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1.  The Effect of Nitrous Oxide Anesthesia on Early Postoperative Opioid Consumption and Pain 
Background and Objectives
Many patients experience moderate to severe postoperative pain. Nitrous oxide exerts analgesia by inhibition of N-Methyl-D-aspartate (NMDA) receptors. Ketamine, another NMDA receptor-antagonist, reduces postoperative opioid consumption and pain. A similar effect of nitrous oxide is plausible, yet understudied. The goal of this study was to determine the effects of nitrous oxide anesthesia on early postsurgical opioid consumption and pain.
Methods
This was a retrospective, secondary analysis of the Vitamins In Nitrous Oxide trial, where 500 patients undergoing general anesthesia for noncardiac surgery received 60% nitrous oxide and 125 received no nitrous oxide (otherwise, inclusion/exclusion criteria were identical). Exclusion criteria for this study were regional anesthesia; not extubated after surgery; transfer to ICU; no available PACU record; postsurgical sedation; or treated with naloxone. Primary outcomes were cumulative opioid consumption measured in morphine equivalents and pain scores during the immediate recovery phase.
Results
Four hundred forty-two patients met inclusion criteria. No difference in intraoperative and postoperative opioid consumption was observed between patients who received nitrous oxide (n=353) and patients who did not (n=89). The median [interquartile range] postoperative morphine equivalent dose was 6.7 mg [1.7–14.1] for patients who received nitrous oxide and 6.7 mg [2.1–15.4] for patients who did not (P = 0.73). The maximum pain score was 6 [4–8] for patients who received nitrous oxide versus 6 [3–8] for patients who received nitrous oxide-free anesthesia (P = 0.52). The prevalence of moderate to severe pain was 69% for patients who received nitrous oxide and 68% for patients who did not (P = 0.90).
Conclusions
Nitrous oxide anesthesia was not associated with decreased opioid administration, pain, or incidence of moderate to severe pain in the early postoperative phase.
doi:10.1097/AAP.0000000000000039
PMCID: PMC3919543  PMID: 24310050
Analgesia; Nitrous Oxide; Pain; Postoperative; Anesthesia; General
2.  Characteristics of Chronic Pain Patients Who Take Opioids and Persistently Report High Pain Intensity 
Background and Objectives
The use of self-report questionnaires to detect characteristics of altered central pain processing, as seen in centralized pain disorders such as fibromyalgia, allow for the epidemiological studies of pain patients. Here, we assessed the relationship between reporting high levels of pain while taking opioids and the presence of characteristics associated with centralized pain.
Methods
We evaluated 582 patients taking opioid medications using validated measures of clinical pain, neuropathic pain symptoms, mood, and functioning. A multivariate linear regression model was used to assess the association between levels of pain while taking opioids and presenting with characteristics consistent with having centralized pain.
Results
We found that 49% of patients taking opioids continued to report severe pain (≥ 7/10). In multivariate analysis, factors associated with having higher levels of pain in opioid users included higher fibromyalgia survey scores (P = 0.001), more neuropathic pain symptoms (P < 0.001), and higher levels of depression (P = 0.002). While only 3.2% were given a primary diagnosis of fibromyalgia by their physician, 40.8% met American College of Rheumatology survey criteria for fibromyalgia.
Conclusions
Our findings suggest that patients with persistently high pain scores despite opioid therapy are more likely than those with lower levels of pain to present with characteristics associated with having centralized pain. This study cannot determine whether these characteristics were present before (fibromyalgia-like patient) or after the initiation of opioids (opioid-induced hyperalgesia). Regardless, patients with a centralized pain phenotype are thought to be less responsive to opioids and may merit alternative approaches.
doi:10.1097/AAP.0000000000000024
PMCID: PMC3960717  PMID: 24310048
3.  Increases in the Use of Prescription Opioid Analgesics and the Lack of Improvement in Disability Metrics Among Users 
Background and Objectives
In the United States, use of oral opioid analgesics has been associated with increasing rates of addiction, abuse, and diversion. However, little is known about recent national use of non-illicit prescription opioid analgesics (those prescribed in a doctor-patient relationship), the primary source of these drugs for the general US population. Our primary objective was to examine trends in the use of prescription opioid analgesics in the United States and to identify defining characteristics of patient users of prescribed opioids from 2000 to 2010.
Methods
We used the nationally representative Medical Expenditure Panel Survey to examine trends in prescription oral opioid analgesic use from 2000 to 2010. We used survey design methods to make national estimates of adults (18 years and older) who reported receiving an opioid analgesic prescription (referred to as opioid users) and used logistic regression to examine predictors of opioid analgesic use. Our primary outcome measures were national estimates of total users of prescription opioid analgesics and total number of prescriptions. Our secondary outcome was that of observing changes in the disability and health of the users.
Results
The estimated total number of opioid analgesic prescriptions in the United States increased by 104%, from 43.8 million in 2000 to 89.2 million in 2010. In 2000, an estimated 7.4% (95% CI, 6.9–7.9) of adult Americans were prescription opioid users compared with 11.8% (95% CI, 11.2–12.4) in 2010. Based on estimates adjusted for changes in the general population, each year was associated with a 6% increase in the likelihood of receiving an opioid prescription from 2000 to 2010. Despite the apparent increase in use, there were no demonstrable improvements in the age- or sex-adjusted disability and health status measures of opioid users.
