Oral Ketamine for Acute Pain Management After Amputation Surgery.

Objective: Intravenous ketamine has been shown to provide postoperative analgesia in many clinical trials, in particular to reduce opioid consumption. The primary objective of this pilot study is to determine if multiple dosing over a three-day perioperative period with oral ketamine is a safe treatment method for acute pain after amputation surgery. Methods: Three consented subjects (age 57-60 years) undergoing elective amputation of the lower extremity were included in the study (Institutional Review Board and Food and Drug Administration Investigational New Drug approved). An analgesic dose of oral ketamine (1.0 mg/kg) was administered one hour before surgery. Eight hours after the preoperative dose, a second dose was given. On the first postoperative day, subjects received oral ketamine (1.0 mg/kg) three times per day; and on the second postoperative day, this dose was reduced to 0.5 mg/kg three times per day. The primary outcome measure was the incidence of adverse events. Results: No serious and unexpected adverse events occurred; therefore, no subject required a dose reduction. The numerical rating score for postoperative pain of the body part adjacent to the amputation site ranged from 0.5-4.0. Morphine milligram equivalent opioid doses were in the range of 0-17.5 mg on the first postop day and 1.0-4.0 mg on the second postop day. Conclusions: Our pilot study suggests that oral ketamine is safe to use at 1 mg/kg three times per day, as well as convenient for hospital floor and potential home use. Future studies will determine if the perioperative oral ketamine also reduces the incidence of chronic stump or phantom limb pain.

Short-term glycemic control is effective in reducing surgical site infection in diabetic rats.

BACKGROUND: Patients and animals with diabetes exhibit enhanced vulnerability to bacterial surgical infections. Despite multiple retrospective studies demonstrating the benefits associated with glycemic control in reducing bacterial infection after cardiac surgery, there are fewer guidelines on the use of glycemic control for noncardiac surgeries. In the current study, we investigated whether long-term (begun 2 weeks before surgery) or immediate (just before surgery) glycemic controls, continued postoperatively, can reduce surgical site infection in type 1 diabetic-induced rats. METHODS: Rats were injected with streptozotocin to induce type 1 diabetes. Four groups of animals underwent surgery and thigh muscle Staphylococcus aureus bacteria challenge (1 × 10 colony forming units) at the time of surgery. Group 1 diabetic rats received insulin treatment just before surgery and continued until the end of study (short-term glycemic control group). Group 2 diabetic rats received insulin treatment 2 weeks before surgery and continued until the end of study (long-term glycemic control). Group 3 diabetic rats received no insulin treatment (no glycemic control group). Group 4 nondiabetic rats served as a healthy control group. Rats were euthanized at 3 or 6 days after surgery. Blood glucose and muscle bacterial burden were measured at 3 or 6 days after surgery. RESULTS: Glycemic control was achieved in both long- and short-term insulin-treated diabetic rats. Compared with untreated diabetic rats, the bacterial burden in muscle was significantly lower in both groups of glycemic controlled diabetic rats at 3 (all P < 0.003) and 6 (all P < 0.0001) days after surgery. CONCLUSIONS: A short-term glycemic control regimen, initiated just before surgery and bacterial exposure, was as effective in reducing surgical site infection as a long-term glycemic control in type 1 diabetic rats. These data suggest that immediately implementing glycemic control in type 1 diabetic surgical patients before undergoing noncardiac surgery may decrease the risk of infection.

Characterization of a new animal model for evaluation and treatment of back pain due to lumbar facet joint osteoarthritis.

