Long-acting Local Anesthetic Research Articles

Local anesthetic systemic toxicity

The practice of regional anesthesia has been revitalized of late with the popularization of ultrasound-guided techniques. Advocates must be vigilant for the effects of unintentionally high blood levels of local anesthetic. Systemic local anesthetic toxicity, though rare, is a potentially devastating occurrence. This narrative review summarizes the effects of local anesthetic toxicity. We highlight how these toxic effects have motivated the search for a safe and long-acting local anesthetic. We outline current prevention and treatment options and appraise an emerging therapy in light of unfolding evidence. A search of the English language literature was conducted using the PubMed database from the National Library of Medicine. Bibliographies of retrieved articles were used to retrieve additional articles. The advent of multiple safety steps has led to a dramatic reduction in the incidence of local anesthetic toxicity over the past 30 years. Rising plasma levels of local anesthetic lead to a progressive spectrum of neurological and cardiac effects. Seizure activity may herald the onset of myocardial depression and ventricular arrhythmias that are often refractory to treatment. In addition to specific measures, such as lipid emulsion therapy, general supportive measures are warranted, for example, Advanced Life Support Guidelines. Vigilance during the performance of regional anesthesia and immediate intervention at the earliest sign of toxicity improve the chances of successful treatment.

A review of local anesthetic cardiotoxicity and treatment with lipid emulsion

Cardiovascular collapse from accidental local anesthetic toxicity is a rare but catastrophic complication of regional anesthesia. The long-acting amide local anesthetics bupivacaine, levobupivacaine and ropivacaine have differential cardiac toxicity, but all are capable of causing death with accidental overdose. In recent times, the chance discovery that lipid emulsion may improve the chance of successful resuscitation has lead to recommendations that it should be available in every location where regional anesthesia is performed. This review will outline the mechanisms of local anesthetic toxicity and the rationale for lipid emulsion therapy.

The effects of lidocaine on bupivacaine-induced cardiotoxicity in the isolated rat heart

Bupivacaine is a widely used long-acting local anaesthetic. In clinical practice, a mixture of bupivacaine and lidocaine is often used in order to combine the faster onset of sensory blockade of lidocaine with more profound and longer duration of blockade by bupivacaine. The aim of this study was to compare the cardiotoxicity of large doses of bupivacaine and mixture of bupivacaine with lidocaine in the isolated rat heart and to estimate whether or not the addition of lidocaine in clinically relevant concentration increases bupivacaine-induced toxicity. Experiments were performed on 21 adult male rats divided into three groups: B (6 microg/ml bupivacaine), BL (6 microg/ml bupivacaine and 12 microg/ml lidocaine) and L (12 microg/ml lidocaine). The experiment consisted of three 30 min periods: stabilisation, perfusion and washout. The isolated hearts were perfused according to Langendorff with Krebs-Henseleit solution at constant pressure (80 mmHg) and 37 degrees C (CaCl(2) 1.25 mM) and the heart rate (based on RR interval assessment), PQ and QRS intervals were measured. The present study shows that the mixture of tested anaesthetics - bupivacaine and lidocaine - impairs the intraventricular conduction parameters (QRS interval prolongation) to a lesser extent than bupivacaine itself, and that this effect is marked mainly at the beginning of perfusion.

Pain Control after Total Hip Replacement Arthroplasty Using Periarticular Multimodal Drug Injection

Purpose: This study attempted to evaluate the pattern of change of the pain after total hip arthroplasty (THA) and to confirm the effect of periarticular multimodal drug injection (PMDI) on controlling the early postoperative pain. Materials and Methods: Of the total patients who underwent primary THA at our hospital because of osteonecrosis of the femoral head from March to October 2008, 60 patients were enrolled in this study. The subjects were divided into three groups. Groups 1 & 2 received periarticular injection. Group 1 included the patients who were injected with a combination of opioid, long-acting local anesthetics, a non-steroidal anti-inflammatory drug and epinephrine. Group 2 received a combination of morphine and ropivacaine and group 3 was not injected with any analgesics. The visual analogue scale (VAS) at 4 hours, 8 hours, 12 hours, 24 hours, 2 days, 3 days, 5 days, 14 days and 1 month after surgery, the frequency that patients pushed the self-controlled pain medication machine for 2 days after surgery and the amount of clonac that was injected according to the needs of the patients were used as objective measures. Results: The VAS score at postoperative 4 hours to 3 days among the groups showed a significant difference (P 0.05). The frequency of pushing the self-controlled pain medication machine among the groups and the amount of clonac according to the needs of the patients among the groups showed that there were significant decreases at the operation day, the postoperative 1, 2 day and the 3 days (P<0.05). Conclusion: PMDI has a significant effect on controlling the early postoperative pain after THA.