Conclusions
The use of prescription opioid analgesics among adult Americans has increased in recent years, and this increase does not appear to be associated with improvements in disability and health status among users. On a public health level, these data suggest that there may be an opportunity to reduce the prescribing of opioid analgesics without worsening of population health metrics.
doi:10.1097/AAP.0000000000000022
PMCID: PMC3955827  PMID: 24310049
4.  Estimating the Incidence of Suspected Epidural Hematoma and the Hidden Imaging Cost of Epidural Catheterization: A Retrospective Review of 43,200 Cases 
Introduction
Hematoma associated with epidural catheterization is rare, but the diagnosis might be suspected relatively frequently. We sought to estimate the incidence of suspected epidural hematoma after epidural catheterization, and to determine the associated cost of excluding or diagnosing an epidural hematoma through radiologic imaging.
Methods
We conducted an electronic retrospective chart review of 43,200 patient charts using 4 distinct search strategies and cost analysis, all from a single academic institution from 2001 through 2009. Charts were reviewed for use of radiological imaging studies to identify patients with suspected and confirmed epidural hematomas. Costs for imaging to exclude or confirm the diagnosis were related to the entire cohort.
Results
In our analysis, over a 9-year period that included 43,200 epidural catheterizations, 102 patients (1:430) underwent further imaging studies to exclude or confirm the presence of an epidural hematoma—revealing 6 confirmed cases and an overall incidence (per 10,000 epidural blocks) of epidural hematoma of 1.38 (95% CI 0, 0.002). Among our patients, 207 imaging studies, primarily lumbar spine MRI, were performed. Integrating Medicare cost expenditure data, the estimated additional cost over a 9-year period for imaging and hospital charges related to identifying epidural hematomas nets to approximately $232,000 or an additional $5.37 per epidural.
Discussion
About 1 in 430 epidural catheterization patients will be suspected to have an epidural hematoma. The cost of excluding the diagnosis, when suspected, is relatively low when allocated across all epidural catheterization patients.
doi:10.1097/AAP.0b013e31829ecfa6
PMCID: PMC3799821  PMID: 23924685
6.  Ultrasound-Guided Root/Trunk (Interscalene) Block for Hand and Forearm Anesthesia 
Background
Historically, the anterolateral interscalene block—deposition of local anesthetic adjacent to the brachial plexus roots/trunks—has been used for surgical procedures involving the shoulder. The resulting block frequently failed to provide surgical anesthesia of the hand and forearm, even though the brachial plexus at this level included all of the axons of the upper extremity terminal nerves. However, it remains unknown whether deposition of local anesthetic adjacent to the seventh cervical root or inferior trunk results in anesthesia of the hand and forearm.
Methods
Using ultrasound guidance and a needle-in-plane posterior approach, a Tuohy needle was positioned with the tip located between the deepest and next-deepest visualized brachial plexus root/trunk, followed by injection of mepivacaine (1.5%). Grip strength and the tolerance to cutaneous electrical current in 5 terminal nerve distributions were measured at baseline and then every 5 minutes following injection for a total of 30 minutes. The primary end point was the proportion of cases in which the interscalene nerve block resulted in a decrease in grip strength of at least 90%, and hand and forearm anesthesia (tolerance to >50 mA of current in all 5 terminal nerve distributions) within 30 minutes. The primary hypothesis was that a single-injection interscalene brachial plexus block produces a similar rate of anesthesia of the hand and forearm to the published success rate of 95% for other brachial plexus block approaches.
Results
Of 55 subjects with blocks placed per protocol, all had a successful block of the shoulder as defined by inability to abduct at the shoulder joint. Thirty-three subjects had measurements at 30 minutes following local anesthetic deposition, and only 5 (15%) of these subjects had a surgical block of the hand and forearm (P < 0.0001; 95% confidence interval [CI]: 6–33%). We therefore reject the hypothesis that the interscalene block as performed in this study provides equivalent anesthesia to the hand and forearm compared with other brachial plexus block techniques. Block failures of the hand and forearm were due to inadequate cutaneous anesthesia of the ulnar (n = 27; 82%), median (n = 26; 78%), or radial (n = 22; 67%) distributions; the medial forearm (n = 25; 76%), and/or the lateral forearm (n = 14; 42%). Failure to achieve at least a 90% reduction in grip strength occurred in 16 subjects (48%).
Conclusions
This study did not find evidence to support the hypothesis that local anesthetic injected adjacent to the deepest brachial plexus roots/trunks reliably results in surgical anesthesia of the hand and forearm.
doi:10.1097/AAP.0b013e3182890d50
PMCID: PMC3631428  PMID: 23528646
8.  Sleep Apnea and Total Joint Arthroplasty under Various Types of Anesthesia 
Background and Objectives
The presence of sleep apnea (SA) among surgical patients has been associated with significantly increased risk of perioperative complications. Although regional anesthesia has been suggested as a means to reduce complication rates among SA patients undergoing surgery, no data are available to support this association. We studied the association of the type of anesthesia and perioperative outcomes in patients with SA undergoing joint arthroplasty.
