Anaesthetic care of patients undergoing primary hip and knee arthroplasty: consensus recommendations from the International Consensus on Anaesthesia-Related Outcomes after Surgery group (ICAROS) based on a systematic review and meta-analysis.

BACKGROUND: Evidence-based international expert consensus regarding anaesthetic practice in hip/knee arthroplasty surgery is needed for improved healthcare outcomes. METHODS: The International Consensus on Anaesthesia-Related Outcomes after Surgery group (ICAROS) systematic review, including randomised controlled and observational studies comparing neuraxial to general anaesthesia regarding major complications, including mortality, cardiac, pulmonary, gastrointestinal, renal, genitourinary, thromboembolic, neurological, infectious, and bleeding complications. Medline, PubMed, Embase, and Cochrane Library including Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, NHS Economic Evaluation Database, from 1946 to May 17, 2018 were queried. Meta-analysis and Grading of Recommendations Assessment, Development and Evaluation approach was utilised to assess evidence quality and to develop recommendations. RESULTS: The analysis of 94 studies revealed that neuraxial anaesthesia was associated with lower odds or no difference in virtually all reported complications, except for urinary retention. Excerpt of complications for neuraxial vs general anaesthesia in hip/knee arthroplasty, respectively: mortality odds ratio (OR): 0.67, 95% confidence interval (CI): 0.57-0.80/OR: 0.83, 95% CI: 0.60-1.15; pulmonary OR: 0.65, 95% CI: 0.52-0.80/OR: 0.69, 95% CI: 0.58-0.81; acute renal failure OR: 0.69, 95% CI: 0.59-0.81/OR: 0.73, 95% CI: 0.65-0.82; deep venous thrombosis OR: 0.52, 95% CI: 0.42-0.65/OR: 0.77, 95% CI: 0.64-0.93; infections OR: 0.73, 95% CI: 0.67-0.79/OR: 0.80, 95% CI: 0.76-0.85; and blood transfusion OR: 0.85, 95% CI: 0.82-0.89/OR: 0.84, 95% CI: 0.82-0.87. CONCLUSIONS: Recommendation: primary neuraxial anaesthesia is preferred for knee arthroplasty, given several positive postoperative outcome benefits; evidence level: low, weak recommendation. RECOMMENDATION: neuraxial anaesthesia is recommended for hip arthroplasty given associated outcome benefits; evidence level: moderate-low, strong recommendation. Based on current evidence, the consensus group recommends neuraxial over general anaesthesia for hip/knee arthroplasty. TRIAL REGISTRY NUMBER: PROSPERO CRD42018099935.

Ropivacaine 0.375% vs. 0.75% with prilocaine for intermediate cervical plexus block for carotid endarterectomy: A randomised trial.

BACKGROUND: Carotid endarterectomy is widely performed under regional anaesthesia. Ultrasound guidance is increasingly used in many regional anaesthetic procedures to improve safety and efficacy, and because it can reduce the amount of local anaesthetic required. Despite this, an ideal approach and dosing regimen for cervical plexus block remain elusive. OBJECTIVE: The aim of this study was to compare two different concentrations of ropivacaine in terms of analgesic adequacy, haemodynamic effects and plasma concentration using an ultrasound-guided triple approach for intermediate cervical plexus blockade. DESIGN: A randomised, placebo-controlled, blinded study. SETTING: University Clinic Salzburg, Department of Anaesthesiology, Perioperative Medicine and Intensive Care, Paracelsus Medical University, Salzburg, Austria, from 16 November 2012 to 17 September 2013. PATIENTS: Forty-six patients prospectively randomised to receive ultrasound-guided intermediate cervical block with either 20 ml ropivacaine 0.75% or 20 ml ropivacaine 0.375% each with 20 ml prilocaine 1%. INTERVENTION: After subcutaneous infiltration, blocks were performed using ultrasound-guided infiltration below the sternocleidomastoid muscle, and ultrasound-guided infiltration of the carotid sheath. Ropivacaine and prilocaine plasma concentrations were measured at intervals. MAIN OUTCOME: The primary study endpoint was the volume of supplementary lidocaine 1% required to achieve adequate surgical anaesthesia. Perioperative haemodynamic variables and pain scores were recorded. RESULTS: There was no statistical difference in the volume of supplementary lidocaine given: 5.0 (±3.63) ml in the ropivacaine 0.375% group and 5.17 (±2.76) ml in the ropivacaine 0.75% group (P = 0.846). Pain scores were similarly low across both groups. Measured concentrations of ropivacaine and prilocaine did not reach toxic levels in either group. Levels of ropivacaine were approximately two-fold higher in the 0.75% group [mean area under the curve (AUC) 10 531.11 (±2912.84) vs. 5264.34 ng (±1594.69), P < 0.0001]. Perioperative cardiovascular stability was excellent in both groups. There were no serious block-related complications. CONCLUSION: An ultrasound-guided intermediate block provides adequate anaesthesia for carotid thrombendarterectomy with a little need for supplementary local anaesthetic. Use of 0.375% ropivacaine provided similarly effective analgesia as 0.75%, but resulted in significantly lower plasma concentrations. TRIAL REGISTRATION: The study was registered at the European Clinical Trial Database (Eudra CT No.: 2012-002769) as well as at ClinicalTrials.gov (NCT01759940).

