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ABSTRACT: 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.
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.
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.
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.
Regional anesthesia and pain medicine 09/2012; 37(6):595-600. · 4.16 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
Pain Medicine 05/2012; 13(6):802-7. · 2.35 Impact Factor
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Xin Li,
Michael B Ellman, Jeffrey S Kroin,
Di Chen,
Dongyao Yan,
Katalin Mikecz,
Ranjan K C,
Guozhi Xiao,
Gary S Stein,
Su-Gwan Kim,
Brian Cole,
Andre J van Wijnen,
Hee-Jeong Im
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ABSTRACT: Existing literature demonstrates that fibroblast growth factor-2 (FGF-2) exerts opposing, contradictory biological effects on cartilage homeostasis in different species. In human articular cartilage, FGF-2 plays a catabolic and anti-anabolic role in cartilage homeostasis, driving homeostasis toward degeneration and osteoarthritis (OA). In murine joints, however, FGF-2 has been identified as an anabolic mediator as ablation of the FGF-2 gene demonstrated increased susceptibility to OA. There have been no previous studies specifically addressing species-specific differences in FGF-2-mediated biological effects. In this study, we provide a mechanistic understanding by which FGF-2 exerts contradictory biological effects in human versus murine tissues. Using human articular cartilage (ex vivo) and a medial meniscal destabilization (DMM) animal model (in vivo), species-specific expression patterns of FGFR receptors (FGFRs) are elucidated between human and murine articular cartilage. In the murine OA model followed by intra-articular injection of FGF-2, we further correlate FGFR profiles to changes in behavioral pain perception, proteoglycan content in articular cartilage, and production of inflammatory (CD11b) and angiogenic (VEGF) mediators in synovium lining cells. Our results suggest that the fundamental differences in cellular responses between human and murine tissues may be secondary to distinctive expression patterns of FGFRs that eventually determine biological outcomes in the presence of FGF-2. The complex interplay of FGFRs and the downstream signaling cascades induced by FGF-2 in human cartilage should add caution to the use of this particular growth factor for biological therapy in the future.
Journal of Cellular Biochemistry 03/2012; 113(7):2532-42. · 2.87 Impact Factor
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Michael B Ellman,
Jae-Sung Kim,
Howard S An, Jeffrey S Kroin,
Xin Li,
Di Chen,
Dongyao Yan,
Doug D Buechter,
Keiichi Nakayama,
Bo Liu,
Stephanie Morgan,
Hee-Jeong Im
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ABSTRACT: Protein kinase Cδ (PKCδ) activation has been shown to be a principal rate-limiting step in matrix-degrading enzyme production in human articular chondrocytes. The aim of this study was to assess the role of the PKC pathways, specifically PKCδ, in intervertebral disc tissue homeostasis.
Using in vitro, ex vivo, and in vivo techniques, we evaluated the pathophysiologic role of the PKCδ pathway by examining 1) proteoglycan deposition, 2) matrix-degrading enzyme production and activity, 3) downstream signaling pathways regulated by PKCδ, and 4) the effect on in vivo models of disc degeneration in genetically engineered PKCδ-knockout mice.
Studies of pathway-specific inhibitors revealed a vital role of the PKCδ/MAPK (ERK, p38, JNK) axis and NF-κB in disc homeostasis. Accordingly, in an in vivo model of disc injury, PKCδ-knockout mice were markedly resistant to disc degeneration.
Suppression of the PKCδ pathway may be beneficial in the prevention and/or treatment of disc degeneration. The results of this study provide evidence for a potential therapeutic role of pathway-specific inhibitors of the PKCδ cascade in the future.
Arthritis & Rheumatism 12/2011; 64(6):1950-9. · 7.87 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
Anesthesia and analgesia 12/2011; 114(2):434-41. · 3.08 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
Arthritis research & therapy 10/2011; 13(5):R165. · 4.27 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
Arthritis & Rheumatism 10/2011; 63(10):2966-73. · 7.87 Impact Factor
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Anesthesia and analgesia 12/2010; 111(6):1335-6. · 3.08 Impact Factor
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ABSTRACT: Central spinal cord sensitization can occur during surgery and may lead to persistent pain after surgery. Pregabalin has been shown to decrease central sensitization in experimental pain paradigms, and so the same antihyperalgesic effect of pregabalin may occur during and immediately after surgery. Our study investigated whether a single 300-mg dose of pregabalin in patients has sufficient central nervous system bioavailability to be useful under acute conditions where brain or spinal cord excitability may lead to long-term disease, such as chronic pain.