Methods
Drawing on a large administrative database (Premier Inc), we analyzed data from approximately 400 hospitals in the United States. Patients with a diagnosis of SA who underwent primary hip or knee arthroplasty between 2006 and 2010 were identified. Perioperative outcomes were compared between patients receiving general, neuraxial, or combined neuraxial-general anesthesia.
Results
We identified 40,316 entries for unique patients with a diagnosis for SA undergoing primary hip or knee arthroplasty. Of those, 30,024 (74%) had anesthesia-type information available. Approximately 11% of cases were performed under neuraxial, 15% under combined neuraxial and general, and 74% under general anesthesia. Patients undergoing their procedure under neuraxial anesthesia had significantly lower rates of major complications than did patients who received combined neuraxial and general or general anesthesia (16.0%, 17.2%, and 18.1%, respectively; P = 0.0177). Adjusted risk of major complications for those undergoing surgery under neuraxial or combined neuraxial-general anesthesia compared with general anesthesia was also lower (odds ratio, 0.83 [95% confidence interval, 0.74–0.93; P = 0.001] vs odds ratio, 0.90 [95% confidence interval, 0.82–0.99; P = 0.03]).
Conclusions
Barring contraindications, neuraxial anesthesia may convey benefits in the perioperative outcome of SA patients undergoing joint arthroplasty. Further research is needed to enhance an understanding of the mechanisms by which neuraxial anesthesia may exert comparatively beneficial effects.
doi:10.1097/AAP.0b013e31828d0173
PMCID: PMC3932239  PMID: 23558371
9.  The kappa opioid receptor agonist U-50488 blocks Ca2+ channels in a voltage-and G protein-independent manner in sensory neurons 
Background and Objectives
Kappa opioid receptor (κ-OR) activation is known to play a role in analgesia and central sedation. The purpose of the present study was to examine the effect of the κ-OR agonist, U-50488 (an arylacetamide), on Ca2+ channel currents and the signaling proteins involved in acutely isolated rat dorsal root ganglia (DRG) neurons expressing the putative promoter region of the tetrodotoxin (TTX)-resistant Na+ channel (NaV 1.8) that is known to be involved in pain transmission.
Methods
Acutely isolated rat DRG neurons were transfected with cDNA coding for enhanced green fluorescent protein (EGFP), whose expression is driven by the Nav 1.8 promoter region. Thereafter, the whole-cell variant of the patch-clamp technique was employed to record Ca2+ channel currents in neurons expressing EGFP.
Results
Exposure of EGFP-expressing DRG neurons to U-50488 (0.3 to 40 μM) led to voltage-independent inhibition of the Ca2+ channel currents. The modulation of the Ca2+ currents did not appear to be mediated by the Gα protein subfamilies: Gαi/o, Gαs, Gαq/11, Gα14 and Gαz. Furthermore, dialysis of the hydrolysis-resistant GDP analog, GDP-β-S (1 mM), did not affect the U-50488-mediated blocking effect, ruling out involvement of other G protein subunits. Finally, U-50488 (20 μM) blocked Ca2+ channels heterologously expressed in HeLa cells that do not express κ-OR.
Conclusion
These results suggest that the antinociceptive actions mediated by U-50488 are likely due to both a direct block of Ca2+ channels in sensory neurons as well as G protein modulation of Ca2+ currents via κ-OR-expressing neurons.
doi:10.1097/AAP.0b013e318274a8a1
PMCID: PMC3530143  PMID: 23222359
10.  In Zucker Diabetic Fatty rats, subclinical diabetic neuropathy increases in vivo lidocaine block duration but not in vitro neurotoxicity 
Background and Objectives
Application of local anesthetics may lead to nerve damage. Increasing evidence suggests that risk of neurotoxicity is higher in patients with diabetic peripheral neuropathy. Additionally, block duration may be prolonged in neuropathy. We sought to investigate neurotoxicity in vitro and block duration in vivo in a genetic animal model of diabetes mellitus type II.
Methods
In the first experiments, neurons harvested from control Zucker Diabetic Fatty (ZDF) rats were exposed to acute (24 hours) or chronic (72 hours) hyperglycemia, followed by incubation with lidocaine 40 mM (approximately 1%). In a second experiment, neurons harvested from control ZDF rats, or diabetic ZDF rats, were incubated with lidocaine, with or without SB203580, an inhibitor of the p38 Mitogen-Activated Protein Kinase. Finally, we performed sciatic nerve block (lidocaine 2%, 0.2 mL) in control or diabetic ZDF rats, and measured motor and nociceptive block duration.
Results
In vitro, neither acute nor chronic hyperglycemia altered neurotoxic properties of lidocaine. In vitro, incubation of neurons with lidocaine resulted in a slightly decreased survival ratio when neurons were harvested from diabetic (57 ± 19) as compared to control (64 ± 9 %) rats. The addition of SB203580 partly reversed this enhanced neurotoxic effect and raised survival to 71 ± 12 in diabetic and 66 ± 9 % in control rats, respectively. In vivo, even though no difference was detected at baseline testing, motor block was significantly prolonged in diabetic as compared to control rats (137 ± 16 min versus 86 ± 17 min).