Demographics and perioperative outcome in patients with depression and anxiety undergoing total joint arthroplasty: a population-based study.

BACKGROUND: Depression and anxiety are highly prevalent psychiatric disorders. However, little is known about their impact on outcomes in the perioperative setting. This study is intended to gain insight into epidemiology and effects on perioperative morbidity, mortality, length of hospital stay, discharge and cost. METHODS: We obtained the National Inpatient Sample from the Hospital Cost and Utilization Project for each year between 2000 and 2008. Entries indicating the performance of primary total hip and knee arthroplasty were identified and separated into four groups: (1) those with concomitant diagnosis of depression or (2) anxiety, (3) both, and (4) none of these diagnoses. The incidence of major complications, non-routine discharge, length, and cost of hospitalization were assessed. Regression analysis was performed to identify if psychiatric comorbidity was an independent risk factor for each outcome. RESULTS: We identified 1,212,493 patients undergoing arthroplasty between 2000 and 2008. The prevalence of depression and anxiety significantly increased over time. Patients with either condition had higher hospital charges, rates of non-routine discharges and comorbidity index. Depression or anxiety were associated with significantly decreased adjusted odds for in-hospital mortality (OR = 0.53, p = 0.0147; OR = 0.58, p = 0.0064). The risk of developing a major complication was slightly lower in patients with depression, anxiety or both (OR=0.95, p = 0.0738; OR = 0.95, p = 0.0259; OR = 0.94, p = 0.7349). CONCLUSIONS: Patients suffering from depression, anxiety, or both require more healthcare resources in a perioperative setting. However, lower short-term mortality in spite of higher comorbidity burden and without extensive changes in perioperative complication profile indicates better outcome for this group of patients.

Ephedrine shows synergistic motor blockade when combined with bupivacaine or lidocaine for spinal anesthesia in a rat model.

BACKGROUND: Ephedrine is a direct/indirect vasoactive drug. In addition, it also possesses intrinsic local anesthetic properties, mainly due to its sodium-channel blockage. We investigated whether ephedrine demonstrates a synergistic effect with bupivacaine and lidocaine when injected via a spinal catheter into the spinal space of rats. METHODS: Spinal catheters were surgically placed in 47 rats (n = 8 per group; 7 rats were excluded.) Bupivacaine, lidocaine, and ephedrine in various concentrations and constant volumes (60 µL) were injected into the spinal catheters to determine the equipotency of each drug. Ephedrine in combination with either bupivacaine or lidocaine was then injected into the spinal catheters. RESULTS: Ephedrine demonstrated statistically significant synergistic effects with bupivacaine as well as with lidocaine in fixed combinations. The combination index reflecting a synergistic effect was 0.792 (95% confidence interval: 0.665-0.919) for ephedrine + bupivacaine and 0.663 (95% confidence interval: 0.532-0.794) for ephedrine + lidocaine. CONCLUSION: Ephedrine combined with either bupivacaine or lidocaine acted synergistically to block motor function and has the potential to reduce the amount of local anesthetic needed for spinal block. The synergistic effect of ephedrine in combination with local anesthetics is an interesting pharmacological phenomenon that warrants further clinical evaluation.

Trends in in-hospital major morbidity and mortality after total joint arthroplasty: United States 1998-2008.

BACKGROUND: The use of total joint arthroplasties is increasing worldwide. In this work we aim to elucidate recent trends in demographics and perioperative outcomes of patients undergoing total hip (THA) or total knee arthroplasty (TKA). METHODS: Data from the US Nationwide Impatient Sample between 1998 and 2008 were gathered for primary THAs and TKAs. Trends in patient age, comorbidity burden, length of hospitalization, frequency of major perioperative complications, and in-hospital mortality were analyzed. In-hospital outcomes were reported as events per 1000 inpatient days to account for changes in length of hospitalization over time. Deyo index, discharge status, and the interaction effect of time and discharge status were included in the adjusted trend analysis for morbidity. RESULTS: Between 1998 and 2008, the average age of patients undergoing TKA and THA decreased by 2 to 3 years (P < 0.001). The average length of stay decreased by approximately 1 day over the time interval studied (P < 0.001). The percentage of patients being discharged home declined from 29.7% to 25.4% after TKA and from 29.3% to 24.2% after THA, in favor of dispositions to long- and short-term care facilities (P < 0.0001). Comorbidity burden as measured by the Deyo comorbidity index increased by 35% and 30% for TKA and THA patients, respectively (P < 0.0001). After TKA, there was an increase in the incidence of the following major complications: pulmonary embolism (coefficient estimate [CE] 0.069; 95% confidence interval [CI], 0.059-0.079; P < 0.0001), sepsis (CE 0.034; 95% CI, 0.014-0.054; P = 0.001), nonmyocardial infarction cardiac complications (CE 0.038; 95% CI, 0.035-0.041; P < 0.0001), and pneumonia (CE 0.039; 95% CI, 0.031-0.047; P < 0.0001). After THA, there was an increase in the incidence of the following major complications: pulmonary embolism (CE 0.031; 95% CI, 0.012-0.049; P = 0.001), sepsis (CE 0.060; 95% CI, 0.039-0.081; P < 0.0001), nonmyocardial infarction cardiac complications (CE 0.040; 95% CI, 0.036-0.043; P < 0.0001), and pneumonia (CE 0.039; 95% CI, 0.029-0.048). In-hospital mortality declined after both TKA (CE -0.059; 95% CI, -0.077 to -0.040; P < 0.0001) and THA (CE -0.068; 95% CI, -0.086 to -0.051; P < 0.0001). CONCLUSION: Between 1998 and 2008, trends show increases in several major in-hospital complications after THA and TKA, including pulmonary embolism, sepsis, nonmyocardial infarction cardiac complications, and pneumonia. Despite the increase in complications, declining in-hospital mortality was noted over this period.