OBJECTIVE: Osteoarthritic (OA) degeneration of the lumbar facet joints has been implicated in low back pain. This study was undertaken to investigate the biologic links between cellular and structural alterations within facet joint components and the development of symptomatic chronic back pain. METHODS: We generated an animal model of facet joint degeneration by intraarticular injection of monosodium iodoacetate (MIA) into facet joints (L3-L4, L4-L5, L5-L6) of Sprague-Dawley rats. Pain sensation due to pressure, which mimics a mechanical stimulus for facet joint injury, was measured using an algometer. Pain response was also assessed in a straight leg raising test. Cartilage alterations were assessed by biochemical evaluation and microfocal computed tomography (micro-CT). Therapeutic modulation of chronic facet joint pain with the use of various pharmacologic agents was investigated. RESULTS: MIA injection resulted in severely damaged facet joint cartilage, proteoglycan loss, and alterations of subchondral bone structure. Micro-CT analyses suggested that the behavioral hyperalgesia from facet joint degeneration was not associated with foraminal stenosis. The biologic and structural changes in facet joints were closely associated with sustained and robust chronic pain. Morphine and pregabalin markedly alleviated pressure hyperalgesia, while celecoxib (a selective inhibitor of cyclooxygenase 2 [COX-2]) produced moderate antihyperalgesic effects and the effect of ketorolac (an inhibitor of COX-1 and COX-2) was negligible. CONCLUSION: Our findings demonstrate that MIA injection provides a useful model for the study of OA changes in the facet joint and indicate that facet joint degeneration is a major cause of chronic low back pain. The treatment results suggest that classes of drugs that are widely used to treat OA, such as nonsteroidal antiinflammatory drugs, may have limited efficacy once joint destruction is complete.

Special Article: Ronald D. Miller: tribute to a past editor-in-chief.

For anesthesiologists around the world who have practiced or trained in the past 4 decades, the name Ronald Miller, MD, has been synonymous with a commitment to excellence that has been evident in all aspects of his remarkable career as a distinguished clinician-scientist, editor, writer, and educator. Dr. Miller's contributions as Editor-in-Chief of Anesthesia & Analgesia (1991-2006) have stimulated this salutation of his career and of his influence on transforming the Journal.

Safety of local anesthetics administered intrathecally in diabetic rats.

OBJECTIVES: Although retrospective studies show the risk of neurological complications after spinal anesthesia with local anesthetics is small in diabetic patients, there is still concern about the safety of different local anesthetics in diabetics undergoing neuroaxial anesthesia. We examined block duration and histology of spinal cord and roots with intrathecal local anesthetics in diabetic rats. METHODS: Rats were made diabetic with streptozotocin injection. Blood glucose levels confirmed diabetes, and diabetic neuropathy was verified by tactile hypersensitivity. Diabetic and nondiabetic rats received four intrathecal injections at 3-4-day intervals of 0.75% bupivacaine, with/without 100 µg/mL epinephrine; and 2% lidocaine, with/without 100 µg/mL epinephrine, and duration of sensory (pinprick) and motor (toe-spreading reflex) response inhibition recorded. Four days after the last drug injection, histology of spinal cord and roots was performed. RESULTS: All streptozotocin rats became diabetic and had pronounced tactile allodynia. Intrathecal injection of local anesthetics showed longer duration of sensory and motor block in diabetic rats vs nondiabetics. Histology of caudal spinal cord showed no difference in neuropathology between diabetic and nondiabetic rats. Necrotic neurons were not seen in either group, and white-matter pathology involved less than 0.1% of fibers. Histology of the spinal roots also showed no difference in pathology between groups, and pathology involved less than 0.1% of fibers. Neuron somas in the dorsal root ganglia were normal. CONCLUSIONS: Duration of local anesthetic spinal block is longer in diabetic animals than in nondiabetics. However, there was no increased pathology of spinal cord, roots, or dorsal root ganglia.

Cerebrospinal fluid neurotransmitter changes during the perioperative period in patients undergoing total knee replacement: a randomized trial.