Conclusions
In vitro, local anesthetic neurotoxicity was more pronounced on neurons from diabetic animals, but the survival difference was small. In vivo, subclinical neuropathy leads to substantial prolongation of block duration. We conclude that early diabetic neuropathy increases block duration, while the observed increase in toxicity was small.
doi:10.1097/AAP.0b013e3182664afb
PMCID: PMC3480545  PMID: 23011115
12.  Intrathecal Oxytocin Inhibits Visceromotor Reflex and Spinal Neuronal Responses to Noxious Distention of the Rat Urinary Bladder 
Background and Objectives
Oxytocin (OXY) is a neuropeptide that has recently been recognized as an important component of descending analgesic systems. The present study sought to determine if OXY produces antinociception to noxious visceral stimulation.
Methods
Urethane-anesthetized female rats had intrathecal catheters placed acutely, and the effect of intrathecal OXY on visceromotor reflexes (VMRs; abdominal muscular contractions quantified using electromyograms) to urinary bladder distension (UBD; 10-60 mm Hg, 20 s; transurethral intravesical catheter) was determined. The effect of OXY applied to the surface of exposed spinal cord was determined in lumbosacral dorsal horn neurons excited by UBD using extracellular recordings.
Results
OXY doses of 0.15 μg or 1.5 μg inhibited VMRs to UBD by 37 ± 8% and 68 ± 10%, respectively. Peak inhibition occurred within 30 minutes and was sustained for at least 60 minutes. The effect of OXY was both reversed and prevented by the intrathecal administration of an OXY receptor antagonist. Application of 0.5 mM OXY to the dorsum of the spinal cord inhibited UBD-evoked action potentials by 76 ± 12%. Consistent with the VMR studies, peak inhibition occurred within 30 minutes and was sustained for greater than 60 minutes.
Conclusions
These results argue that intrathecal OXY produces an OXY receptor specific antinociception to noxious UBD, with part of this effect due to inhibition of spinal dorsal horn neurons. To our knowledge, these studies provide the first evidence that intrathecal OXY may be an effective pharmacological treatment for visceral pain.
doi:10.1097/AAP.0b013e318266352d
PMCID: PMC3426637  PMID: 22878524
13.  Duration and local toxicity of sciatic nerve blockade with co-injected site 1 sodium channel blockers and quaternary lidocaine derivatives 
Background and Objectives
Quaternary lidocaine derivatives (QLDs) have recently received much attention because of their potential application in prolonged or sensory-selective local anesthesia. However, associated tissue toxicity is an impeding factor that makes QLDs unfavorable for clinical use. Based on the proposed intracellular site of action, we hypothesized that nerve blocks obtained from lower concentrations of QLDs would be enhanced by the co-application of extracellularly acting site-1 sodium channel blocker, resulting in prolonged block duration but with minimal tissue toxicity.
Methods
QLDs (QX-314 and QX-222), site 1 sodium channel blockers (tetrodotoxin, 30 μM or saxitoxin, 12.5 μM), or both were injected in the vicinity of the sciatic nerve. Thermal nociceptive block was assessed using a modified hot plate test; motor block by a weight-bearing test. Tissue from the site of injection was harvested for histological assessment.
Results
Co-application of 25 mM QX-314 and 100 mM QX-222 with site 1 sodium channel blockers produced an 8- to 10- fold increase in the duration of nerve blocks (P<0.05), compared to QLDs or site 1 blockers alone. QLDs elicited severe myotoxicity; this was not exacerbated by co-injection of the site-1 sodium channel blockers.
Conclusion
Co-administration of site 1 sodium channel blockers and QLDs greatly prolongs the duration of peripheral nerve block without enhancing local tissue injury, but minimal myotoxicity still persists. It is not clear that the risks of QLDs are outweighed by the benefits in providing prolonged nerve blockade.
doi:10.1097/AAP.0b013e31826125b3
PMCID: PMC3428729  PMID: 22914659
14.  Effect of adjuvants on the action of local anesthetics in isolated rat sciatic nerves 
Background and Objectives
There is increasing clinical use of adjuvant drugs to prolong the duration of local anesthetic-induced block of peripheral nerves. However, the mechanistic understanding regarding drug interactions between these compounds in the periphery is quite limited. Accordingly, we undertook this study to determine whether selected adjuvants are efficacious in blocking action potential propagation in peripheral nerves at concentrations used clinically, and whether these drugs influence peripheral nerve block produced by local anesthetics.
Methods
Isolated rat sciatic nerves were used to assess (1) the efficacy of buprenorphine, clonidine, dexamethasone, or midazolam, alone and in combination, on action potential propagation; and (2) their influence on the blocking actions of local anesthetics ropivacaine and lidocaine. Compound action potentials (CAPs) from A- and C-fibers were studied before and after drug application.
Results
At estimated clinical concentrations, neither buprenorphine nor dexamethasone affected either A- or C-waves of the CAP. Clonidine produced a small, but significant attenuation of the C-wave amplitude. Midazolam attenuated both A- and C-wave amplitudes, but with greater potency on the C-wave. The combination of clonidine, buprenorphine, and dexamethasone had no influence on the potency or duration of local anesthetic- or midazolam-induced block of A-and C-waves of the CAP.