Prolonged suppression of postincisional pain by a slow-release formulation of lidocaine.

BACKGROUND: Postoperative pain can occur despite nerve blocks during the surgical period. Here we tested Xybrex (Orthocon, Inc., Irvington, NY), a slow-release formulation of lidocaine that blocks rat sciatic nerve for 1-2 days, for its ability to suppress postincisional pain. METHODS: A plantar paw incision was made in rats, either along the midline (Brennan model) or at the lateral edge, 30 min after different treatment groups received either lidocaine (0.2 ml, 2%) or Xybrex implant at the ipsilateral sciatic nerve or Xybrex at the contralateral sciatic nerve. Behavioral testing by von Frey filaments occurred at 2 and 6 h postoperatively and for the next 10 postoperative days. The fractional response (paw withdrawal responses per 10 pokes) was scored at each time. RESULTS: Mechanosensitivity from the Brennan paw incision was reduced throughout the postoperative period by ipsilateral Xybrex, although lidocaine injection almost had no effect. Contralateral Xybrex had a weaker but still significant antihyperalgesic effect, converging to that from ipsilateral Xybrex at postoperative day 2. Xybrex at the nuchal midline reduced allodynia for only postoperative days 1-3, whereas hyperalgesia was reduced continuously after postoperative day 2. Hyperalgesia from the lateral incision was also reduced by ipsilateral Xybrex but not by contralateral Xybrex. CONCLUSIONS: Implants of slow-release lidocaine formulations are most effective against postincisional pain when placed at the ipsilateral nerve innervating the area of incision. Contralateral nerve implants are somewhat less effective, probably acting by releasing lidocaine into the systemic circulation. There appears to be a differential role of central sensitization between postincisional allodynia and hyperalgesia.

Peripheral nerve block anesthesia/analgesia for patients undergoing primary hip and knee arthroplasty: recommendations from the International Consensus on Anesthesia-Related Outcomes after Surgery (ICAROS) group based on a systematic review and meta-analysis of current literature.

BACKGROUND: Evidence-based international expert consensus regarding the impact of peripheral nerve block (PNB) use in total hip/knee arthroplasty surgery. METHODS: A systematic review and meta-analysis: randomized controlled and observational studies investigating the impact of PNB utilization on major complications, including mortality, cardiac, pulmonary, gastrointestinal, renal, thromboembolic, neurologic, infectious, and bleeding complications.Medline, PubMed, Embase, and Cochrane Library including Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, NHS Economic Evaluation Database, were queried from 1946 to August 4, 2020.The Grading of Recommendations Assessment, Development, and Evaluation approach was used to assess evidence quality and for the development of recommendations. RESULTS: Analysis of 122 studies revealed that PNB use (compared with no use) was associated with lower ORs for (OR with 95% CIs) for numerous complications (total hip and knee arthroplasties (THA/TKA), respectively): cognitive dysfunction (OR 0.30, 95% CI 0.17 to 0.53/OR 0.52, 95% CI 0.34 to 0.80), respiratory failure (OR 0.36, 95% CI 0.17 to 0.74/OR 0.37, 95% CI 0.18 to 0.75), cardiac complications (OR 0.84, 95% CI 0.76 to 0.93/OR 0.83, 95% CI 0.79 to 0.86), surgical site infections (OR 0.55 95% CI 0.47 to 0.64/OR 0.86 95% CI 0.80 to 0.91), thromboembolism (OR 0.74, 95% CI 0.58 to 0.96/OR 0.90, 95% CI 0.84 to 0.96) and blood transfusion (OR 0.84, 95% CI 0.83 to 0.86/OR 0.91, 95% CI 0.90 to 0.92). CONCLUSIONS: Based on the current body of evidence, the consensus group recommends PNB use in THA/TKA for improved outcomes. RECOMMENDATION: PNB use is recommended for patients undergoing THA and TKA except when contraindications preclude their use. Furthermore, the alignment of provider skills and practice location resources needs to be ensured. Evidence level: moderate; recommendation: strong.

