Prolonged Nerve Block Research Articles

Polymeric Prodrugs using Dynamic Covalent Chemistry for Prolonged Local Anesthesia.

Depot-type drug delivery systems are designed to deliver drugs at an effective rate over an extended period. Minimizing initial "burst" can also be important, especially with drugs causing systemic toxicity. Both goals are challenging with small hydrophilic molecules. The delivery of molecules such as the ultrapotent local anesthetic tetrodotoxin (TTX) exemplifies both challenges. Toxicity can be mitigated by conjugating TTX to polymers with ester bonds, but the slow ester hydrolysis can result in subtherapeutic TTX release. Here, we developed a prodrug strategy, based on dynamic covalent chemistry utilizing a reversible reaction between the diol TTX and phenylboronic acids. These polymeric prodrugs exhibited TTX encapsulation efficiencies exceeding 90 % and the resulting polymeric nanoparticles showed a range of TTX release rates. In vivo injection of the TTX polymeric prodrugs at the sciatic nerve reduced TTX systemic toxicity and produced nerve block lasting 9.7±2.0 h, in comparison to 1.6±0.6 h from free TTX. This approach could also be used to co-deliver the diol dexamethasone, which prolonged nerve block to 21.8±5.1 h. This work emphasized the usefulness of dynamic covalent chemistry for depot-type drug delivery systems with slow and effective drug release kinetics.

Comparative evaluation of two methods of prolonged femoral nerve block using an elastomeric pump after knee arthroplasty: a prospective randomized controlled study

BACKGROUND: The number of knee arthroplasty (KA) surgeries is increasing annually. These surgeries are associated with severe pain. The optimal method of choice in perioperative analgesia in these patients remains controversial. The use of regional analgesia, including prolonged analgesia, allows for high pain relief and increased patient satisfaction. Modern elastomeric pumps (EP) provide prolonged conduction analgesia, which significantly expands the possibilities of perioperative pain relief. OBJECTIVE: To evaluate the effectiveness of prolonged femoral nerve block using EP with and without bolus after KA. MATERIALS AND METHODS: This prospective randomized study included 75 patients who were divided into two clinical groups: group 1 (n=36), patients who received prolonged regional analgesia using EP with controlled injection without bolus, and group 2 (n=39), patients who received prolonged regional analgesia using EP with bolus. In the postoperative period, the level of pain at rest and during movement was assessed after 6, 12, 24, and 48 hours as well as the need for opioid analgesics, consumption of local anesthetic for various options of continued regional analgesia, quadriceps femoris muscle function, and distance traveled by patients after surgery in the first 2 days. RESULTS: No significant differences were noted in pain level at rest and during movement in the observation period between the groups (p=0.213). No additional prescription of opioid analgesics was required. Local anesthetic consumption was lower in group 2 (group 1.384±33.4 ml; group 2.237±25.1 ml; p=0.031). Patients in group 2 had greater activity in knee extension and, thus, greater distance traveled after surgery. CONCLUSION: The use of EP with a bolus has been demonstrated to provide adequate levels of analgesia and better functional recovery in patients with bolus after KA than in patients without bolus. This technique is recommended as a component of enhanced recovery program after surgery.

Targeted local anesthesia: a novel slow-release Fe3O4-lidocaine-PLGA microsphere endowed with a magnetic targeting function.

Lidocaine microspheres can prolong the analgesic time to 24-48h, which still cannot meet the need of postoperative analgesia lasting more than 3 days. Therefore, we added Fe3O4 to the lidocaine microspheres and used an applied magnetic field to attract Fe3O4 to fix the microspheres around the target nerves, reducing the diffusion of magnetic lidocaine microspheres to the surrounding tissues and prolonging the analgesic time. Fe3O4-lidocaine-PLGA microspheres were prepared by the complex-emulsion volatilization method to characterize and study the release properties in vitro. The neural anchoring properties and in vivo morphology of the drug were obtained by magnetic resonance imaging. The nerve blocking effect and analgesic effect of magnetic lidocaine microspheres were evaluated by animal experiments. The mean diameter of magnetically responsive lidocaine microspheres: 9.04±3.23μm. The encapsulation and drug loading of the microspheres were 46.18±3.26% and 6.02±1.87%, respectively. Magnetic resonance imaging showed good imaging of Fe3O4-Lidocain-PLGA microspheres, a drug-carrying model that slowed down the diffusion of the microspheres in the presence of an applied magnetic field. Animal experiments demonstrated that this preparation had a significantly prolonged nerve block, analgesic effect, and a nerve anchoring function. Magnetically responsive lidocaine microspheres can prolong analgesia by slowly releasing lidocaine, which can be immobilized around the nerve by a magnetic field on the body surface, avoiding premature diffusion of the microspheres to surrounding tissues and improving drug targeting.