Conclusions
These results suggest that the reported clinical efficacy of clonidine, buprenorphine, and dexamethasone influence the actions of local anesthetics via indirect mechanisms. Further identification of these indirect mechanisms may enable the development of novel approaches to achieve longer duration, modality-specific peripheral nerve block.
doi:10.1097/AAP.0b013e3182485965
PMCID: PMC3616512  PMID: 22430023
15.  Comparative Perioperative Outcomes Associated With Neuraxial Versus General Anesthesia for Simultaneous Bilateral Total Knee Arthroplasty 
Background and Objectives
The influence of the type of anesthesia on perioperative outcomes after bilateral total knee arthroplasty (BTKA) remains unknown. Therefore, we examined a large sample of BTKA recipients, hypothesizing that neuraxial anesthesia would favorably impact on outcomes.
Methods
We identified patient entries indicating elective BTKA between 2006 and 2010 in a national database; subgrouped them by type of anesthesia: general (G), neuraxial (N), or combined neuraxial-general (NG); and analyzed differences in demographics and perioperative outcomes.
Results
Of 15,687 identified procedures, 6.8% (n = 1066) were performed under N, 80.1% (n = 12,567) under G, and 13.1% (n = 2054) under NG. Comparing N to G and NG, patients in group N were, on average, younger (63.9, 64.6, and 64.8 years; P = 0.030) but did not differ in overall comorbidity burden. Patients in group N required blood product transfusions significantly less frequently (28.5%, 44.7%, 38.0%; P < 0.0001). In-hospital mortality, 30-day mortality, and complication rates tended to be lower in group N, without reaching statistical significance. After adjusting for covariates, N and NG were associated with 16.0% and 6.0% reduction in major complications compared with G, but only the reduced odds for the requirement of blood transfusions associated with N reached statistical significance (N vs G: odds ratio, 0.52 [95% CI, 0.45–0.61], P < 0.0001; NG vs G: odds ratio, 0.77 [95% CI, 0.69–0.86], P < 0.0001).
Conclusions
Neuraxial anesthesia for BTKA is associated with significantly lower rates of blood transfusions and, by trend, decreased morbidity. Although by itself the effect may be limited, N might be used within a multimodal approach to reduce complications after BTKA.
doi:10.1097/AAP.0b013e31826e1494
PMCID: PMC3653590  PMID: 23080348
16.  Primary Payer Status is Associated with the Use of Nerve Block Placement for Ambulatory Orthopedic Surgery 
Introduction
Although more than 30 million patients in the United States undergo ambulatory surgery each year, it remains unclear what percentage of these patients receive a perioperative nerve block. We reviewed data from the 2006 National Survey of Ambulatory Surgery (NSAS) to determine the demographic, socioeconomic, geographic, and clinical factors associated with the likelihood of nerve block placement for ambulatory orthopedic surgery. The primary outcome of interest was the association between primary method of payment and likelihood of nerve block placement. Additionally, we examined the association between type of surgical procedures, patient demographics, and hospital characteristics with the likelihood of receiving a nerve block.
Methods
This cross-sectional study reviewed 6,000 orthopedic anesthetics from the 2006 NSAS dataset, which accounted for over 3.9 million orthopedic anesthetics when weighted. The primary outcome of this study addressed the likelihood of receiving a nerve block for orthopedic ambulatory surgery according to the patient’s primary method of payment. Secondary endpoints included differences in demographics, surgical procedures, side effects, complications, recovery profile, anesthesia staffing model, and total perioperative charges in those with and without nerve block.
Results
Overall, 14.9% of anesthetics in this sample involved a peripheral nerve block. Length of time in postoperative recovery, total perioperative time, and total charges were less for those receiving nerve blocks. Patients were more likely to receive a nerve block if their procedures were performed in metropolitan service areas (OR 1.86, 95% CI 1.19-2.91, p=0.007) or freestanding surgical facilities (OR 2.27, 95% CI 1.74-2.96, p<0.0001), and if payment for their surgery was supported by government programs (OR 2.5, 95% CI 1.01-6.21, p=0.048) or private insurance (OR 2.62, 95% CI 1.12-6.13, p=0.03) versus self-pay or charity care.
Conclusion
For patients receiving ambulatory orthopedic surgery in the United States, our results suggest that geographic and socioeconomic factors are associated with different likelihoods of perioperative peripheral nerve block placement.
doi:10.1097/AAP.0b013e31824889b6
PMCID: PMC3337363  PMID: 22430024
18.  Modulating Pain in the Periphery: Gene-based Therapies to Enhance Peripheral Opioid Analgesia Bonica Lecture, ASRA 2010 
This article provides a brief overview of earlier work of our group on the peripheral signaling of pain, summarizes more recent studies on the role of opioids in chronic neuropathic pain, and speculates on the future of gene-based therapies as novel strategies to enhance the peripheral modulation of pain. Neurophysiological and psychophysical studies have revealed features of primary afferent activity from somatic tissue that led to improved understanding of the physiology and pathophysiology of pain signaling by nociceptive and non-nociceptive fibers. The demonstration of peripheral opioid mechanisms in neuropathic pain suggests a potential role for these receptors in the modulation of pain at its initiation site. Our work has focused on characterizing this peripheral opioid analgesia in chronic neuropathic pain such that it can be exploited to develop novel and potent peripheral analgesics for its treatment. Ongoing research on virus-mediated gene transfer strategies to enhance peripheral opioid analgesia is presented.