Employment of lipid emulsion in the resuscitation for long-acting local anesthetic toxirity

There are no effective and convenient therapeutic management on refractory cardiac arrest induced by long-acting local anesthetic toxicity. Although there are no any randomly controlled trials showing the effectiveness of lipid emulsion for anesthetic toxicity resuscitation in human beings mostly because of ethic issues, lipid emulsion has been proved to be effective in animal models undergoing local anesthetic toxicity. This novel approach to treating potentially fatal cardiac toxicity is still at an early stage but holds promise for clinical application. Literatures suggest that lipid emulsion resuscitation should be as a reserve step because of lacking clinical investigative evidence. However, more and more case reports indicate that lipid emulsion should be used earlier in order to avoid local anesthetic toxicity deteriorated. Further work is required to explore mechanism of lipid emulsion on resuscitation of local anesthetic toxicity and optimize the treatment regimens with respect to efficacy and safety of lipid rescue. Key words: Local anesthetic; Lipid emulsion; Cardiac toxicity

Serum Ropivacaine Concentrations and Systemic Local Anesthetic Toxicity in Trauma Patients Receiving Long-Term Continuous Peripheral Nerve Block Catheters

Ropivacaine is a long-acting local anesthetic used frequently for peripheral nerve blocks and continuous peripheral nerve block catheters. Combat trauma patients at Walter Reed Army Medical Center often receive continuous peripheral nerve block catheters as part of their pain regimen. These catheters remain in situ for several days to weeks. In this study, we evaluated the free ropivacaine drug levels over time in trauma patients by measuring the serum concentration of bound and unbound local anesthetic. The corresponding alpha(1)-acid glycoprotein concentration in patients with prolonged ropivacaine infusions was also measured. Fifteen patients were enrolled in the study; 2 patients were excluded because only a single ropivacaine level was obtained. Of the remaining 13 patients in the study, 2 had peripheral nerve catheters placed at the time of enrollment; the remaining 11 patients had catheters placed before enrollment. These patients were already receiving 0.2% ropivacaine infusions for a period of 18-126 h before the first assessment of local anesthetic level. Catheters infused 0.2% ropivacaine at a rate of 6-14 mL/h; catheter boluses were administered with 0.5% ropivacaine. Local anesthetic blood concentrations were scheduled to be measured on Days 1, 3, 5, 7, and 10 and every 3 days thereafter until all catheters were removed, although not all patients underwent each assessment. Specimens were assayed using high-performance liquid chromatography for total and free serum ropivacaine concentrations. Alpha(1)-acid glycoprotein was also measured. Thirteen patients remained in the study, for a total of 59 blood samples. The median number of days catheters remained in situ for the duration of acute pain therapy was 7 days (range: 6-27 days). The median number of days catheters remained in situ after enrollment into the study was 7 days (range: 4-25 days). The median number of blood samples collected per patient was 4 (range: 2-10 samples). Two patients had isolated increased concentrations of free ropivacaine into a previously identified toxic range with no obvious mitigating factors; both patients had received a 300-mg bolus of 0.5% ropivacaine approximately 24 h before that blood collection. The median ropivacaine concentration over the length of the study was 0.11 mg/L (range: undetectable to 0.63 mg/L). During the first week of the study, the median change in ropivacaine concentration per patient was 0.00 mg/L (range: -0.35 to 0.47 mg/L). Although 2 patients demonstrated isolated serum ropivacaine concentration spikes into a previously identified toxic range, continuous peripheral nerve block catheter management and local anesthetic doses as practiced at Walter Reed Army Medical Center did not result in clinically evident systemic ropivacaine toxicity. There was no correlation between free ropivacaine concentration and alpha(1)-acid glycoprotein concentration except in patients who had already been receiving ropivacaine infusions before entering the study. Despite this lack of correlation, the total duration of local anesthetic infusion did not seem to influence the free concentration of the drug.