BACKGROUND: Total knee replacement (TKR) is of enormous benefit to patients with osteoarthritis of the knee; however, the acute postoperative pain can be severe and difficult to manage. The role of major spinal cord neurotransmitters in this acute postoperative period is not clear, although there are a few studies in humans. We performed the first prospective clinical study undertaken to delineate the changes in the spinal neurotransmitters after a surgery such as TKR. Furthermore, we also determined whether antihyperalgesic drugs at clinically acceptable doses modulate spinal neurotransmitter concentrations in patients during the perioperative period. METHODS: All patients had a spinal needle placed in the lumbar region and cerebrospinal fluid (CSF) obtained for baseline measurement of the neurotransmitters. An intrathecal catheter was then placed for spinal anesthesia for standard TKR and for continuous spinal postoperative analgesia. The spinal catheter was also used postoperatively to sample CSF at 2, 4, 8, 12, 24, and 32 hours after catheter placement. CSF samples were assayed for norepinephrine, substance P, calcitonin gene-related peptide (CGRP), and glutamate concentrations. SF-36 (36-item Short Form Health Survey) was measured preoperatively. Numerical rating scale (NRS) pain scores and intrathecal analgesic consumption were recorded postsurgery at 4-hour intervals for 32 hours. We performed a randomized, placebo-controlled, double-blind trial with 3 drug groups (n = 16 per group): placebo; single-dose pregabalin (150 mg administered before surgery); and multidose pregabalin (150 mg administered presurgery and 12 and 24 hours later), to determine the effect of an antihyperalgesic drug such as pregabalin on spinal neurotransmitters. RESULTS: Forty-eight patients were randomly assigned to the 3 perioperative treatment groups, and multiple CSF samples were successfully obtained from 44 patients. Before surgery, increased bodily pain (from preoperative SF-36 measure) was correlated with increased CSF norepinephrine concentration (P = 0.044). Compared with presurgery values, norepinephrine levels were lower in the placebo group at the 2- and 4-hour time points (P < 0.005) whereas in the single and multidose groups, the reduction (P < 0.001) continued until 12 and 24 hours, respectively. Substance P CSF levels had an early peak value (at 2 hours) in all 3 groups, and then returned to baseline. Compared with baseline value, the CGRP CSF levels only decreased at the 32-hour time point in the placebo group, but in both pregabalin groups, CGRP levels decreased over the 4- to 32-hour period. In the placebo group only, CSF glutamate decreased over 4 to 32 hours compared with presurgery values. However, there was no difference in the CSF neurotransmitter concentrations among the 3 treatment groups over the 32-hour sampling period. In the placebo group, the early NRS pain score area under the curve, AUC [0-12 hours], was positively correlated (R = 0.67, P = 0.0088) with the CSF norepinephrine concentration AUC [12-24 hours], but none of the other neurotransmitters was correlated with the NRS. None of the CSF neurotransmitter concentrations correlated with postoperative analgesic consumption. CONCLUSION: In the perioperative period, the concentration changes of the 4 spinal neurotransmitters have a distinct time course. CSF substance P seems to increase very rapidly with surgical intervention, whereas the CSF norepinephrine concentration tends to decrease. At clinical doses, pregabalin does not seem to modulate these spinal neurotransmitter concentrations.

Perioperative oral pregabalin reduces chronic pain after total knee arthroplasty: a prospective, randomized, controlled trial.

BACKGROUND: Despite the enormous success of total knee arthroplasty (TKA), chronic neuropathic pain can develop postoperatively and is both distressing and difficult to treat once established. We hypothesized that perioperative treatment with pregabalin, a chronic pain medication, would reduce the incidence of postsurgical neuropathic pain. METHODS: We performed a randomized, placebo-controlled, double-blind trial of pregabalin (300 mg) administered before TKA and for 14 days after TKA (150-50 mg twice daily). Patients were screened for the presence of neuropathic pain at 3 and 6 mo postoperatively using the Leeds Assessment of Neuropathic Symptoms and Signs scale. Secondary outcomes included postsurgical recovery and rehabilitation measures, including knee range of motion, opioid consumption, postoperative pain scores, sleep disturbance, and time to discharge as well as the occurrence of postoperative systemic complications. RESULTS: Of the 240 patients randomly assigned to the 2 treatment groups (120 in each), data for the primary outcome were obtained from 113 pregabalin patients and 115 placebo patients. At both 3 and 6 mo postoperatively, the incidence of neuropathic pain was less frequent in the pregabalin group (0%) compared with the placebo group (8.7% and 5.2% at 3 and 6 mo, respectively; P = 0.001 and P = 0.014). Patients receiving pregabalin also consumed less epidural opioids (P = 0.003), required less oral opioid pain medication while hospitalized (P = 0.005), and had greater active flexion over the first 30 postoperative days (P = 0.013). There were no differences in the actual recorded duration of hospitalization between the 2 groups, although time to achieve hospital discharge criteria was longer for placebo patients, 69.0 +/- 16.0 h (mean +/- SD), than that of pregabalin patients, 60.2 +/- 15.8 h (P = 0.001). Sedation (P = 0.005) and confusion (P = 0.013) were more frequent on the day of surgery and postoperative day 1 in patients receiving pregabalin. CONCLUSION: Perioperative pregabalin administration reduces the incidence of chronic neuropathic pain after TKA, with less opioid consumption and better range of motion during the first 30 days of rehabilitation. However, in the doses tested, it is associated with a higher risk of early postoperative sedation and confusion.