Prolonged blockade of the sciatic nerve in the treatment of pain in patients with chronic limb-threatening ischemia: prospective longitudinal clinical study

BACKGROUND: Systemic multimodal analgesia does not always relieve ischemic pain, and the side effects of its components may be intolerable in patients with comorbid and physically debilitation with chronic limb-threatening ischemia (CLTI). An alternative effective and safe method of pain relief for patients with CLTI is needed.
 OBJECTIVE: To evaluate the efficacy and safety of prolonged popliteal sciatic nerve block in patients with CLTI at the stages of treatment.
 MATERIALS AND METHODS: A prospective clinical study was performed in 31 patients with CLTI. Pain intensity was assessed by a numerical rating scale at the stages of treatment: (1) on admission, (2) presence of systemic multimodal analgesia (paracetamol, ketoprofen, tramadol, and morphine), (3) after catheter insertion to the popliteal sciatic nerve and prolonged nerve block with 0.5% ropivacaine solution, (4) after revascularization without anesthesia, (5) after revascularization in the presence of nerve blockade, and (6) upon discharge. Catheter insertion was performed under ultrasound control and neurostimulation. Pain intensity, frequency of insomnia, and forced lowering of the limb, need for narcotic analgesics, and patient satisfaction with treatment were assessed.
 RESULTS: Regional block before surgery provided better pain relief than systemic multimodal analgesia (p 0.001) and reduced the need for narcotic analgesics (p 0.001). Insomnia was observed less frequently with prolonged blockade of the sciatic nerve than with systemic multimodal analgesia (p 0.05), as well as forced lowering of the limb (p 0.05). Revascularization of the lower extremity has an analgesic effect; however, pain relief is required for most patients. Pain relief through sciatic nerve block at all stages of CLTI treatment, sleep normalization, and freedom from forced posture improved the quality of life and satisfaction with treatment. No complications associated with the regional blockade were recorded.
 CONCLUSION: Prolonged popliteal sciatic nerve block effectively relieves pain in patients with CLTI, is safe, and can be an alternative to systemic anesthesia.

Light activated pulsatile drug delivery for prolonged peripheral nerve block

Regional anesthesia is widely used in peripheral nerve block and in neuraxial anesthesia to reduce anesthetics systemic side effects and shorten recovery times. However, when applied as a single injection (e.g., peripheral nerve block) it is limited by the duration of its effect. Herein, we develop a thermoresponsive nanogel based on poly(oligoethylene glycol methacrylate) containing the long-lasting anesthetic bupivacaine, which can be externally activated by using near-infrared light due to the photothermal properties of hollow gold nanoparticles embedded in the nanogel which facilitate its phase transition, triggering drug release at a controlled temperature above body temperature. Bupivacaine in vitro release can be repeatedly triggered to achieve a controlled pulsatile release of the drug due to the reversible nature of the thermosensitive nanogel, achieving a spatio-temporal control of the release. In vivo sciatic nerve block demonstrates that whereas the administered dose of free bupivacaine produces sensory block and impaired motor function for 2 h, the equivalent bupivacaine dose included in the developed release system can significantly prolong its neurobehavioral anesthetic effect for over 6 h. This release system can also be reactivated multiple times by subsequent irradiation cycles without observing detrimental toxicity in the infiltrated tissues.

Two clinical cases of unintentionally prolonged sciatic nerve block

This study describes two clinical cases of unexpectedly long duration of motor block after anterior sciatic nerve block. In two patients who underwent total knee replacement, the motor block reversion in the area of sciatic nerve innervation did not occur at the expected time. Ultrasound examination revealed the deposition of a local anesthetic near the sciatic nerve. In these two clinical cases, unintentionally prolonged sciatic nerve blockade was caused by combined age-related factors of reduced tissue perfusion and the vasoconstrictor properties of levobupivacaine. Subsequently, the block was successfully resolved in 3638 h without any neurological consequences.

Pharmacodynamics and Pharmacokinetics of Lidocaine in a Rodent Model of Diabetic Neuropathy.