Long-Acting Local Anesthetics Attenuate FMLP-induced Acute Lung Injury in Rats

Endothelin-1 (ET-1) is a mediator of lung diseases and a potent pulmonary vasoconstrictor. In addition to thromboxane A2, it participates in the formation of lung edema. Both lidocaine and mepivacaine attenuate the increase of pulmonary arterial pressure (PAP) and lung edema development. We examined the effects of procaine, bupivacaine, and ropivacaine on experimentally evoked PAP increase and ET-1 release. PAP and lung weight were measured in isolated rat lungs during perfusion with Krebs-Henseleit hydroxyethyl starch buffer. Bupivacaine, ropivacaine, or procaine was added to the solution at concentrations of 10(-2)-10(-7) mg/kg. ET-1 levels were measured in the perfusate by enzyme-immunoassay, and thromboxane A2 levels were assayed by radioimmunoassay. N-formyl-L-leucine-methionyl-L-phenylalanine was used to activate human polymorphonuclear neutrophils. Bupivacaine, ropivacaine, and procaine significantly attenuated increases of PAP (P < 0.05) and resulted in a reduction of lung weight in these treatment groups compared with the sham group (P < 0.05). The long-acting anesthetics bupivacaine and ropivacaine (P < 0.05), but not procaine, reduced ET-1 levels, produced low inflammation rates, and did not affect lung structures at doses from 10(-3) to 10(-6) mg/kg. Bupivacaine and ropivacaine attenuated N-formyl-L-leucine-methionyl-L-phenylalanine-induced PAP, reduced lung edema, and diminished ET-1 release. Lidocaine and mepivacaine are more effective in reducing PAP and edema formation, but long-acting local anesthetics also inhibit ET-1 depletion and therefore have increased anti-inflammatory properties.

Third-Degree Heart Block Associated with Bupivacaine Infusion Following Total Knee Arthroplasty

Total knee arthroplasty is one of the most successful operations performed. Multiple modalities are utilized for pain management in the perioperative period. Regional anesthesia is a common, effective method associated with high patient satisfaction. It typically provides exceptional local pain control without the systemic side effects that have been associated with oral or parenteral narcotics. Alleviation of pain allows for earlier mobilization and potentially shorter hospital stays. However, continuous infusion of a long-acting local anesthetic is not without risk. Case reports of severe complications such as hypotension, arrhythmia, seizure, and cardiovascular collapse have been reported, but all involved intra-articular injections or a single injection of a large dose of anesthetic medication to attain a regional block1-6. We found no reports of arrhythmia in association with an indwelling catheter in patients who were receiving regional anesthesia. We present the case of a patient in whom a third-degree heart block developed in association with a continuous bupivacaine infusion through an indwelling femoral catheter. The patient was informed that data concerning the case would be submitted for publication, and she consented. ### History A seventy-eight-year-old woman who weighed 59 kg had a five-year history of progressive, debilitating, left knee pain that was most severe with walking, stair-climbing, and arising from a seated position. As nonoperative treatment had failed to provide relief, the decision was made to perform a total knee replacement. Her medical history included osteoarthritis of both knees, peptic ulcer disease, a cerebrovascular accident in 1993, and cirrhosis of the liver secondary to alcohol abuse. The patient had previously undergone a right total knee arthroplasty with no complications. Physical examination of the left lower extremity demonstrated a 20° valgus deformity and an arc of knee motion from 15° to 115°. Due to the known fact that the patient had liver …

Clonidine as an Adjuvant to Local Anesthetics for Peripheral Nerve and Plexus Blocks

The effect of adding clonidine to local anesthetics for nerve or plexus blocks remains unclear. The authors searched for randomized placebo-controlled trials testing the impact of adding clonidine to local anesthetics for peripheral single-injection nerve or plexus blocks in adults undergoing any surgery (except eye) without general anesthesia. Twenty trials (1,054 patients, 573 received clonidine) published 1992-2006 tested plexus (14 brachial, 1 cervical) and nerve blocks (2 sciatic/femoral, 1 midhumeral, 1 ilioinguinal/iliohypogastric, 1 ankle). Clonidine doses ranged from 30 to 300 microg; most patients received 150 microg. Clonidine prolonged the duration of postoperative analgesia (weighted mean difference 122 min; 95% confidence interval [CI] 74-169), sensory block (weighted mean difference 74 min; 95% CI 37-111), and motor block (weighted mean difference 141 min; 95% CI 82-199). In a subgroup of patients receiving an axillary plexus block, these effects were independent of whether clonidine was added to an intermediate or a long-acting local anesthetic. Clonidine increased the risk of arterial hypotension (odds ratio 3.61; 95% CI 1.52-8.55; number-needed-to-harm 11), orthostatic hypotension or fainting (odds ratio 5.07; 95% CI 1.20-21.4; number-needed-to-harm 10), bradycardia (odds ratio 3.09; 95% CI 1.10-8.64; number-needed-to-harm 13), and sedation (odds ratio 2.28; 95% CI 1.15-4.51; number-needed-to-harm 5). There was a lack of evidence of dose-responsiveness for beneficial or harmful effects. Clonidine added to intermediate or long-acting local anesthetics for single-shot peripheral nerve or plexus blocks prolongs duration of analgesia and motor block by about 2 h. The increased risk of hypotension, fainting, and sedation may limit its usefulness. Dose-responsiveness remains unclear.