Acute postoperative pain is an independent predictor of chronic postsurgical pain following total knee arthroplasty at 6 months: a prospective cohort study.

BACKGROUND: Approximately 15% of patients report persistent knee pain despite surgical success following total knee arthroplasty (TKA). The purpose of this study was to determine the association of acute-postsurgical pain (APSP) with chronic postsurgical pain (CPSP) 6 months after TKA controlling for patient, surgical and psychological confounding factors. METHODS: Adult patients with osteoarthritis undergoing primary elective tricompartmental TKA, with the operated knee the primary source of preoperative pain, were studied between March 2011 and February 2017. Patients received standard operative management and a perioperative multimodal analgesia regimen. The primary outcome was CPSP at 6 months. The primary variable of interest was the APSP (weighted mean pain score) for 72 hours postoperatively. Patient, surgical and psychological confounders were assessed using binary logistic regression. RESULTS: 245 cases were analyzed. The incidence of CPSP was 14% (95% CI 10% to 19%). Median APSP values were 4.2 (2.2-5.0) in the CPSP group and 2.8 (1.8-3.7) without CPSP, difference 1.4 (95% CI 0.1 to 1.8, p=0.005). The unadjusted odds for CPSP with an increase of 1 in APSP was 1.46 (95% CI 1.14 to 1.87, p=0.002)). After multivariable risk adjustment, the OR for CPSP for an increase of 1 in the APSP was 1.53 (95% CI 1.12 to 2.09, p=0.008). CONCLUSIONS: APSP is a risk factor for CPSP following TKA even after adjusting for confounding variables such as pain catastrophizing, anxiety, depression and functional status. Studies are needed to determine if APSP is a modifiable risk factor for the development of CPSP.

A new knee surgery model in rats to evaluate functional measures of postoperative pain.

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 microg/kg, p.o. pregabablin 10-20 mg/kg, or drug vehicle; or intrathecally: morphine sulfate 0.3-1 microg, ketorolac 4-80 microg, L-745,337 80 microg, pregabalin 15 microg, neostigmine 0.5 microg, 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 microg did not increase rearing or ambulation, but the 80 microg 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.

Upregulation of dorsal horn microglial cyclooxygenase-1 and neuronal cyclooxygenase-2 after thoracic deep muscle incisions in the rat.

BACKGROUND: Plantar hindpaw incision produces hyperalgesia, transient upregulation of cyclooxygenase-2 (COX-2) and prolonged upregulation of cyclooxygenase-1 (COX-1) in rat lumbar spinal cord. Our hypothesis in this study was that a deep thoracic incision causes COX-1 and COX-2 upregulation in the dorsal horn coincident with pain-related behavior, and that specific cell types contribute to this increase in COX expression. METHODS: A left lateral thoracic skin incision was made in anesthetized rats, and superficial and deep muscles were incised. Postoperative pain-related behavior was quantified by recording exploratory rearing. Four and 24 h postsurgery, COX-1 and COX-2 immunohistochemistry, with co-labeling for cell type, were performed on the spinal cord. RESULTS: Deep thoracic muscle incision produced a 42% decrease in rearing compared to sham skin-incision controls at 4 h postsurgery (P = 0.001). There was an increase in both COX-1 and COX-2 immunoreactivity in the thoracic dorsal horn at 4 h postsurgery on the ipsilateral side of surgery animals compared to the ipsilateral side of control animals, contralateral side of surgery animals or contralateral side of control animals. No surgery-induced differences were seen at the lumbar level. At 24 h postsurgery, there was no longer a decrease in rearing, and no surgery-induced differences in COX-1 or COX-2 were seen at any level. At 4 h postsurgery, 96% of COX-1 immunoreactive cells co-localized with microglia and 98% of COX-2 immunoreactive cells co-localized with neurons. CONCLUSIONS: A unilateral deep thoracic wound produces pain-related behavior and, at the same time, ipsilateral upregulation of microglial COX-1 and neuronal COX-2 in the thoracic dorsal horn.