Clinical and experimental data show that peripheral nerve blocks last longer in the presence of diabetic neuropathy. This may occur because diabetic nerve fibers are more sensitive to local anesthetics or because the local anesthetic concentration decreases more slowly in the diabetic nerve. The aim of this study was to investigate both hypotheses in a rodent model of neuropathy secondary to type 2 diabetes. We performed a series of sciatic nerve block experiments in 25 Zucker Diabetic Fatty rats aged 20 weeks with a neuropathy component confirmed by neurophysiology and control rats. We determined in vivo the minimum local anesthetic dose of lidocaine for sciatic nerve block. To investigate the pharmacokinetic hypothesis, we determined concentrations of radiolabeled (C) lidocaine up to 90 min after administration. Last, dorsal root ganglia were excised for patch clamp measurements of sodium channel activity. First, in vivo minimum local anesthetic dose of lidocaine for sciatic nerve motor block was significantly lower in diabetic (0.9%) as compared to control rats (1.4%). Second, at 60 min after nerve block, intraneural lidocaine was higher in the diabetic animals. Third, single cell measurements showed a lower inhibitory concentration of lidocaine for blocking sodium currents in neuropathic as compared to control neurons. We demonstrate increased sensitivity of the diabetic neuropathic nerve toward local anesthetics, and prolonged residence time of local anesthetics in the diabetic neuropathic nerve. In this rodent model of neuropathy, both pharmacodynamic and pharmacokinetic mechanisms contribute to prolonged nerve block duration.

The quaternary lidocaine derivative QX-314 in combination with bupivacaine for long-lasting nerve block: Efficacy, toxicity, and the optimal formulation in rats.

ObjectiveThe quaternary lidocaine derivative (QX-314) in combination with bupivacaine can produce long-lasting nerve blocks in vivo, indicating potential clinical application. The aim of the study was to investigate the efficacy, safety, and the optimal formulation of this combination.MethodsQX-314 and bupivacaine at different concentration ratios were injected in the vicinity of the sciatic nerve in rats; bupivacaine and saline served as controls (n = 6~10). Rats were inspected for durations of effective sensory and motor nerve blocks, systemic adverse effects, and histological changes of local tissues. Mathematical models were established to reveal drug-interaction, concentration-effect relationships, and the optimal ratio of QX-314 to bupivacaine.Results0.2~1.5% QX-314 with 0.03~0.5% bupivacaine produced 5.8~23.8 h of effective nerve block; while 0.5% bupivacaine alone was effective for 4 h. No systemic side effects were observed; local tissue reactions were similar to those caused by 0.5% bupivacaine if QX-314 were used < 1.2%. The weighted modification model was successfully established, which revealed that QX-314 was the main active ingredient while bupivacaine was the synergist. The formulation, 0.9% QX-314 plus 0.5% bupivacaine, resulted in 10.1 ± 0.8 h of effective sensory and motor nerve blocks.ConclusionThe combination of QX-314 and bupivacaine facilitated prolonged sciatic nerve block in rats with a satisfactory safety profile, maximizing the duration of nerve block without clinically important systemic and local tissue toxicity. It may emerge as an alternative approach to post-operative pain treatment.

Can neural blocks prevent phantom limb pain?

Phantom limb syndrome (PLS) is a syndrome including stump pain, phantom limb pain and not-painful phantom sensations, which involves a large part of amputee patients and often has devastating effects on their quality of life. The efficacy of standard therapies is very poor. Nerve blocks have been investigated for the treatment and prevention of PLS. Epidural and peripheral blocks limited to the first three postamputation days can only reduce acute pain but cannot prevent the later development of PLS. Recent studies have shown that ambulatory prolonged peripheral nerve block (up to 30 days postamputation) may represent a new possible option to treat phantom pain and prevent the development of PLS and chronic pain.

Comparison of dexmedetomidine and epinephrine as an adjuvant to 1% mepivacaine in brachial plexus block.

BackgroundDexmedetomidine extends the duration of nerve block when administered perineurally together with local anesthetics by central and/or peripheral action. In this study, we compared the duration of nerve block between dexmedetomidine and epinephrine as an adjuvant to 1% mepivacaine in infraclavicular brachial plexus block.Methods Thirty patients, scheduled for upper limb surgery were assigned randomly to 3 groups of 10 patients each. We performed brachial plexus block using a nerve stimulator. In the control group (group C), patients received 40 ml of 1% mepivacaine. In group E, patients received 40 ml of 1% mepivacaine containing 200 µg of epinephrine as an adjuvant. In group D, patients received 40 ml of 1% mepivacaine containing 1 µg/kg of dexmedetomidine as an adjuvant. Sensory block duration, motor block duration, time to sense pain, and onset time were assessed. We also monitored blood pressure, heart rate, oxygen saturation and bispectral index.ResultsIn group D and group E, sensory block duration, motor block duration and time to sense first pain were prolonged significantly compared to group C. However, there was no significant difference between group D and group E.ConclusionsPerineural 1 µg/kg of dexmedetomidine similarly prolonged nerve block duration compared to 200 µg of epinephrine, but slowed heart rate. Thus, dexmedetomidine is expected to be a good alternative as an adjuvant to local anesthesia in patients who are cautioned against epinephrine.