Nine patients undergoing primary total knee replacement received pregabalin 300 mg orally, 1 hr before surgery. An intrathecal catheter was inserted for anesthesia, postoperative analgesic drug administration, and cerebrospinal fluid (CSF) sampling. Blood and CSF were then simultaneously sampled at 2, 4, 6, 8, and 24 hrs after oral pregabalin administration. Pregabalin concentration in plasma and CSF was measured using a validated high-pressure liquid chromatography assay.
By 2 hrs after pregabalin administration, the CSF pregabalin concentration is high enough (0.115 μg/mL) to have anticonvulsant activity, and by 6 hrs after pregabalin administration, the CSF pregabalin level is high enough (0.359 μg/mL) to reduce central nervous system hypersensitivity. The median time to peak pregabalin concentration in CSF was at 8 hrs. The pregabalin CSF/plasma based on area under the curve (AUC[0-24 hrs]) was 0.098 ± 0.016, and for AUC[0-∞], the ratio was 0.176 ± 0.064.
Sufficient central nervous system drug concentrations are reached after oral administration of pregabalin, suggesting that postoperative pain hypersensitivity can be reduced. Decreasing this acute brain or spinal cord excitability may prevent chronic pain from developing after surgery.
Regional anesthesia and pain medicine 11/2010; 35(6):535-8. · 4.16 Impact Factor
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Hee-Jeong Im,
Jae-Sung Kim,
Xin Li,
Naomi Kotwal,
Dale R Sumner,
Andre J van Wijnen,
Francesca J Davis,
Dongyao Yan,
Brett Levine,
James L Henry,
Jacques Desevré, Jeffrey S Kroin
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ABSTRACT: To verify the biologic links between progressive cellular and structural alterations within knee joint components and development of symptomatic chronic pain that are characteristic of osteoarthritis (OA), and to investigate the molecular basis of alterations in nociceptive pathways caused by OA-induced pain.
An animal model of knee joint OA pain was generated by intraarticular injection of mono-iodoacetate (MIA) in Sprague-Dawley rats, and symptomatic pain behavior tests were performed. Relationships between development of OA with accompanying pain responses and gradual alterations in cellular and structural knee joint components (i.e., cartilage, synovium, meniscus, subchondral bone) were examined by histologic and immunohistologic analysis, microscopic examination, and microfocal computed tomography. Progressive changes in the dynamic interrelationships between peripheral knee joint tissue and central components of nociceptive pathways caused by OA-induced pain were examined by investigating cytokine production and expression in sensory neurons of the dorsal root ganglion and spinal cord.
We observed that structural changes in components of the peripheral knee joint correlate with alterations in the central compartments (dorsal root ganglia and the spinal cord) and symptomatic pain assessed by behavioral hyperalgesia. Our comparative gene expression studies revealed that the pain pathways in MIA-induced knee OA may overlap, at least in part, with neuropathic pain mechanisms. Similar results were also observed upon destabilization of the knee joint in the anterior cruciate ligament transection and destabilization of the medial meniscus models of OA.
Our results indicate that MIA-induced joint degeneration in rats generates an animal model that is suitable for mechanistic and pharmacologic studies on nociceptive pain pathways caused by OA, and provide key in vivo evidence that OA pain is caused by central sensitization through communication between peripheral OA nociceptors and the central sensory system. Furthermore, our data suggest a mechanistic overlap between OA-induced pain and neuropathic pain.
Arthritis & Rheumatism 10/2010; 62(10):2995-3005. · 7.87 Impact Factor
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ABSTRACT: Background and Objectives: A concern for anesthesiologists is whether local anesthetics are more toxic to peripheral nerves in diabetic patients. A previous study in streptozotocin-induced diabetic rats showed that larger doses of lidocaine produce moderate nerve injury after nerve block in normal rats and worse injury in diabetic rats. However, it is not clear whether a smaller local anesthetic dose that produces negligible nerve fiber damage in normal rats will produce significant nerve damage in diabetic rats and if adding adjuvant drugs modulates this effect.
Methods: Rats were intravenously injected with 50 mg/kg streptozotocin to induce diabetes (blood glucose levels >250 mg/dL) and diabetic neuropathy. After waiting 35 days, an injection (0.1 mL) of 1% lidocaine alone, or with 5 μg/mL epinephrine or 7.5 μg/mL clonidine added, or 0.5% ropivacaine alone was performed at the left sciatic notch in both diabetic and nondiabetic rats. The duration of sensory (pin prick) and motor (toe spreading reflex) nerve block in the hind paws was determined. For histologic controls, all rats also received saline vehicle injection into the right sciatic notch. Another group of uninjected rats was used as naive controls. Left and right nerves were removed 2 days after injection and fixed in situ with a 4% glutaraldehyde solution. Myelinated axon profiles suggestive of neuropathy (myelin figures, pale and swollen, or dark-staining axoplasm) were counted and expressed as a percentage of the total number of fibers in each rat sciatic nerve.