doi:10.1097/AAP.0b013e31823b145f
PMCID: PMC3288690  PMID: 22189620
19.  Beyond Repeated measures ANOVA: advanced statistical methods for the analysis of longitudinal data in anesthesia research 
Background and Objectives
Research in the field of anesthesiology relies heavily on longitudinal designs for answering questions about long-term efficacy and safety of various anesthetic and pain regimens. Yet, anesthesiology research is lagging in the use of advanced statistical methods for analyzing longitudinal data. The goal of this paper is to increase awareness of the advantages of modern statistical methods and promote their use in anesthesia research.
Methods
Here we introduce 2 modern and advanced statistical methods for analyzing longitudinal data: the generalized estimating equations (GEE) and mixed effects models (MEM). These methods are compared to the conventional repeated measures ANOVA (RM-ANOVA) through a clinical example with 2 types of endpoints (continuous and binary). In addition, we compare GEE and MEM to RM-ANOVA through a simulation study with varying sample sizes, varying number of repeated measures, and scenarios with and without missing data.
Results
In the clinical study, the 3 methods are found to be similar in terms of statistical estimation, while the parameter interpretations are somewhat different. The simulation study shows that the methods of GEE and MEM are more efficient in that they are able to achieve higher power with smaller sample size or lower number of repeated measurements in both complete and missing data scenarios.
Conclusions
Based on their advantages over RM-ANOVA, GEE and MEM should be strongly considered for the analysis of longitudinal data. In particular, GEE should be utilized to explore overall average effects, and MEM should be employed when subject-specific effects (in addition to overall average effects) are of primary interest.
doi:10.1097/AAP.0b013e31823ebc74
PMCID: PMC3249227  PMID: 22189576
20.  Local Anesthetic Schwann Cell Toxicity is Time and Concentration-Dependent 
Background
Peripheral nerve blocks (PNB’s) with local anesthetics (LA’s) are commonly performed to provide surgical anesthesia or postoperative analgesia. Nerve injury resulting in persistent numbness or weakness is a potentially serious complication. LA’s have previously been shown to damage neuronal and Schwann cells via several mechanisms. We sought to test the hypothesis that LA’s are toxic to Schwann cells and that the degree of toxicity is directly related to the concentration of LA and duration of exposure. Intraneural injection of LA’s has been shown to produce nerve injury. We sought to test the hypothesis that a prolonged extraneural infusion of LA can also produce injury.
Materials and Methods
Schwann cells cultured from neonatal rat sciatic nerves were incubated with LA’s at different concentrations (10, 100, 500 and 1000 μM), and each concentration was assessed for toxicity after 4, 24, 48 and 72 hours of exposure. LA’s tested were lidocaine, mepivacaine, chloroprocaine, ropivacaine and bupivacaine. Cell death was assessed by LDH release measured by optical density.
In a separate experiment, a microcatheter was placed along the sciatic nerves of Sprague-Dawley rats. Rats were randomly assigned to receive either 0.9% saline (n = 8) or bupivacaine (0.5% n = 4, 0.75% n = 4) via the perineural catheters for 72 hours. The rats were then euthanized and their nerves sectioned and stained for analysis. Sections were stained for myelin and with an anti-macrophage (CD68) antibody.
Results
None of the LA’s tested produced significant Schwann cell death at very low concentrations (10mM, or 0.0003%) even after prolonged exposure. With prolonged exposure (48 or 72 hours) to high concentrations (1000 μM, o r 0.03%), all of the LA’s tested produced significant Schwann cell death (increased LDH release relative to control as measured by optical density 0.384–0.974, all p-values < 0.001). Only bupivacaine produced significant cell death (0.482, p < 0.001) after prolonged exposure to low concentrations (100 μM, or 0.003%). At intermediate concentrations (500 μM, or 0.015%), cell death was more widespread with bupivacaine (0.768, p < 0.001) and ropivacaine (0.675, p < 0.001) than the other agents (0.204–0.368, all p-values < 0.001).
Prolonged extraneural exposure of rat sciatic nerves to bupivacaine caused significant demyelination and infiltration of nerves with inflammatory cells.
Conclusions
LA’s induce Schwann cell death in a time and concentration-dependent manner. Bupivacaine and ropivacaine have greater toxicity at intermediate concentrations, and prolonged exposure to bupivacaine produces significant toxicity even at low concentrations. Brief exposure to high concentrations of bupivacaine damages Schwann cells. Prolonged extraneural infusion of bupivacaine results in nerve injury.
doi:10.1097/AAP.0b013e318228c835
PMCID: PMC3380610  PMID: 21857272
21.  Changes in anesthesia related factors in ambulatory knee and shoulder surgery: United States 1996–2006 
Background
Analyses of existing nationally representative information on how changes in ambulatory orthopedic surgery have affected anesthesia practice over time are rare. We sought to characterize temporal changes in factors surrounding ambulatory orthopedic surgery and anesthesia.