THIS MONTH IN Anesthesiology

Etomidate, has limited clinical utility due to suppression of adrenocortical steroid synthesis. The first etomidate analogue, (R)-3-methoxy-3-oxopropyl1-(1-phenylethyl)-1H-imidazole-5-carboxylate (MOC-etomidate), was designed to be susceptible to ultra-rapid metabolism to reduce this effect. MOC-etomidate potently enhanced γ-aminobutyric acid type A receptor function and demonstrated first-order metabolism in human liver homogenates with an in vitro half-life of 4.4 min compared with &gt; 40 min for etomidate. A rapid, brief loss of righting reflex and minimal hemodynamic changes were observed in rats without adrenocortical suppression MOC-etomidate, is rapidly metabolized, ultra–short-acting, and does not produce prolonged adrenocortical suppression and maintains the favorable pharmacologic properties of etomidate. See the accompanying Editorial View on page 229 Blood transfusion may have an adverse effect on long-term health. A prospective observational study assessed long-term survival in patients undergoing coronary artery surgery who received a perioperative allogeneic blood transfusion. Health outcomes of 1,841 consecutive patients with isolated nonemergency first-time coronary artery surgery and survival &gt; 60 days after surgery were determined. Of the 1,062 patients transfused, 266 died (mean follow-up of 8.1 yr). A new malignant condition was recorded on the death certificate of 27% of patients who were transfused, compared with 43% who were not. Transfusion of blood products was not associated with long-term survival. Patients undergoing coronary artery surgery who have received moderate amounts of blood (≤ 6 units) should be reassured that they are unlikely to experience a reduction in long-term survival.To assess the prognostic value of elevated brain natriuretic peptide (BNP) or N -terminal pro-brain natriuretic peptide (NT-proBNP) levels in predicting mortality and major adverse cardiovascular events (MACE), a meta-analysis was performed of studies in patients undergoing noncardiac surgery using unrestricted MEDLINE and EMBASE searches. Preoperative BNP elevation was significantly associated with an increased risk of short-term MACE (&lt; 43 days postsurgery), all cause mortality, and cardiac death. Elevated NT-proBNP levels were also predictive. Preoperative BNP elevation was also significantly associated with an increased risk of long-term MACE (&gt; 6 months) and all cause mortality. These data suggest that elevated BNP and NT-proBNP levels may identify patients undergoing major noncardiac surgery at high risk of cardiac events.Growing evidence suggests that microvascular dysfunction is the key element of the pathogenesis of septic shock. This retrospective study assessed the outcome and muscle tissue oxygenation (Sto2) of septic shock patients after early resuscitation using early goal-directed therapy. Sto2was monitored in septic shock patients using a tissue spectrometer. No difference was observed between groups with the exception of pulse oximetry saturation (Spo2; 94% vs. 97%, P = 0.04). The Sto2values were significantly lower in nonsurvivors than in survivors (73% vs. 84%, P = 0.02). Further investigations are required to determine if correction of an impaired level of Sto2improves patient outcomes.Clonidine added to intermediate or long-acting local anesthetics for single-shot nerve blocks prolongs duration by about 2 h. Side effects may limit its usefulness.A process-dissociation procedure, which corrected for guessing, was used to determine if more accurate results of auditory memory could be obtained.The perioperative implications of adults with congenital heart disease undergoing noncardiac surgery are reviewed.Intravenous infusion tests have limited utility for predicting analgesia in chronic pain patients.