The effects of resiniferatoxin in an experimental rat thoracotomy model.

BACKGROUND: Chronic pain after thoracotomy has been reproduced in a rat model that allows investigation of drugs that might reduce the incidence of allodynia after thoracotomy. Previous studies suggest that morphine, clonidine, neostigmine, gabapentin, and bupivacaine reduce the incidence of allodynia in the rat postthoracotomy pain model. One purpose of this study was to test whether intercostal injection of resiniferatoxin (RTX) decreased the amount of allodynia in an animal model of chronic postthoracotomy pain. We also tested whether RTX induced a transient mechanical hyperalgesic response in uninjured animals. METHODS: Male Sprague-Dawley rats were anesthetized, and the right fourth and fifth ribs were surgically exposed. The pleura was opened, and the ribs were retracted. Intercostal RTX 0.8 or 8 microg was injected in animals that developed allodynia after surgery; a control group underwent rib retraction and received vehicle only. An additional group of uninjured animals received RTX. Rats were tested for mechanical allodynia at a predetermined area around the incision site for 3 wk. RESULTS: Allodynia developed in 42% of the animals that underwent thoracotomy. A transient hyperalgesic response was noted in the uninjured group that underwent drug injections. Intercostal RTX did not modify the course of allodynia in injured rats. DISCUSSION: The current results suggest that intercostal RTX causes a transient hyperalgesic response in uninjured animals and is ineffective in reducing the mechanical allodynia after thoracotomy.

The relationship between functional sciatic nerve block duration and the rate of release of lidocaine from a controlled-release matrix.

BACKGROUND: Nerve blocks of long duration are often desirable in perioperative and postoperative situations. The relationship between the duration of such blocks and the rate at which a local anesthetic is released is important to know for developing a localized drug delivery system that will optimize block duration. METHODS: Lidocaine concentration was varied in 1 series of formulations (OSB-L) containing a constant amount of release rate modifier. In another series (OST-R), the release rate modifier was varied while the lidocaine content was held constant. Release kinetics were measured in vitro and correlated to the in vivo duration of antinociceptive and motor block effects when the formulation was implanted next to the rat sciatic nerve. In parallel studies, rats receiving different formulations of slow-release lidocaine were fixed by intracardiac perfusion with 4% paraformaldehyde and nerve-muscle tissue taken for histopathological analysis. RESULTS: In this study, we have demonstrated that the most important variable for effecting functional nerve block, i.e., the blockade of impulses in the relevant fibers of the sciatic nerve, is the rate of lidocaine release at that time. For the OSB-L formulations (lidocaine concentrations of 1.875%, 3.75%, 7.5%, and 15% at a constant release rate modifier of 5%), the average in vitro release rates at 50% recovery of motor block and nociceptive block were 0.91 +/- 0.28 and 1.75 +/- 0.61 mg/h, respectively. For the OST-R formulations (16% lidocaine with release rate modifier concentrations of 1.875%, 3.75%, 7.5%, and 15%), the average in vitro release rates at 50% recovery of motor block and nociceptive block were 2.33 +/- 1.39 and 4.34 +/- 1.09 mg/h, respectively. The OSB-L formulations showed a dose-dependent increase in block duration proportional to an increase in initial lidocaine concentration, whereas the OST-R formulations showed a nonmonotonic relationship between release rate modifier concentration and block duration. The histopathological studies at 24 hours, 3, 5, or 7 days, and 4 weeks after the implantation revealed inflammatory reactions with degrees correlated with lidocaine content, but limited to the connective tissue and muscle immediately surrounding the implanted material. Despite these observed inflammatory reactions, nociceptive and motor block function returned to normal, preimplantation values in all animals. CONCLUSIONS: Increasing initial lidocaine content proportionately increased the duration of functional sciatic nerve block. However, decreasing the release rate per se does not give a proportional increase in block duration. Instead, there seems to be an optimal, intermediate release rate for achieving the maximum duration of block.

Resiniferatoxin combined with antidepressants preferentially prolongs sensory/nociceptive block in rat sciatic nerve.

BACKGROUND: Current techniques of peripheral nerve block have major limitations, including lack of differentiation between motor and sensory fibers and potential toxicity of local anesthetics. Recent studies have suggested that a nociceptive-selective nerve block can be achieved via a transient receptor potential vanilloid type 1 activator (capsaicin) along with local anesthetics. We hypothesized that the combination of potent transient receptor potential vanilloid type 1 agonist resiniferatoxin (RTX) and selected antidepressants (amitriptyline, doxepin, and fluoxetine, also potent sodium channel blockers) would produce prolonged and predominantly sensory nerve block. METHODS: Rats were anesthetized with isoflurane, and 0.2 mL of amitriptyline, doxepin, or fluoxetine was deposited next to the surgically exposed sciatic nerves (n = 8 per group). Some animals received a second injection containing RTX (n = 8 per group). The effect of nerve block was assessed by neurobehavioral tests of the motor function (extensor postural thrust) and the nocifensive reaction (mechanical pinch). RESULTS: A single application of RTX produced nociceptive-selective sciatic nerve block, whereas antidepressants produced nociceptive and motor block. The combined administration of RTX and antidepressant resulted in a predominantly nociceptive nerve block. Compared with antidepressants or RTX alone, the combination prolonged the nociceptive nerve block more than the motor block. CONCLUSIONS: The combined application of RTX and antidepressants produced a markedly prolonged nociceptive peripheral nerve block in rat sciatic nerves compared with either agent alone. However, the 2-drug regimen also elicited prolonged blockade of the motor function, although disproportionately less compared with the nociceptive modality, suggesting the existence of nontransient receptor potential vanilloid type 1-mediated mechanisms. The mechanisms through which RTX affects nociceptive signal transduction/transmission have yet to be fully elucidated.