Upregulation of cerebrospinal fluid and peripheral prostaglandin E2 in a rat postoperative pain model.

Analgesic management of postoperative pain associated with thoracic surgery remains a difficult clinical challenge. In the present study we used a thoracic muscle incision model to characterize pain-related behavior and changes in prostaglandin E2 (PGE2) in both thoracic cerebrospinal fluid (CSF) and incision site tissues. A deep muscle incision was made in the left thoracic region of rats anesthetized with isoflurane, propofol, or spinal bupivacaine. Thoracic CSF and incision site tissue concentrations of PGE2 were monitored for 6 h using microdialysis loop catheters. Postoperative pain-related behavior was assessed by recording exploratory locomotive activity. Thoracic muscle surgery decreased rearing and ambulation. Oral ketorolac or rofecoxib 3 mg/kg restored normal rearing and ambulation. Postoperative CSF PGE2 concentration increased most (threefold) with spinal anesthesia, and not at all with propofol. With surgery under isoflurane or spinal bupivacaine, presurgical oral administration of ketorolac or rofecoxib 3 mg/kg reduced postsurgical CSF PGE2 levels and tissue PGE2 levels. Intrathecal ketorolac (4 microg) reduced CSF PGE2 after surgery without affecting tissue PGE2 levels, whereas intrathecal L-745,337 (80 microg) did not reduce CSF PGE2. Thoracic surgical wounds increase pain-related behavior and CSF and tissue PGE2 levels, all of which can be attenuated by oral cyclooxygenase inhibitors.

Relative Contribution of Adjuvants to Local Anesthetic for Prolonging the Duration of Peripheral Nerve Blocks in Rats.

BACKGROUND AND OBJECTIVES: A chemically compatible, safe 4-drug multimodal formulation of bupivacaine combined with 3 adjuvants (clonidine, buprenorphine, and dexamethasone) has been proposed for long-lasting single-injection peripheral nerve blocks in patients. However, the relative importance of each of the adjuvants of the 4-drug formulation in producing long-lasting nerve blocks has not been determined. The aim of this study in rats was to determine which adjuvants (clonidine, buprenorphine, or dexamethasone) are essential for producing a long-lasting nerve block. METHODS: After baseline sensory and motor responses were recorded, 0.1 mL of drug solution was injected into the sciatic notch of rats. Animals were reevaluated at 10-minute intervals after injection for the absence or presence of sensory and motor response in the sciatic nerve. The 4-drug formulation of 0.25% bupivacaine plus all 3 adjuvants (clonidine, buprenorphine, and dexamethasone), 0.25% bupivacaine with 1 or 2 of the adjuvants added separately, and 0.25% bupivacaine alone were compared for duration of nerve block. RESULTS: The 4-drug multimodal solution produced a longer duration of sensory and motor nerve block than 0.25% bupivacaine alone (P < 0.0001). Bupivacaine plus clonidine also produced a longer duration of nerve block than 0.25% bupivacaine alone (P = 0.0157), but bupivacaine plus buprenorphine or bupivacaine plus dexamethasone did not prolong nerve block compared to bupivacaine alone. There was no difference (P = 0.1414) in the duration of nerve block between the 4-drug multimodal solution versus bupivacaine plus clonidine. CONCLUSIONS: This animal study confirmed that the 4-drug multimodal formulation proposed for clinical nerve block produces superior duration of action compared to local anesthetic alone. This rat sciatic nerve model also indicated that one of the 3 adjuvants, clonidine, could by itself account for the extended duration of nerve block of bupivacaine.

Local Drug Infiltration Analgesia During Knee Surgery to Reduce Postoperative Pain in Rats.