Potentiation of Local Anesthetic Activity of Neosaxitoxin with Bupivacaine or Epinephrine: Development of a Long-Acting Pain Blocker

Local anesthetics effectively block and relieve pain, but with a relatively short duration of action, limiting its analgesic effectiveness. Therefore, a long-acting local anesthetic would improve the management of pain, but no such agent is yet available for clinical use. The aim of this study is to evaluate the potentiation of the anesthetic effect of neosaxitoxin, with bupivacaine or epinephrine in a randomized double-blind clinical trial. Ten healthy males were subcutaneously injected into the left and right forearms with a randomized pair of the following treatments: (i) bupivacaine (5 mg); (ii) neosaxitoxin (10 microg); (iii) neosaxitoxin (10 microg) plus bupivacaine (5 mg), and (iv) neosaxitoxin (10 microg) plus epinephrine (1:100.000), but all participant received all four formulations (in 2 ml; s.c.), with 1 month elapsing between the two round of experiments. A validated sensory and pain paradigm was used for evaluating the effect of the treatment 0-72 h after the injections, measuring sensory, pain, and mechanical touch perception threshold. The duration of the effect produced by combined treatments was longer than that by the single drugs. In conclusion, bupivacaine and epinephrine potentiate the local anesthetic effect of neosaxitoxin in humans when co-injected subcutaneously. The present results support the idea that neosaxitoxin is a new long-acting local pain blocker, with highly potential clinical use.

Un effet direct de la ropivacaïne implique l’activation des voies de la lipoxygénase dans le muscle lisse de l’aorte du rat

Ropivacaine is a long-acting amino-amide local anesthetic that induces vasoconstriction in vitro and in vivo. The aim of this study was to investigate the pathways involved in arachidonic acid metabolism associated with S-ropivacaine-induced contraction of rat aortic smooth muscle in vitro. Rat thoracic aortic rings without endothelium were isolated and suspended for isometric tension recording. Cumulative dose-response curves were generated with concentrations of 10(-5) to 10(-3) M ropivacaine enantiomer in the presence or absence of quinacrine dihydrochloride, nordihydroguaiaretic acid, quinacrine dihydrochloride plus nordihydroguaiaretic acid, indomethacin, fluconazole, AA-861, and verapamil. The maximal S-ropivacaine-induced contractile response achieved at 3x10(-4) M was also assessed in aortic rings pretreated with normal or calcium-free Krebs solution. Ropivacaine enantiomers induced dose-dependent biphasic contractions in aortic rings. S-ropivacaine (10(-4), 3x10(-4) M) induced a stronger contraction than R-ropivacaine. Quinacrine dihydrochloride (2x10(-5), 4x10(-5) M) attenuated the S-ropivacaine-induced biphasic contraction in a dose-dependent manner. Indomethacin (3x10(-5), 6x10(-5) M), nordihydroguaiaretic acid (10(-5) M), and AA-861 (10(-5) M) also attenuated the S-ropivacaine-induced dose-dependent biphasic contraction, whereas fluconazole (3x10(-5)) had no effect. Combined pretreatment with quinacrine dihydrochloride and nordihydroguaiaretic acid almost completely abolished the S-ropivacaine-induced contraction. S-ropivacaine-induced contractile responses were attenuated by verapamil (10(-5) M) and calcium-free Krebs solution. S-ropivacaine induces dose-dependent biphasic contractions in rat aortic smooth muscle through a mechanism requiring extracellular calcium that is mediated by activation of the lipoxygenase pathway and, to a lesser extent, the cyclooxygenase pathway.

A Comparison of the Pharmacodynamics and Pharmacokinetics of Bupivacaine, Ropivacaine (with Epinephrine) and Their Equal Volume Mixtures with Lidocaine Used for Femoral and Sciatic Nerve Blocks: A Double-Blind Randomized Study