Coapplication of lidocaine and the permanently charged sodium channel blocker QX-314 produces a long-lasting nociceptive blockade in rodents.

BACKGROUND: Nociceptive-selective local anesthesia is produced by entry of the permanently charged lidocaine-derivative QX-314 into nociceptors when coadministered with capsaicin, a transient receptor potential vanilloid 1 (TRPV1) channel agonist. However, the pain evoked by capsaicin before establishment of the QX-314-mediated block would limit clinical utility. Because TRPV1 channels are also activated by lidocaine, the authors tested whether lidocaine can substitute for capsaicin to introduce QX-314 into nociceptors through TRPV1 channels and produce selective analgesia. METHODS: Lidocaine (0.5% [17.5 mM], 1% [35 mM], and 2% [70 mM]) alone, QX-314 (0.2% [5.8 mM]) alone, and a combination of the two were injected subcutaneously and adjacent to the sciatic nerve in rats and mice. Mechanical and thermal responsiveness were measured, as was motor block. RESULTS: Coapplication of 0.2% QX-314 with lidocaine prolonged the nociceptive block relative to lidocaine alone, an effect attenuated in TRPV1 knockout mice. The 0.2% QX-314 alone had no effect when injected intraplantary or perineurally, and it produced only weak short-lasting inhibition of the cutaneous trunci muscle reflex. Perisciatic nerve injection of lidocaine with QX-314 produced a differential nociceptive block much longer than the transient motor block, lasting 2 h (for 1% lidocaine) to 9 h (2% lidocaine). Triple application of lidocaine, QX-314, and capsaicin further increased the duration of the differential block. CONCLUSIONS: Coapplication of lidocaine and its quaternary derivative QX-314 produces a long-lasting, predominantly nociceptor-selective block, likely by facilitating QX-314 entry through TRPV1 channels. Delivery of QX-314 into nociceptors by using lidocaine instead of capsaicin produces sustained regional analgesia without nocifensive behavior.

An absorbable local anesthetic matrix provides several days of functional sciatic nerve blockade.

BACKGROUND: Functional blockade of peripheral nerves is the primary objective of local anesthesia, and it is often desirable to have a persistent blockade, sustained throughout and beyond a surgical procedure. Current local anesthetics give effective analgesia for <8-12 h after a single bolus injection. We report on an implantable, controlled-release drug delivery system intended for use in bone and consisting of a Food and Drug Administration-approved matrix containing lidocaine that is capable of local delivery for several days. METHODS: Xybrex, an absorbable, controlled-release delivery system containing 16% (w/w) lidocaine, was implanted next to the sciatic nerve of male rats (300-350 gm), at lidocaine doses of 5.3, 10.6, 16, and 32 mg lidocaine per rat. For comparison, a lidocaine HCl solution (0.2 mL, 2% = 4 mg) was injected in close proximity to the sciatic nerve. Rats were assessed behaviorally for analgesia by a forceps pinch of the lateral digits, and for motor block by quantifying the extensor postural thrust. Potential neurotoxicity of sciatic nerves was evaluated histologically at 24 h, 4 days, and 4 wk after implantation. The kinetics of lidocaine's release from the matrix was measured in vitro by ultraviolet detection of lidocaine in samples collected at 2.5, 6.5, 20, and 24.25 h. RESULTS: Xybrex at the highest doses (300 and 600 mg/kg, containing 16 and 32 mg of lidocaine free base, respectively) provided complete analgesia to an intense pinch for 7.0 +/- 2.0 h, 6.9 +/- 1.7 h and partial analgesia for 60.0 +/- 5.4 h, 58.8 +/- 4.2 h, respectively, compared to 0.61 +/- 0.03 h of complete analgesia and 0.96 +/- 0.03 h of partial analgesia by sciatic block from the 2% lidocaine solution (containing 4 mg lidocaine). These same high doses of Xybrex produced complete motor block for 17.0 +/- 3.3 h, 17.6 +/- 3.3 h with full recovery in 352.0 +/- 55.7 h (14.7 +/- 2.3 days), 579.0 +/- 36.1 h (24.1 +/- 1.5 days) respectively. Data are reported as mean +/- SE. P < 0.001 for all Xybrex groups compared to the 2% lidocaine group. Minor local tissue inflammation/pathology, primarily in the connective tissue and muscle 0.1 mm adjacent to the nerve, was observed equally in animals treated with Xybrex and 2% lidocaine solution. There were no behavioral signs of systemic toxicity. The in vitro release followed exponential kinetics and its comparison to the time-course of functional nociceptive deficit implied that the duration of nociception represented the local, immediate interaction of lidocaine between the nerve and the matrix and not a cumulative effect of previously released drug. CONCLUSIONS: Xybrex is an absorbable, controlled-release drug delivery system that provides several days of analgesia for rat peripheral nerves without apparent significant local neurotoxicity or systemic toxicity.