Methods
Data from the National Survey of Ambulatory Surgery for the years of 1996 and 2006 were analyzed. Entries indicating the performance of knee ligamentoplasty, meniscectomy or shoulder arthroscopy were identified and included in the sample. Temporal changes in a number of variables associated with orthopedic ambulatory surgery were assessed, including: 1) the number of procedures being performed, 2) patient and health care system related demographics and 3) anesthesia related variables.
Results
Nationwide, the total number of ligamentoplasties, meniscectomies and shoulder arthroscopies increased from 1996 to 2006 by 66% (N=258,932 to N=428,712), 51% (N=456,698 to N=690,164), and 349% (N=93,105 to N=418,188) respectively (P<0.0001). Between 1996 and 2006 the use of peripheral nerve blocks increased from 0.6% to 9.8% for meniscectomies (P<0.0001), from 1.5% to 13.7% for ligamentoplasties (P<0.0001), and from 11.5% to 23.9% for shoulder arthroscopies (P<0.0001), respectively. Neuraxial anesthesia utilization fell from 11.8% to 6.3% for meniscectomies (P<0.0001) and 13.6% to 7.3% for ligamentoplasties (P<0.0001) from 1996 to 2006, respectively.
Conclusion
Substantial increases in the number of ambulatory knee and shoulder procedures occurred over time, relating to increased demand for anesthesia providers in this field. Trends towards increased use of peripheral nerve blocks may have to be considered by educators when preparing residents for practice.
doi:10.1097/AAP.0b013e318217703c
PMCID: PMC3121915  PMID: 21490521
22.  Transient Heat Hyperalgesia During Resolution of Ropivacaine Sciatic Nerve Block in the Rat 
Background
Preliminary studies using perineural sciatic ropivacaine in rat demonstrated unexpected heat hyperalgesia after block resolution. To better characterize the time course relative to mechanical anesthesia-analgesia, we tested the hypothesis that ropivacaine 0.5% leads to transient heat hyperalgesia in rat independent of mechanical nociception. We also evaluated functional toxicity (e.g., long-term hyperalgesia and/or tactile allodynia 2 weeks post-injection).
Methods
Under surgical exposure, left sciatic nerve block was performed in 2 groups of adult male rats – ropivacaine (200 μL, 5 mg/mL, n=14) versus vehicle (n=11). The efficacy and duration of block was assessed with serial heat, mechanical (Randall-Selitto testing), and tactile (von Frey-like monofilaments) tests; motor-proprioceptive (rotarod) and sedation tests were employed 1 hr and 7 hr post-injection. The presence of nerve injury was assessed by repeating the heat, tactile, and motor tests 12–14 days post-injection.
Results
Ropivacaine-induced anesthesia was fully manifest at 1 hr post-injection. At 3 hr post-injection, heat hypersensitivity was present in the setting of resolved mechanical analgesia. All behavioral measures returned to baseline by 2 wk post-injection. There was no evidence of (i) behavioral sedation, (ii) persistent changes in heat or mechanical sensitivity, or (iii) persistent changes in proprioceptive-motor function at 12–14 days post-injection.
Conclusions
Ropivacaine 0.5% induces transient heat hyperalgesia in the setting of resolved mechanical analgesia, further suggestive of modality and/or nociceptive fiber specificity. Whether this finding partially translates to “rebound pain” after patients’ nerve blocks wear off requires further study.
doi:10.1097/AAP.0b013e3182176f5a
PMCID: PMC3085276  PMID: 21451438
23.  Ultrasound-Guided (Needle In-Plane) Perineural Catheter Insertion: The Effect of Catheter Insertion Distance on Postoperative Analgesia 
Background
When using ultrasound guidance to place a perineural catheter for a continuous peripheral nerve block, keeping the needle-in plane and nerve in short-axis results in a perpendicular needle-to-nerve orientation. Many have opined that when placing a perineural catheter via the needle, the acute angle may result in the catheter bypassing the target nerve when advanced beyond the needle tip. Theoretically, greater catheter tip-to-nerve distances result in less local anesthetic-to-nerve contact during the subsequent perineural infusion, leading to inferior analgesia. While a potential solution may appear obvious—advancing the catheter tip only to the tip of the needle, leaving the catheter tip at the target nerve—this technique has not been prospectively evaluated. We therefore hypothesized that during needle in-plane ultrasound-guided perineural catheter placement, inserting the catheter a minimum distance (0-1 cm) past the needle tip is associated with improved postoperative analgesia compared with inserting the catheter a more-traditional 5-6 cm past the needle tip.
Methods
Preoperatively, subjects received a popliteal-sciatic perineural catheter for foot or ankle surgery using ultrasound guidance exclusively. Subjects were randomly assigned to have a single-orifice, flexible catheter inserted either 0-1 (n=50) or 5-6 cm (n=50) past the needle tip. All subjects received a single-injection mepivacaine (40 mL of 1.5% with epinephrine) nerve block via the needle, followed by catheter insertion and a ropivacaine 0.2% infusion (basal 6 mL/h, bolus 4 mL, 30 min lockout), through at least the day following surgery. The primary end point was average surgical pain as measured with a 0-10 numeric rating scale the day following surgery. Secondary end points included time for catheter insertion, incidence of catheter dislodgement, maximum (“worst”) pain scores, opioid requirements, fluid leakage at the catheter site, and the subjective degree of an insensate extremity.