Mixtures of lidocaine with a long-acting local anesthetic are commonly used for peripheral nerve block. Few data are available regarding the safety, efficacy, or pharmacokinetics of mixtures of local anesthetics. In the current study, we compared the effects of bupivacaine 0.5% or ropivacaine 0.75% alone or in a mixed solution of equal volumes of bupivacaine 0.5% and lidocaine 2% or ropivacaine 0.75% and lidocaine 2% for surgery after femoral-sciatic peripheral nerve block. The primary end point was onset time. In a double-blind, randomized study, 82 adults scheduled for lower limb surgery received a sciatic (20 mL) and femoral (20 mL) peripheral nerve block with 0.5% bupivacaine (200 mg), a mixture of 0.5% bupivacaine 20 mL (100 mg) with 2% lidocaine (400 mg), 0.75% ropivacaine (300 mg) or a mixture of 0.75% ropivacaine 20 mL (150 mg) with 2% lidocaine (400 mg). Each solution contained epinephrine 1:200,000. Times to perform blocks, onset times (end of injection to complete sensory and motor block), duration of sensory and motor block, and morphine consumption via IV patient-controlled analgesia were compared. Venous blood samples of 5 mL were collected for determination of drug concentration at 0, 5, 15, 30, 45, 60, and 90 min after placement of the block. Patient demographics and surgical times were similar for all four groups. Sciatic onset times (sensory and motor block) were reduced by combining lidocaine with the long-acting local anesthetic. The onset of bupivacaine-lidocaine was 16 +/- 9 min versus 28 +/- 12 min for bupivacaine alone. The onset of ropivacaine-lidocaine was 16 +/- 12 min versus 23 +/- 12 for ropivacaine alone. Sensory blocks were complete for all patients within 40 min for those receiving bupivacaine-lidocaine versus 60 min for those receiving bupivacaine alone and 30 min for those receiving ropivacaine-lidocaine versus 40 min for those receiving ropivacaine alone (P < 0.05). Duration of sensory and motor block was significantly shorter in mixture groups. There was no difference among groups for visual analog scale pain scores and morphine consumption during the 48 h postoperative period, except for bupivacaine alone (median: 9 mg) versus bupivacaine-lidocaine mixture (15 mg), P < 0.01. There was no difference in the incidence of adverse events among groups. Plasma concentrations of bupivacaine and ropivacaine were higher, and remained elevated longer, in patients who received only the long-acting local anesthetic compared to patients who received the mixture of long-acting local anesthetic with lidocaine (P < 0.01). Mixtures of long-acting local anesthetics with lidocaine induced faster onset blocks of decreased duration. Whether there is a safety benefit is unclear, as the benefit of a decreased concentration of long-acting local anesthetic may be offset by the presence of a significant plasma concentration of lidocaine.

Binding of Long-lasting Local Anesthetics to Lipid Emulsions

Rapid infusion of lipid emulsion has been proposed to treat local anesthetic toxicity. The authors wanted to test the buffering properties of two commercially available emulsions made of long- and of long- and medium-chain triglycerides. Using the shake-flask method, the authors measured the solubility and binding of racemic bupivacaine, levobupivacaine, and ropivacaine to diluted Intralipid (Fresenius Kabi, Paris, France) and Medialipide (B-Braun, Boulogne, France). The apparent distribution coefficient expressed as the ratio of mole fraction was 823 +/- 198 and 320 +/- 65 for racemic bupivacaine and levobupivacaine, and ropivacaine, respectively, at 500 mg in the Medialipide/buffer emulsion; and 1,870 +/- 92 and 1,240 +/- 14 for racemic bupivacaine and levobupivacaine, and ropivacaine, respectively, in the Intralipid/buffer emulsion. Decreasing the pH from 7.40 to 7.00 of the Medialipide/buffer emulsion led to a decrease in ratio of molar concentration from 121 +/- 3.8 to 46 +/- 2.8 for bupivacaine, and to a lesser extent from 51 +/- 4.0 to 31 +/- 1.6 for ropivacaine. The capacity of the 1% emulsions was 871 and 2,200 microM for the 1% Medialipide and Intralipid emulsions, respectively. The dissociation constant was 818 and 2,120 microM for racemic bupivacaine and levobupivacaine, and ropivacaine, respectively. Increasing the temperature from 20 to 37 degrees C led to a greater increase in affinity for ropivacaine (55%) than for bupivacaine (27%). When the pH of the buffer was decreased from 7.40 to 7.00, the affinity was decreased by a factor of 1.68, similar for both anesthetics. The solubility of long-acting local anesthetics in lipid emulsions and the high capacity of binding of these emulsions most probably explain their clinical efficacy in case of toxicity. The long-chain triglyceride emulsion Intralipid appears to be about 2.5 times more efficacious than the 50/50 medium-chain/long-chain Medialipide emulsion. Also, because of their higher hydrophobicity, racemic bupivacaine and levobupivacaine seem to clear more rapidly than ropivacaine.