Capsaicin combined with local anesthetics preferentially prolongs sensory/nociceptive block in rat sciatic nerve.

BACKGROUND: Transient receptor potential vanilloid 1 channels integrate nociceptive stimuli and are predominantly expressed by unmyelinated C-fiber nociceptors, but not low-threshold mechanoreceptive sensory or motor fibers. A recent report showed that the transient receptor potential vanilloid 1 channel agonist capsaicin allows a hydrophilic quaternary ammonium derivative of lidocaine, QX-314, to selectively block C fibers without motor block. The authors tested whether a similar differential block would be produced using amphipathic N-methyl amitriptyline, amitriptyline, bupivacaine, or lidocaine, either alone or together with 0.05% capsaicin, in a rat sciatic nerve block model. METHODS: Rats (n = 8/group) were anesthetized with sevoflurane, and 0.2 ml of drug was injected either alone or with capsaicin (simultaneously or 10 min later) next to the sciatic nerve in the sciatic notch. Motor function was assessed by the extensor postural thrust. Nociception was evaluated by the nocifensive withdrawal reflex and vocalization evoked by pinch of a skin fold over the lateral metatarsus (cutaneous pain) with a serrated forceps. RESULTS: N-Methyl amitriptyline, amitriptyline, bupivacaine, or lidocaine, followed by injection of capsaicin 10 min later, each elicited a predominantly nociceptive-specific blockade. In comparison, simultaneous application of each local anesthetic with capsaicin did not elicit a clinically significant differential block, with the exception of N-methyl amitriptyline. CONCLUSIONS: Both tertiary amine local anesthetics and their quaternary ammonium derivatives can elicit a predominantly sensory/nociceptor selective block when followed by injection of capsaicin. The combined application of transient receptor potential vanilloid 1 channel agonists and various local anesthetics or their quaternary ammonium derivatives is an appealing strategy to achieve a long-lasting differential block in regional analgesia.

Low-dose systemic bupivacaine prevents the development of allodynia after thoracotomy in rats.

BACKGROUND: Chronic pain after thoracotomy has been recently reproduced in a rat model that allows investigation of the effect of drugs that might reduce the incidence of allodynia after thoracotomy. Previous studies suggest that intrathecal or systemic morphine, clonidine, neostigmine, and gabapentin reduce the incidence of allodynia in the rat postthoracotomy pain model. Our purpose was to test whether intercostal and systemic injection of bupivacaine prevented the development of allodynia in an animal model of chronic intercostal neuropathic pain. METHODS: Male Sprague-Dawley rats were anesthetized and the right 4th and 5th ribs surgically exposed. The pleura were opened and the ribs were retracted for 1 h. Intercostal or systemic bupivacaine 1 mg (0.2 mL at 0.5%) was injected before and after surgery, or before surgery; a control group underwent rib retraction and did not receive any drug. Rats were tested for mechanical allodynia at a predetermined area around the incision site during the 3 wk after surgery. RESULTS: Allodynia developed in 43% of the animals that did not receive bupivacaine (control group); in contrast, allodynia developed in only 6%, 12%, and 12% of those animals that received intercostal bupivacaine before surgery, after surgery, or systemically before surgery, respectively. DISCUSSION: Previous studies suggest that allodynia after rib retraction can be prevented by opioids, alpha2-adrenergic agonists, neostigmine, and gabapentin. The current results suggest that bupivacaine is effective in preventing mechanical allodynia, whether given by intercostal injection before or after surgery, or systemically before surgery.

In vitro, inhibition of mitogen-activated protein kinase pathways protects against bupivacaine- and ropivacaine-induced neurotoxicity.