Results
Average pain scores the day following surgery for subjects of the 0-1 cm group was a median (interquartile) of 2.5 (0.0-5.0), compared with 2.0 (0.0-4.0) for subjects of the 5-6 cm group (p=0.42). Similarly, among the secondary end points, no statistically significant differences were found between the two treatment groups. There was a trend of more catheter dislodgements in the minimum-insertion group (5 vs. 1; p=0.20).
Conclusions
This study did not find evidence to support the hypothesis that for popliteal-sciatic perineural catheters placed using ultrasound guidance and a needle in-plane technique, inserting the catheter a minimum distance (0-1 cm) past the needle tip improves (or worsens) postoperative analgesia compared with inserting the catheter a more-traditional distance (5-6 cm). Caution is warranted if extrapolating these results to other catheter designs, ultrasound approaches, or anatomic insertion sites.
doi:10.1097/AAP.0b013e31820f3b80
PMCID: PMC3085850  PMID: 21519311
24.  Neurotoxicity of Adjuvants used in Perineural Anesthesia and Analgesia in Comparison with Ropivacaine 
Background and Objectives
Clonidine, buprenorphine, dexamethasone, and midazolam (C,B,D,M) have been used to prolong perineural local anesthesia in the absence of data on the influence of these adjuvants on local anesthetic (LA)-induced neurotoxicity. Therefore, the impact of these adjuvants on ropivacaine (R)-induced death of isolated sensory neurons was assessed.
Methods
The trypan blue exclusion assay was used to assess death of sensory neurons isolated from adult male Sprague-Dawley rats. Drugs were applied, alone or in combination, for 2 or 24 hrs at 37°C.
Results
Neuronal viability was halved by 24 hr exposure to R (2.5 mg/mL), far exceeding the neurotoxicity of C, B, D, or M (at 2–100 times estimated clinical concentrations). Plain M at twice the estimated clinical concentration produced a small but significant increase in neurotoxicity at 24 hr. After 2 hr exposure, high concentrations of B, C, and M increased the neurotoxicity of R; the combination of R+M killed over 90% of neurons. Estimated clinical concentrations of C+B (plus 66 µg/mL D) had no influence on (i) R-induced neurotoxicity, (ii) the increased neurotoxicity associated with the combination of R+M, or (iii) the neurotoxicity associated with estimated clinical concentrations of M. There was dose-response neurotoxicity with 133 µg/mL D combined with R+C+B
Conclusions
Results with R re-affirm the need to identify ways to mitigate LA-induced neurotoxicity. While having no protective effect on R-induced neurotoxicity in vitro, future research with adjuvants should address if the C+B+D combination can enable reducing R concentrations needed to achieve equi-analgesia (and/or provide equal or superior duration, in preclinical in vivo models).
doi:10.1097/AAP.0b013e3182176f70
PMCID: PMC3085859  PMID: 21519308
25.  Long-Term Pain, Stiffness, and Functional Disability Following Total Knee Arthroplasty With and Without an Extended Ambulatory Continuous Femoral Nerve Block: A Prospective, One-Year Follow-Up of a Multicenter, Randomized, Triple-Masked, Placebo-Controlled Trial 
Background
Previously, we have demonstrated that extending a continuous femoral nerve block from overnight to four days following total knee arthroplasty provides clear benefits during the infusion, but not subsequent to catheter removal. However, there were major limitations in generalizing the results of that investigation, and we subsequently performed a very similar study using a multicenter format, with many healthcare providers, in patients on general orthopedic wards; thus, greatly improving inference of the results to the general population. Not surprisingly, the perioperative/short-term outcomes differed greatly from the first, more-limited, study. We now present a prospective follow-up study of the previously published, multicenter, randomized, controlled clinical trial to investigate the possibility that an extended ambulatory continuous femoral nerve block decreases long-term pain, stiffness, and functional disability following total knee arthroplasty; which greatly improves inference of the results to the general population.
Methods
Subjects undergoing total knee arthroplasty received a continuous femoral nerve block with ropivacaine 0.2% from surgery until the following morning, at which time patients were randomized to either continue perineural ropivacaine (n=28) or normal saline (n=26). Patients were discharged with their catheter and a portable infusion pump, and catheters were removed on postoperative day 4. Health-related quality-of-life was measured using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index preoperatively and then at 7 days, as well as 1, 2, 3, 6, and 12 months following surgery. This index evaluates pain, stiffness, and physical functional disability. For inclusion in the analysis, we required a minimum of four of the six time points, including day 7 and at least two of months 3, 6, and 12.
Results
The two treatment groups had similar WOMAC scores for the mean area under the curve calculations (point estimate for the difference in mean area under the curve for the two groups [overnight infusion group – extended infusion group]=3.8, 95% confidence interval: −3.8 to +11.3; p=0.32) and at all individual time points (p>0.05).
Conclusions
This investigation found no evidence that extending an overnight continuous femoral nerve block to four days improves (or worsens) subsequent pain, stiffness, or physical function following TKA in patients of multiple centers convalescing on general orthopedic wards.
PMCID: PMC3073537  PMID: 21425510

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