Results: All streptozotocin-injected rats became diabetic and had pronounced tactile allodynia. All rats had sensory and motor nerve blocks lasting for at least 50 mins after injection of local anesthetic. The duration of sensory and motor nerve block was longer in diabetic rats than in nondiabetic rats for all drug groups tested. None of the sciatic nerves examined showed greater than 3% nerve fiber degeneration. Although lidocaine in diabetic rats did not produce nerve fiber damage, diabetic rats receiving lidocaine/clonidine or ropivacaine had more abnormal myelinated axon profiles than did nondiabetic rats receiving the same drug.
Conclusions: The duration of sciatic nerve block with local anesthetics is longer in diabetic compared with nondiabetic rats. A small, but statistically significant, increase in nerve damage occurred in diabetic rats after nerve block with ropivacaine alone or when duration of lidocaine block was extended with clonidine. These findings may have implications for dosing of local anesthetics in diabetic patients undergoing regional analgesia with nerve blocks.
Regional Anesthesia and Pain Medicine 06/2010; 35(4):343-350. · 4.08 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
Anesthesia and analgesia 11/2009; 110(1):199-207. · 3.08 Impact Factor
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ABSTRACT: After surgery, cytokines and chemokines are released at the surgical wound site, which can contribute to postoperative pain, local inflammation, and tissue repair. Multiple cell types are present that can release cytokines/chemokines at the wound site and, thus, the exact cellular source of these molecules is unclear. We sought to better understand the contribution of neutrophils to cytokine/chemokine gene expression at the surgical wound site during the initial postsurgery phase of total hip arthroplasty (THA).
Hip drain fluid was collected at 24 h postsurgery from six patients undergoing standardized THA. In addition, venous blood was collected presurgery and 24 h postsurgery. Neutrophils were isolated, total RNA extracted, and a biotinylated cRNA probe generated. The probes were hybridized with a cDNA microarray containing approximately 100 oligonucleotide sequences representing various human cytokines/chemokines or receptor genes. Changes in gene expression seen in the microarray were verified by reverse transcription polymerase chain reaction.
In the microarray analysis of hip drain neutrophils, interleukin-1 receptor antagonist (IL1RN), interleukin-18 receptor 1 (IL18R1), macrophage migration inhibitory factor (MIF), and macrophage inflammatory protein 3alpha (CCL20) were upregulated, whereas interleukin-8 receptor beta (IL8RB/CXCR2) was consistently downregulated, compared with presurgery blood neutrophils. All of these changes were confirmed by reverse transcription polymerase chain reaction.
There is a distinct cytokine gene expression profile in neutrophils at the THA surgical wound site at 24 h postsurgery when compared with that found in presurgery circulating neutrophils. Understanding these changes may allow us to knowledgeably manipulate neutrophil activity to reduce postoperative pain and inflammation without impairing wound healing.
Anesthesia and analgesia 10/2009; 109(3):959-64. · 3.08 Impact Factor
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ABSTRACT: The authors report the case of a 56-year-old previously healthy man who presented with a 4-month history of postural headache accompanied by nausea and vomiting. The results of initial imaging studies of the brain were normal. Repeated MR imaging demonstrated bilateral subdural hematomas which were drained and reaccumulated over a period of time. Spinal myelography revealed a cerebrospinal fluid leak at the C1-2 level. A cervical epidural blood patch, with repeated injections of 10 ml autologous blood at the site of the leak, dramatically improved the headache within 24 hours and eliminated the recurrent subdural hematomas. The results of follow-up computed tomography of the brain at 1, 4, 8, and 16 weeks were normal, and at 1-year follow-up the patient was completely free of symptoms and working.
Journal of Neurosurgery Spine 12/2008; 9(5):483-7. · 1.53 Impact Factor
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Anesthesia and analgesia 11/2008; 107(4):1093-4. · 3.08 Impact Factor
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ABSTRACT: A new partial nerve lesion (PNL) model is needed to better simulate traumatic lesions seen clinically that result in both dysfunction and neuropathic pain. We assessed surgical variability and several outcome measures including histology during the acute postoperative period. A surgical lesion was created in the rat tibial nerve by removing a segment, later confirmed by myelinated axon counts. Variability in the model was assessed with four different outcome measures during the first postoperative week (n=24), with additional histological outcomes at 7 days (n=13) and pain testing at 21 days (n=9). At 7 days postoperative, the PNL resulted in a tibial functional index (TFI) of -41.3% distinct from a percent motor deficit (PMD) of -76.3%. However, the respective deficits from 2 to 7 days were similar. Either test could detect outliers, but PMD measurements had a lower coefficient of variation and were easier to perform and analyze. The deleted segment contained 26% of the myelinated axons and resulted in distal degeneration that was either 46% based on axon counts or 54% based on area. Replicated experiments confirmed the PMD, muscle atrophy, and formation of neuropathic pain. In conclusion, our partial lesion histologically progresses twofold during the first postoperative week with profound behavioral deficits involving both motor and sensory loss. These results based on sensitive and correlative outcome measures support the application of this novel model in experimental nerve lesion studies.