BACKGROUND: Animal models show us that specific activation of the p38 mitogen-activated protein kinase (MAPK) may be a pivotal step in lidocaine neurotoxicity, but this has not been investigated in the case of two very widely used local anesthetics, bupivacaine and ropivacaine. We investigated the hypotheses that these drugs (A) are less neurotoxic than the prototype local anesthetic, lidocaine (B) are selectively toxic for subcategories of dorsal root ganglion neurons and (C) induce activation of either p38 MAPK or related enzymes, such as the c-jun terminal N-kinase (JNK) and extracellular signal-regulated kinase (ERK). METHODS: We incubated primary sensory neuron cultures with doses of lidocaine, bupivacaine, and ropivacaine equipotent at blocking sodium currents. Next, we sought to determine potential selectivity of bupivacaine and ropivacaine toxicity on neuron categories defined by immunohistochemical staining, or size. Subsequently, the involvement of p38 MAPK, JNK, and ERK was tested using enzyme-linked immunosorbent assays. Finally, the relevance of MAPK pathways in bupivacaine- and ropivacaine-induced neurotoxicity was determined by selectively inhibiting activity of p38 MAPK, JNK, and ERK. RESULTS: We found that the neurotoxic potency of bupivacaine and ropivacaine is dose-dependent and similar in vitro, but is not selective for any of the investigated subgroups of neurons. Neurotoxicity of bupivacaine and ropivacaine was mediated, at least in part, by MAPKs. Specifically, we demonstrated the relevance of both p38 MAPK and JNK pathways for the neurotoxicity of bupivacaine and characterized the involvement of the p38 MAPK pathway in the neurotoxicity of ropivacaine. CONCLUSIONS: Given equipotent doses, the neurotoxic potential of lidocaine does not appear to be significantly different from that of bupivacaine and ropivacaine in vitro. Moreover, bupivacaine and ropivacaine do not exert their neurotoxicity differently on specific subsets of dorsal root ganglion neurons. Their neurotoxic effects are brought about through the activation of specific MAPKs; the specific pharmacologic inhibition of these kinases attenuates toxicity in vitro.

Use of bulleyaconitine A as an adjuvant for prolonged cutaneous analgesia in the rat.

BACKGROUND: Bulleyaconitine A (BLA) is an analgesic and antiinflammatory drug isolated from Aconitum plants. BLA has several potential targets, including voltage-gated Na+ channels. We tested whether BLA elicited long-lasting cutaneous analgesia, when co-injected with lidocaine and epinephrine, as a model for prolonged infiltration anesthesia. METHODS: The local anesthetic properties of BLA were assessed by the patch-clamp technique in HEK293t cells expressing Nav1.7 and Nav1.8 neuronal Na+ channels, both crucial for nociception. Drug solutions (0.6 mL) were injected subcutaneously via rat shaved dorsal skin. Inhibition of the cutaneous trunci muscle reflex was evaluated by pinpricks. Skin cross-sections were stained with hematoxylin and eosin or with antibodies against PGP9.5. RESULTS: BLA at 10 microM interacted minimally with resting or inactivated Nav1.7 and Nav1.8 Na+ channels when infrequently stimulated to +50 mV for 3 ms. However, when stimulated at 2 Hz for 1000 pulses, their peak Na+ currents were >90% reduced by BLA. This use-dependent inhibition was not significantly reversed after 15-min washing. Complete nociceptive blockade after injection of lidocaine (0.5%)/epinephrine (1:200,000) lasted for approximately 1 h in rats; full recovery occurred after approximately 6 h. Co-injection of 0.125 mM BLA with lidocaine/epinephrine increased the duration of complete nociceptive blockade to 24 h. Full recovery occurred after approximately 6 days. Skin histology including peripheral nerve fibers appeared unaffected by BLA. CONCLUSIONS: BLA inhibits Nav1.7 and Nav1.8 Na+ currents in a use-dependent manner. Co-injection of BLA at

Phase 1A safety assessment of intravenous amitriptyline.

UNLABELLED: The antidepressant amitriptyline is used as an adjuvant in the treatment of chronic pain. Among its many actions, amitriptyline blocks Na+ channels and nerves in several animal and human models. As perioperative intravenous lidocaine has been suggested to decrease postoperative pain, amitriptyline, because of its longer half-life time, might be more useful than lidocaine. However, the use of intravenous amitriptyline is not approved by the US Food and Drug Administration. We therefore investigated the adverse effects of preoperative intravenous amitriptyline in a typical phase 1A trial. After obtaining written Food and Drug Administration and institutional review board approval, we obtained written consent for preoperative infusion of amitriptyline in an open-label, dose-escalating design (25, 50, and 100 mg, n=5 per group). Plasma levels of amitriptyline/nortriptyline were determined, and adverse effects were recorded in a predetermined symptom list. Infusion of 25 and 50 mg amitriptyline appears to be well tolerated; however, the study was terminated when 1 subject in the 100-mg group developed severe bradycardia. Intravenous infusion of amitriptyline (25 to 50 mg over 1 hour) did not create side effects beyond dry mouth and drowsiness, or dizziness, in 2 of our 10 otherwise healthy participants receiving the 25- to 50-mg dose. An appropriately powered future trial is necessary to determine a potential role of amitriptyline in decreasing postoperative pain. PERSPECTIVE: Amitriptyline potently blocks the persistently open Na+ channels, which are known to be instrumental in various pain states. As this occurs at very low plasma concentrations, a single preoperative intravenous infusion of amitriptyline could provide long-lasting pain relief and decrease the incidence of chronic pain.

In vitro, lidocaine-induced axonal injury is prevented by peripheral inhibition of the p38 mitogen-activated protein kinase, but not by inhibiting caspase activity.