The toxicity of local anesthetics: the place of ropivacaine and levobupivacaine

Ropivacaine and levobupivacaine were developed after evidence of bupivacaine-related severe toxicity. Despite a comparable analgesic profile, quantitative differences become evident with regard to their specific rate of systemic toxicity. The present article provides a concise review of the toxic potencies of levobupivacaine and ropivacaine. As lipophilicity is known to be a major determinant in local anesthetic toxicity, the clinical safety profile of ropivacaine seems to be more favorable than that of levobupivacaine. Experimental studies and case reports confirm this hypothesis, showing that ropivacaine is characterized by fewer (cardio) toxic effects and, most probably, a greater margin of safety. Both agents also may dose dependently damage neurons and skeletal muscle tissue at the injection site. Although their specific rate of neurotoxicity appears to be rather low, levobupivacaine is characterized by an outstanding myotoxic potential. Compared with bupivacaine, both agents may be considered as 'more well tolerated' but not as 'totally well tolerated', as they are still capable of inducing systemic and local toxicity. However, ropivacaine seems to have the greatest margin of safety of all long-acting local anesthetics at present.

The Local Anesthetic Butamben Inhibits Total and L-Type Barium Currents in PC12 Cells

Butamben or n-butyl-p-aminobenzoate is a long-acting experimental local anesthetic for the treatment of chronic pain when given as an epidural suspension. We have investigated whether Cav1.2/L-type calcium channels may be a target of this butamben action. The effect of butamben on these channels was studied in undifferentiated rat PC12-cells with the whole-cell patch-clamp technique in voltage-clamp. Ba(2+) ions were used as the charge carriers in the calcium channel currents, whereas K(+) currents were removed using K(+) free solutions. Butamben 500 microM reversibly suppressed the total whole-cell barium current by 90% +/- 3% (n = 15), whereas 10 microM nifedipine suppressed this barium current by 75% +/- 7% (n = 6). Preexposure to butamben followed by washout decreased the inhibition by nifidepine to 47% +/- 5% (n = 10). These suppressive effects were not due to the measurement procedure and the drug vehicles in the solutions (<0.1% ethanol; n = 6). Butamben inhibits the total barium current through expressed calcium channel types in PC12 cells, including Cav1.2/L-type channels. Because Cav1.2 channels may also occur in human nociceptive C fibers, this result allows the possibility that these L-type channels are involved in the analgesic action of butamben.

Pain and Anxiety Control: An Online Study Guide

The Editorial Board of the Journal of Endodontics has developed a literature-based study guide of topical areas related to endodontics. This study guide is intended to give the reader a focused review of the essential endodontic literature and does not cite all possible articles related to each topic. Although citing all articles would be comprehensive, it would defeat the idea of a study guide. This section will cover pain theories and dentin hypersensitivity, referred pain, oral pain not of dental origin, barodontalgia, local anesthetics, long-acting local anesthetics, intrapulpal anesthesia, intraligamentary anesthesia, intraosseous anesthesia, inferior alveolar nerve block anesthesia, Gow-Gates anesthesia technique, Vazirani-Akinosi anesthesia technique, second-division block anesthesia technique, endodontic postoperative pain, effect of occlusal adjustment on endodontic pain, paresthesia associated with periradicular pathosis, analgesics, sedation, and endodontic flare-ups.

Pain Control in Augmentation Mammaplasty: Safety and Efficacy of Indwelling Catheters in 644 Consecutive Patients

In an effort to give patients an additional effective form of analgesia, indwelling catheters for the instillation of a long-acting local anesthetic have been used to alleviate postoperative pain in patients undergoing augmentation mammaplasty. This prospective study analyzes the safety and efficacy of this form of pain control in a consecutive series of 644 patients. Patients were given a choice of intermittent bolus or continuous flow catheters for pain control. Prior to discharge, 20 mL of 0.25% bupivicaine with 1:400,000 epinephrine was instilled by a nurse into catheters for those patients receiving bolus self-administration. Pain scores for each side were recorded both before and 30 minutes after instillation. Patients then instilled 1 to 2 additional doses of bupivicaine during the first 24 hours and continued to record pain scores in the evening and following morning. For patients using continuous flow catheters, 0.25% bupivicaine without epinephrine was used to fill pumps that allowed up to 2 days of continuous flow at a rate of 2 mL per hour per side. Patients recorded pain at time intervals similar to those of patients using bolus self-administration. Questionnaires were given to all patients to determine the extent of pain reduction following the instillation of local anesthesia. More than 200 complete questionnaires were gathered, and pain scores from each of these were analyzed to gauge the efficacy of the instillation regimen. Eighty-nine percent of the patients who self-administered a bolus of bupivacaine reported pain reduction on the evening of surgery, and 78% reported a reduction on the following morning, before implant mobility exercises. Catheters were maintained for 1 day postoperatively by 544 patients (84%) and for 2 days by 100 patients (16%). One patient developed an infection of unknown etiology that ultimately resulted in the loss of a unilateral implant. A prospective study of 644 consecutive augmentation mammaplasty patients shows that indwelling catheters for the postoperative instillation of bupivacaine are both safe and effective in the management of postoperative pain. This gives the patient an additional form of analgesia, limited to the operative site, which is helpful in a multimodal pain management program. Both continuous flow and intermittent bolus self-administration systems are effective and their patient ratings are indistinguishable.

