation in control animals, did not improve spontaneous activity postsurgery (Table 3). Intrathecal neostigmine at 0.5 µg also did not improve rearing or ambulation (Table 3); larger doses could not be tested because they decreased spontaneous activity in control animals.
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DISCUSSION |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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This study has presented a new simple, reproducible rat model that responds to therapeutic interventions, to assess function and discomfort after knee surgery. The new model is indicative of what one would expect of a human after TKA because: (1) it produces severe pain-related behavior for 3 days after surgery; (2) it responds in a predictable manner to morphine, with both systemic and intrathecal administration. A rat knee surgery model has not been described in the literature; however methods for the functional assessment of discomfort (pain) have been described and validated for rats.8,9,12,18 Surgery in this model involved trauma to the tendon and bone, in addition to the skin, fascia, and muscle traumatized in the commonly used foot incision model.7 This study further evaluated systemic and intrathecal pharmacological interventions to reduce pain in a new rat model; future research using this model can be geared towards improving multiple outcomes after knee surgery in patients.
This new rat knee surgery model was created to mimic current trends in clinical knee surgery. Minimally invasive surgery (MIS) TKA19 is performed via a small incision (<13 cm) with the quadriceps tendon and muscles not violated to preserve the extensor mechanism. In addition the vastus medialis is not split. The patella is not everted but subluxed. The MIS TKA has been shown to have improved functionality as patients can undergo physical therapy earlier.19 Increasing interest in MIS among patients and surgeons has been a driving force in the development of MIS TKA. Similarly, we designed this new rat knee surgery model to mimic conditions in a patient having MIS. In our knee surgery model, the incision was made over the midline of the knee and the patella was subluxed. Care was exercised to not violate the extensor muscles of the knee joint in the rat.20 Once adequate exposure of the knee joint was obtained, although no artificial prosthesis was inserted, holes were drilled in the femur and tibia in order to simulate clinical knee surgery. This process likely produces pain and an inflammatory response that is similar to clinical knee surgery.
Spontaneous exploratory behavior decreased and vocalization with applied pressure increased in the knee surgery rats on postoperative days 1, 2, and 3 compared with sham skin incision rats, demonstrating that this model produces postoperative pain that is severe. Vocalization due to pressure on the operated knee (similar to testing in patients) is a nociceptive test, not subject to adaptation with once-a-day testing, so the lack of difference in response between the two groups at day four postsurgery suggests that postoperative pain is resolving in the model by that time point. Although it would have strengthened our assertion that this knee surgery model produces pain in the animal if we had more widely used nociceptive tests to correlate with the above measures, the standard pain tests in rats (e.g., those used after plantar foot incision) were not appropriate for measuring pain at the knee joint.
Sensitivity of spontaneous locomotor behavior to morphine in this knee surgery model is similar to other surgical models. Systemic morphine at 1 mg/kg completely reversed pain-related behavior 24 h after knee surgery, and this same dose improved rearing and ambulation after laparotomy.8 Morphine at that dose also reversed tactile allodynia in the plantar foot incision model.15 In our control rats, 1 mg/kg morphine did not significantly increase spontaneous locomotor activity, which matches the results of a previous study using activity monitoring chambers.8 Other studies with different behavioral paradigms have shown that morphine over a limited dose range can have a stimulant effect, but the reasons for not seeing this during short-term testing in activity chambers may be complex.8 Intrathecal morphine at 1 µg completely reversed rearing and ambulation deficits after knee surgery, and this dose was just as effective in reversing pain-related behavior after laparotomy.9 Intrathecal morphine at a similar dose (0.76 µg) also reversed tactile allodynia in the planter foot incision model.16
The mixed COX-1/COX-2 inhibitor ketorolac partially, but significantly, reversed pain-related behavior at 5 mg/kg (i.p.) and completely restored behavior to normal at 20 mg/kg, in the knee surgery model. Ketorolac at 5 mg/kg i.p. was not effective at improving spontaneous exploratory behavior after laparotomy in a rat model.8 In a thoracic muscle incision animal model, ketorolac 3 mg/kg given at the start of surgery completely reversed deficits in rearing and ambulation over the next 6 h postsurgery.12 Intrathecal ketorolac at 80 µg, but not 40 µg or lower, completely reversed rearing and ambulation deficits after rat knee surgery. This was not due to systemic redistribution since that intrathecal dose (80 µg) corresponds to only a 0.3 mg/kg systemic dose, and 2.5 mg/kg i.p. was ineffective in reversing impairment of ambulatory variables. By comparison, intrathecal ketorolac at 50 µg significantly improved ambulation but not rearing after the laparotomy model.9 Intrathecal ketorolac had a relatively weak effect in reducing tactile allodynia in the plantar foot incision model, with only a 30% recovery at 150 µg.9
The opioid-sparing effect of systemic ketorolac (ineffective doses of ketorolac 2.5 mg/kg + morphine 0.3 mg/kg) that reversed pain-related behavior in our knee surgery model was similarly observed in the laparotomy animal model (5 mg/kg ketorolac + morphine 0.3 mg/kg).8 This phenomena of opioid sparing with COX-1/COX-2 inhibitor has been demonstrated in clinical studies in orthopedic surgery.21–23
We did not observe any significant improvement in rearing or ambulation with an oral COX-2 selective inhibitor administered 24 h after knee surgery. In contrast, we had previously noted a complete reversal of pain-related behavior with a COX-2 inhibitor given at the start of deep thoracic muscle surgery.12 This difference could be due to more extensive surgical trauma (in bone) in the rat knee surgery model compared with the thoracic muscle incision model. Intrathecal administration of a COX-2 inhibitor alone did not improve rearing or ambulation after knee surgery, failed to improve exploratory behavior after laparotomy,9 and did not reduce mechanical allodynia after plantar foot incision.11 Efficacy could not be shown for ketamine, pregabalin, clonidine, or neostigmine in this knee surgery model.
In conclusion, we have established a new reliable and reproducible animal model of knee surgery that can be used to assess functional measures of postoperative pain. This model responds to common drugs used for the treatment of postoperative pain, and should enable future research on the mechanism of pain from TKA and therapeutic interventions that can lead to improvement in outcome of patients.
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Footnotes |
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Accepted for publication March 3, 2008.
Supported by University Anesthesiologists SC, Chicago, IL.
Reprints will not be available from the author.
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REFERENCES |
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