BACKGROUND: All local anesthetics (LAs) are, to some extent, neurotoxic. Toxicity studies have been performed in dissociated neuron cultures, immersing both axon and soma in LA. This approach, however, does not accurately reflect the in vivo situation for peripheral nerve blockade, where LA is applied to the axon alone. METHODS: We investigated lidocaine neurotoxicity in compartmental sensory neuron cultures, which are composed of one central compartment containing neuronal cell bodies and a peripheral compartment containing their axons, allowing for selective incubation. We applied lidocaine +/- neuroprotective drugs to neuronal somata or axons, and assessed neuron survival and axonal outgrowth. RESULTS: Lidocaine applied to the peripheral compartment led to a decreased number of axons (to 59% +/- 9%), without affecting survival of cell bodies. During axonal incubation with lidocaine, the p38 mitogen-activated protein kinase inhibitor SB203580 (10 microM) attenuated axonal injury when applied to the axon (insignificant reduction of maximal axonal distance to 93% +/- 9%), but not when applied to the cell body (deterioration of maximal axonal length to 48% +/- 6%). Axonal co-incubation of lidocaine with the caspase inhibitor z-vad-fmk (20 microM) was not protective. CONCLUSIONS: Whereas inhibition of either p38 mitogen-activated protein kinase or caspase activity promote neuronal survival after LA treatment of dissociated neuronal cultures, axonal degeneration induced by lidocain (40 mM) is prevented by p38 MAP kinase but not by caspase inhibition. We conclude that processes leading to LA-induced neurotoxicity in dissociated neuronal culture may be different from those observed after purely axonal application.

Safety evaluation of topically applied amitriptyline in porcine full-thickness wounds.

BACKGROUND AND OBJECTIVES: The tricyclic antidepressant amitriptyline is frequently used in pain clinics for management of pain. It has also been suggested that topical application of amitriptyline could be useful for the treatment of neuropathic pain. In this report we investigated the effect of amitriptyline on porcine full thickness wounds resembling excised burn wounds. We assessed if daily topical application of amitriptyline into the wound chambers for 10 days impedes wound healing as measured by (1) wound contraction and (2) histopathological findings. METHODS: Full-thickness wounds measuring 1.5 cm square were created on the dorsum of Yorkshire pigs and were enclosed in polyurethane wound chambers. Amitriptyline was applied daily at various concentrations. Bupivacaine (0.5%) or normal saline were used as controls. Daily wound serum levels were obtained and the level of amitriptyline and nortriptyline obtained. Pictures were taken daily and the wound surface analyzed for contraction. Cross-sectional, full-thickness skin biopsies were obtained at days 2, 8 and 10 and evaluated microscopically for re-epithelialization, inflammation, and necrosis. RESULTS: The high serum level of amitriptyline and nortriptyline did not affect wound healing; re-epithelialization, wound contraction, and inflammation were not significantly different between amitriptyline and control groups. CONCLUSION: Amitriptyline at the concentrations of 0.0625% and 0.125% applied daily via chambers covering wounds in a full-thickness pig excision model has no overt toxic effect on wound healing as measured by wound contraction and histological assessment.

Magnesium sulfate diminishes the effects of amide local anesthetics in rat sciatic-nerve block.

BACKGROUND AND OBJECTIVES: Magnesium sulfate (MgSO(4)) is well known as an antagonist of N-methyl-d-aspartate receptors and was used for intrathecal analgesia a century ago. However, the effects of MgSO(4) combined with local anesthetics (LAs) on peripheral nerves are unclear. We tested the hypothesis that MgSO(4) could be used as an adjuvant to prolong and intensify conduction block by amide-type LAs in a rat sciatic-nerve block model. Further, the mechanism of possible synergy between LAs and MgSO(4) was investigated in whole-cell mode patch-clamp experiments. METHODS: Sciatic nerves were exposed to 2%/73.9 mM lidocaine, 0.25%/7.7 mM bupivacaine, and 0.5%/15.4 mM ropivacaine, with or without addition of 1.25%, 2.5%, or 5% MgSO(4)/50.7 mM, and nerve block characteristics were assessed. To elucidate the LA-MgSO(4) interaction, voltage-dependent inactivation curves were determined in cultured rat GH(3) cells that expressed neuronal Na(+) channels. RESULTS: Unexpectedly, the addition of MgSO(4) overall significantly shortened the duration of block by lidocaine, bupivacaine, and ropivacaine. The steady-state inactivation of Na(+) channels in the presence of 300 muM lidocaine was almost unchanged by the addition of 10 mM MgSO(4), indicating that MgSO(4) does not affect the potency of lidocaine toward the inactivated Na(+) channel. CONCLUSIONS: MgSO(4) coadministered with amide-type LAs shortened the duration of sciatic-nerve block in rats. Therefore, it does not seem to be useful as an adjuvant for peripheral-nerve block. The mechanism of this observed antagonism is unclear but appears to be independent of the action of LAs and MgSO(4) at the LA receptor within the Na(+) channel.