BACKGROUND AND OBJECTIVES: There is increasing interest in local infiltration analgesia (LIA) to reduce postoperative pain with knee surgery. Despite widespread use of LIA, wide variations in drug combinations, infiltration techniques, and the concomitant use of systemic analgesics have made it difficult to determine the optimal drug combination for LIA.Using a previously validated animal knee surgery model, we aimed to determine the optimal combination of medications to reduce postoperative pain, and the best anatomical location and timing for local drug injection during surgery. METHODS: Knee surgery was performed in an adult rat model under isoflurane anesthesia. During surgery, combinations of bupivacaine, ketorolac, dexamethasone, and morphine were injected around the knee and compared to saline placebo. Similar medications were injected systemically as a comparator group. Postoperative pain was assessed by measuring spontaneous rearing activity. Injections were given after bone drilling and/or just before wound closure. RESULTS: The 3-drug LIA combination of bupivacaine, ketorolac, and dexamethasone increased rearing (decreased pain) at 2 hours (P = 0.0198) and 24 hours (P = 0.0384) postsurgery compared to saline. The same drugs injected systemically had no effect. The ketorolac/dexamethasone combination for LIA was also effective at 2 hours (P = 0.0006) and 24 hours (P = 0.0279), and ketorolac alone reduced pain at 2 hours (P = 0.0045). Bupivacaine alone was less effective, and the addition of morphine had no effect. The 3-drug combination infiltrated just after creating holes in bone was more effective than when given into the wound just before wound closure. CONCLUSIONS: Our animal study suggests that clinical trials with LIA combinations of local anesthetic, nonsteroidal anti-inflammatory drug, and corticosteroid might be useful for reducing postoperative pain after knee surgery, with the nonsteroidal anti-inflammatory drug having the greatest effect.Perioperative physicians should consider delivering LIA earlier during the procedure as opposed to solely at the time of wound closure.

Local Infiltration of Analgesics at Surgical Wound to Reduce Postoperative Pain After Laparotomy in Rats.

BACKGROUND AND OBJECTIVES: There is an increasing use of local infiltration analgesia (LIA) to reduce postoperative pain. Despite widespread use of LIA, wide variations in drug combinations and concomitant use of systemic analgesics have made it difficult to determine the optimal drug combinations for LIA. Using a previously validated rat laparotomy model, the optimal LIA combination of medications to reduce postoperative pain was determined. METHODS: Laparotomy was performed in an adult rat model under isoflurane anesthesia. During surgery, combinations of bupivacaine, ketorolac, and dexamethasone were injected over the sutured muscle wound before skin closing, and compared to saline (placebo). The same medications were injected systemically as controls. Postoperative pain was assessed by measuring spontaneous rearing activity. RESULTS: A high-dose 3-drug LIA combination (50 µL of bupivacaine 0.75%, ketorolac 6.0 mg/mL, and dexamethasone 2.0 mg/mL) increased rearing (decreased pain) at 2 hours (P = 0.0032) postsurgery compared to saline. However, the same 3 drugs injected systemically had a similar analgesic effect (P = 0.0002). Bupivacaine 0.75% alone was not effective for LIA. When low-dose (9-fold reduction) 3-drug LIA combination was used, LIA increased rearing (P = 0.0034) whereas the same 3 drugs injected systemically had no effect. Low-dose LIA ketorolac/dexamethasone (2-drug combination) also increased rearing (P = 0.0393). CONCLUSIONS: Our animal study suggests that clinical trials with low-dose LIA combinations of local anesthetic, nonsteroidal anti-inflammatory drug, and corticosteroid may be useful for reducing postoperative pain after laparotomy.

Cyclooxygenase-2 inhibition potentiates morphine antinociception at the spinal level in a postoperative pain model.

BACKGROUND AND OBJECTIVES: After peripheral inflammatory stimuli, spinal cord cyclooyxgenase-2 (COX-2) mRNA and protein levels increase, whereas COX-1 is unchanged. In animal models of inflammatory pain, intrathecal COX-2 selective inhibitors suppress hyperalgesia. However, the role of spinal COX-2 inhibition in postoperative pain is not well elucidated. This study investigates whether a water-soluble COX-2 selective inhibitor, L-745337, can modify allodynic responses in a rat model of postoperative pain. METHODS: Allodynia was induced in the left plantar hindpaw by surgical incision. Animals then received intrathecal (0-80 micro g) or subcutaneous (0-30 mg/kg) L-745337 coadministered with intrathecal morphine (0-2 nmol). Reduction of mechanical allodynia (increased withdrawal threshold) was quantified with calibrated von Frey hairs. RESULTS: L-745337 alone, whether intrathecal or systemic, had no effect on withdrawal threshold. When intrathecal L-745337 at doses of 40 to 80 micro g was combined with a subthreshold dose (0.5 nmol) of morphine, withdrawal thresholds were increased in a dose-dependent manner. Adding 80 micro g L-745337 to 1 nmol morphine produced an antiallodynic effect greater than that of morphine at twice the dose. Subcutaneous L-745337, up to 30 mg/kg combined with intrathecal morphine resulted in the same antiallodynic response as morphine alone. CONCLUSION: These results suggest a spinal interaction of COX-2 inhibition with opiate analgesia may allow a reduction of postoperative pain with lower doses of opiate.