Journal of Neuroscience Methods 08/2008; 172(2):236-44. · 1.98 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
Anesthesia and analgesia 07/2008; 107(1):300-8. · 3.08 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
Anesthesia and analgesia 05/2008; 106(4):1288-95, table of contents. · 3.08 Impact Factor
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ABSTRACT: Total knee arthroplasty (TKA) is associated with considerable postoperative pain, which, if unrelieved, may result in prolonged hospital stay, inability to participate in rehabilitation programs, poor outcomes, and greater use of healthcare resources. The hypothesis of this study is that perioperative administration of celecoxib will improve analgesic efficacy, with a resultant improvement in short- and long-term clinical outcomes after TKA.
We studied 200 patients undergoing elective TKA in a prospective, randomized, double-blind, placebo-controlled fashion. All patients underwent a similar perioperative anesthetic/analgesic procedure. After completion of surgery, patients were started on an epidural infusion with patient-controlled epidural analgesia. Patients were instructed to keep their numerical rating score pain < or = 3. Patients were randomly assigned to one of two groups: celecoxib or placebo. The celecoxib group received celecoxib 100 mg orally twice a day 7 days before surgery. On the day of surgery, celecoxib 400 mg was administered 1-2 h before surgery and then 200 mg every 12 h for 10 postoperative days. The control group received matching placebo capsules at the same times. The primary objective of this study was to determine whether the perioperative use of celecoxib reduces the amount of postoperative opioid consumption. Secondary objectives were to determine whether celecoxib is associated with improved clinical outcomes and a reduction in opioid-related adverse effects.
The celecoxib group required less patient-controlled epidural analgesia over the 40-h postoperative period: placebo 232.8 +/- 2.0 mL, celecoxib 209.1 +/- 1.8 mL (P < 0.001). At home over days 4-10 after surgery, the celecoxib group had reduced pain intensity with movement (F = 109.7, P < 0.001) at all time points. The celecoxib group also consumed less oxycodone at home than placebo group (F = 417.8, P < 0.001). With active movement, range of motion (ROM) differed between the two groups over postoperative days 1-3 (F = 50.7, P < 0.001), with the celecoxib group having greater ROM at all time points. There was earlier achievement of 90 degrees knee flexion with celecoxib compared with placebo (P < 0.001). Celecoxib patients had a better overall Knee Society Score (93.3 +/- 0.6) than placebo patients (86.4 +/- 0.9) at 12-mo follow-up (P < 0.001). The incidence of side effects (nausea, vomiting, and pruritus) in the immediate postoperative period was less in the celecoxib group.
Perioperative use of celecoxib reduces postoperative pain, opioid consumption, opioid-related adverse effects, and is associated with long-term benefits including improved knee function and less time to achieve effective knee ROM after TKA.
Anesthesia and analgesia 04/2008; 106(4):1258-64, table of contents. · 3.08 Impact Factor
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ABSTRACT: It is not known how different analgesic regimes affect the brain when reducing postoperative pain. We performed positron emission tomography (PET) scans on a 69-yr-old woman in the presence of moderate postoperative pain and then with epidural analgesia producing complete analgesia, during the first 2 days after total knee arthroplasty. Day 2 postsurgery PET scan data (no pain with epidural analgesia) were subtracted from Day 1 postsurgery PET scan data (time of moderate pain without epidural analgesia) to determine the brain regions activated. Postsurgical pain was associated with increased activity in the contralateral primary somatosensory cortex. Other brain regions showing increased postsurgical activity were the contralateral parietal cortex, bilateral pulvinar and ipsilateral medial dorsal nucleus of the thalamus, contralateral putamen, contralateral superior temporal gyrus, ipsilateral fusiform gyrus, ipsilateral posterior lobe, and contralateral anterior cerebellar lobe. This study demonstrates the feasibility of evaluating the central processing of acute postoperative pain using PET.
Anesthesia and analgesia 01/2008; 105(6):1784-6, table of contents. · 3.08 Impact Factor