Effects of different doses and concentrations of ropivacaine in axillary brachial plexus block

To evaluate clinic pharmacodynamics of ropivacaine hydrochloride, a new long-acting amide type local anaesthetic, in Chinese patients undergoing neurolysis and tendolysis of forearm through axillary brachial plexus block. Two hundred ASAI-II persons, aged 18-65,weighing 60-75 kg, undergoing neurolysis and tendolysis of forearm under axillary brachial plexus block were randomly assigned to 4 equal groups to received ropivacaine of the doses of 1.00 mg/kg (Group I), 1.25 mg/kg (Group II), 1.50 mg/kg (Group III), and 2.00 mg/kg (Group IV). Each group was subdivided into 5 equal subgroups according to the concentrations (0.15%, 0.20%, 0.25%, 0.30%, and 0.35%). The effects were analyzed. Results There was no significant difference in starting time, consummating time, and persisting time of sensory and motor nerve block between Group I and Group II (all P > 0.05). The starting time and consummating time of Group III and Group IV were all significantly shorter than those of Group I (all P < 0.05), and the persisting times of Groups III and IV were all significantly longer than those of Group I (P < 0.05). 90 minutes after brachial plexus block the degrees of muscle strength Groups I and II were M1 and M2 respectively, hence, the sensory and motor nerves block was in dissociation. When motor never block was above M3 and M4 the interval of brachial plexus block was 55 min and 27 min in Group III and Group IV respectively. Sensory and motor never can be blocked perfectly when the dose of ropivacaine is between 1.5 mg/kg and 2.0 mg/kg and the concentration is between 0.30%-0.35%. When the doses of ropivacaine is 1.25 mg/kg and the concentration is 0.20%-0.25% the starting and consummating time are longer and persisting time is shorter. When the doses of ropivacaine is 1.00 mg/kg and the concentration is 0.15%-0.20% the starting and consummating time are longer and only satisfies external debridement and suture without tourniquets.

Efficacy of Intravesical Ropivacaine Injection on Urinary Symptoms Following Ureteral Stenting: A Randomized, Controlled Study

Previous studies suggest that intravesical administration of nonsteroidal anti-inflammatory drugs may reduce the troublesome voiding symptoms and pain related to ureteral stenting. The objective of this study was to investigate the effectiveness of a long-acting local anesthetic, ropivacaine, injected submucosally into the bladder to control ureteral stent-associated symptoms. A randomized, single-blinded, study approved by our Institutional Review Board of adult patients scheduled for ureteroscopic stone surgery and possible stent placement was conducted. Patients were randomized to either the treatment cohort, who received five injections of 2 mL 0.5% ropivacaine around the ureteral orifice or to the control cohort, who received five injections of 2 mL of 0.9% normal saline in identical locations. Pain scale questionnaires were provided to each subject preoperatively and at postoperative hours 2, 4, 8, 24, and 48 as well as on the day of stent removal. Student's t test and Wilcoxon signed rank sum tests were used for Gaussian and nonparametric data, respectively. Twenty-two patients were randomized evenly into the two cohorts. The ropivacaine group consisted of 11 patients (eight men and three women) with a mean age of 56.2 years (standard deviation [SD] = 12, range 27-69), and the saline group consisted of eleven patients (six men and five women) with a mean age of 47.8 years (SD = 6.6, range 37-58). Intraoperative parameters appeared similar between the two cohorts. Intraoperative and postoperative narcotic usage was not different between the two groups, except at postoperative hour 2 when it favored the ropivacaine cohort (P = 0.05). Trends favoring ropivacaine in flank pain, bladder pain, genitalia pain, and hematuria domains were seen as long as 8 hours and up to the day of stent removal. Trends of less magnitude and duration were seen in the dysuria domain. No differences were seen in the frequency and urgency domains. Our preliminary investigation with intravesical injection of ropivacaine before ureteroscopic surgery demonstrated trends toward decreased pain and voiding symptoms in this small-sample study. Inclusion of a larger sample should definitively address the effectiveness of intravesical ropivacaine and its impact on stent-related symptoms.