Effects of perioperative administration of a selective cyclooxygenase 2 inhibitor on pain management and recovery of function after knee replacement: a randomized controlled trial.

CONTEXT: Controlling postoperative pain after knee replacement while reducing opioid-induced adverse effects and improving outcomes remains an important challenge. OBJECTIVE: To assess the effect of combined preoperative and postoperative administration of a selective inhibitor of cyclooxygenase 2 on opioid consumption and outcomes after total knee arthroplasty (TKA). DESIGN, SETTING, AND PATIENTS: Randomized, placebo-controlled, double-blind trial conducted June 2001 through September 2002, enrolling 70 patients aged 40 to 77 years and undergoing TKA at a university hospital in the United States. INTERVENTIONS: Patients were randomly assigned to receive 50 mg of oral rofecoxib at 24 hours and at 1 to 2 hours before TKA, 50 mg daily for 5 days postoperatively, and 25 mg daily for another 8 days, or matching placebo at the same times. MAIN OUTCOME MEASURES: Postoperative outcomes including postsurgical analgesic consumption and pain scores achieved, nausea and vomiting, joint range of motion, sleep disturbance, patient satisfaction with analgesia, and hematologic and coagulation parameters. RESULTS: Total epidural analgesic consumption and in-hospital opioid consumption were less in the group receiving rofecoxib compared with the group receiving placebo (P<.05). Median pain score (visual analog scale [VAS], 0-10) achieved for the knee was lower in the rofecoxib group compared with the placebo group during hospital stay (2.2 [interquartile range [IQR], 1.4-3.2] vs 3.5 [IQR, 2.7-4.3], P<.001) and 1 week after discharge (2.6 [IQR, 1.4-3.5] vs 3.7 [IQR, 2.9-4.7], P =.03). There was less postoperative vomiting in the rofecoxib group (6%) compared with the placebo group (26%) (P =.047), as well as a decrease in sleep disturbance compared with the placebo group on the night of surgery (P =.006) and on the first (P =.047) and second (P<.001) days postoperatively. Knee flexion was increased in the rofecoxib group compared with the placebo group at discharge (active flexion: mean [SD], 84.2 degrees [11.1 degrees ] vs 73.2 degrees [13.6 degrees ], P =.03; passive flexion: 90.5 degrees [6.8 degrees ] vs 81.8 degrees [13.4 degrees ], P =.05) and at 1 month postoperatively (109.3 degrees [8.5 degrees ] vs 100.8 degrees [11.8 degrees ], P =.01), with shorter time in physical therapy to achieve effective joint range of motion. The rofecoxib group was more satisfied with analgesia and anesthesia at discharge compared with the placebo group (median satisfaction score, 4.3 [IQR, 3.0-4.7] vs 3.3 [IQR, 2.3-4.3], respectively; P =.03), and the differences persisted at 2-week and at 1-month follow-up. There was no intergroup difference in surgical blood loss (P>.05 for both intraoperative and postoperative blood loss). CONCLUSION: Perioperative use of an inhibitor of cyclooxygenase 2 is an effective component of multimodal analgesia that reduces opioid consumption, pain, vomiting, and sleep disturbance, with improved knee range of motion after TKA.

Effect of acute versus continuous glycemic control on duration of local anesthetic sciatic nerve block in diabetic rats.

BACKGROUND AND OBJECTIVES: The duration of nerve block is longer in streptozotocin (STZ)-induced diabetic rats for all local anesthetics (with and without adjuvants) compared with normal rats. Perioperative glycemic control is currently practiced to reduce adverse events in many at-risk patients, especially in diabetic patients, to prevent neuropathy, poor wound healing, and greater incidence of infection. The aim of this study was to investigate in diabetic rats the importance of glycemic control before peripheral nerve block. METHODS: To induce diabetes, rats were intravenously injected with a single dose of 50 mg/kg STZ to destroy pancreatic beta cells. Tactile allodynia in response to von Frey filament stimulation of the plantar hind paws was used as the criterion for diabetic neuropathy. Diabetic rats were randomly divided into experimental treatment groups. The continuous glycemic control experiment compared: 3 U/d insulin implant for 14 days, 1.5 U/d insulin implant for 14 days, and placebo treatment. The acute glycemic control experiment compared a single 6U Human Insulin Isophane Suspension (NPH) injection and placebo treatment. Nondiabetic rats received placebo implants or injections. Following treatment, 0.1 mL of 1% lidocaine hydrochloride with 5 µg/mL epinephrine hydrochloride was injected into the left sciatic notch. Animals were then reevaluated at 10-minute intervals for the absence or presence of sensory and motor response. RESULTS: All STZ-injected rats had blood glucose levels greater than 350 mg/dL and tactile allodynia. After insulin implants or injections, diabetic rats had much lower blood glucose levels than diabetic rats with placebo treatment. With both 3 and 1.5 U/d continuous glycemic control, the local anesthetic solution produced a shorter duration of sensory and motor nerve block in insulin-treated diabetic rats compared with placebo-treated diabetic rats, and shorter duration was similar to nondiabetic rats. With 6 U acute glycemic control in diabetic rats, there was no reduction in nerve block duration compared with placebo-treated diabetic rats. CONCLUSIONS: With continuous glycemic control in diabetic rats, the duration of sensory and motor nerve block was about 40 minutes shorter than that in the untreated diabetic rats and similar to that of normal rats. However, acute glycemic control did not affect nerve block duration, suggesting that this neuropathy cannot be rapidly reversed.

The rat intervertebral disk degeneration pain model: relationships between biological and structural alterations and pain.

INTRODUCTION: Degeneration of the interverterbral disk is as a cause of low-back pain is increasing. To gain insight into relationships between biological processes, structural alterations and behavioral pain, we created an animal model in rats. METHODS: Disk degeneration was induced by removal of the nucleus pulposus (NP) from the lumbar disks (L4/L5 and L5/L6) of Sprague Dawley rats using a 0.5-mm-diameter microsurgical drill. The degree of primary hyperalgesia was assessed by using an algometer to measure pain upon external pressure on injured lumbar disks. Biochemical and histological assessments and radiographs of injured disks were used for evaluation. We investigated therapeutic modulation of chronic pain by administering pharmaceutical drugs in this animal model. RESULTS: After removal of the NP, pressure hyperalgesia developed over the lower back. Nine weeks after surgery we observed damaged or degenerated disks with proteoglycan loss and narrowing of disk height. These biological and structural changes in disks were closely related to the sustained pain hyperalgesia. A high dose of morphine (6.7 mg/kg) resulted in effective pain relief. However, high doses of pregabalin (20 mg/kg), a drug that has been used for treatment of chronic neuropathic pain, as well as the anti-inflammatory drugs celecoxib (50 mg/kg; a selective inhibitor of cyclooxygenase 2 (COX-2)) and ketorolac (20 mg/kg; an inhibitor of COX-1 and COX-2), did not have significant antihyperalgesic effects in our disk injury animal model. CONCLUSIONS: Although similarities in gene expression profiles suggest potential overlap in chronic pain pathways linked to disk injury or neuropathy, drug-testing results suggest that pain pathways linked to these two chronic pain conditions are mechanistically distinct. Our findings provide a foundation for future research on new therapeutic interventions that can lead to improvements in the treatment of patients with back pain due to disk degeneration.

The intraoperative management of patients with pericardial tamponade.

The anesthetic management of patients with pericardial tamponade is challenging, as they present with not only the cardiovascular compromise that defines pericardial tamponade, but often have comorbid conditions that increase the complexity of their management. This review describes the pathophysiology, etiology, clinical presentation, and anesthetic management of patients with pericardial tamponade, with an emphasis on the intraoperative period and the management of pericardial window procedures, the most common clinical scenario where anesthesiologists will encounter pericardial tamponade.