Prolonged Nerve Block by Microencapsulated Bupivacaine Prevents Acute Postoperative Pain in Rats

To minimize acute postoperative pain, a new formulation of slowly released bupivacaine was developed. Bupivacaine was microencapsulated at 60% (wt/wt) in poly-lactide-co-glycolide polymers and characterized for physicochemical properties and bupivacaine release kinetics. This formulation was injected around the rat sciatic nerve to produce an antinociceptive effect to toe pinch. Mechanical hyperalgesia following lateral plantar paw incision in rats was assessed for 7 to 14 days when the bupivacaine slow-release formulation was placed at the ipsilateral sciatic nerve and compared with the hyperalgesia that developed with various controls. Bupivacaine was released in vitro at a relatively constant rate over a period of ≈ 72 to 96 hours. Complete antinociception, shown as no response to toe pinch, lasted for 23 ± 7 hours, with a half-recovery time of 42 ± 8 hours after sciatic nerve injection of 0.4 mL of the microspheres delivering 34 mg of bupivacaine. Solutions of 0.5% (wt/vol) bupivacaine-HCl (0.1 mL) produced complete antinociception for less than 2 hours and recovery half-times of 2 hours. Postincisional mechanical hyperalgesia, shown by increased withdrawal responses to von Frey filaments, was absent for 24 hours and was lower than control for 96 hours, when the sciatic nerve was blocked by bupivacaine microspheres, whereas the 0.5% bupivacaine solution reduced postincisional pain for only 4 hours. Corresponding to its far greater functional blocking time, the microsphere-bupivacaine formulation was able to significantly reduce postoperative pain below control levels for up to 4 days. These findings of several days of postoperative pain relief, for an injectable formulation containing a single active agent, present an improved and potentially promising therapy to prevent acute pain after surgery.

Prolonged Cutaneous Analgesia With Transdermal Application of Amitriptyline and Capsaicin

Capsaicin selectively binds to TRPV1, the vanilloid subtype 1 of the superfamily of transient receptor potential ion channels, which is highly expressed in pain-transmitting C fibers. Recent reports have demonstrated that the coadministration of capsaicin with a local anesthetic (LA) at the rat sciatic nerve elicits a prolonged nociceptive-selective nerve block, suggesting that activation of the TRPV1 receptor may allow LAs to enter the nerve through the TRPV1 pore. In previous studies, we demonstrated that transdermal amitriptyline achieves clinical analgesic effects and is more potent than lidocaine. Here we examine whether the combined application of amitriptyline and capsaicin as a transdermal patch will produce prolonged cutaneous analgesia compared with amitriptyline alone. Male Sprague-Dawley rats (weights 250-300 g) were assigned to five treatment groups (n = 6-8 per group). Transdermal patches containing amitriptyline with different concentrations of capsaicin were applied for 3 hrs to rats' shaved backs: 2.5% amitriptyline alone (control group) and in combination with 0.05%, 0.15%, 1%, and 8% capsaicin. Behavioral testing for cutaneous nociception was conducted before drug application and after patch removal using the cutaneous trunci muscle reflex. In addition, skin appearance was assessed to determine irritation by these formulations. The cutaneous analgesic effect is significantly prolonged when amitriptyline is applied in combination with 8% capsaicin. Amitriptyline alone provided a complete block to pinprick for 4.5 hrs, and the time to full recovery was 96 hrs. Amitriptyline with 8% capsaicin produced a complete block to pinprick for 6 to 9 hrs, and the time to full recovery was 216 hrs (P = 0.002). Amitriptyline alone causes toxic effects in skin, whereas the higher the concentration of capsaicin, the less skin irritation was noted, and the combination of amitriptyline 2.5% with capsaicin 8% caused no adverse skin reactions. This study demonstrates that the combined application of amitriptyline and capsaicin results in prolonged cutaneous analgesia compared with amitriptyline alone, suggesting that the activation of the TRPV1 channel by capsaicin facilitates the passage of amitriptyline into nociceptors. This transdermal patch achieves far longer cutaneous analgesia than currently available patch applications such as EMLA cream. The mechanism that underlies the lesser skin irritation noted when amitriptyline is combined with higher doses of capsaicin compared with amitriptyline alone is unclear and may be related to a counteraction of amitriptyline-induced vasoconstriction.

Spinalanästhesie – Ambulante Spinalanästhesie – Neue Trends einer alten Technik

Day case surgery is becoming more and more important. In order to perform these services cost-efficiently it is of primary importance to ensure that procedures can be scheduled with the largest possible patient satisfaction. Up to now spinal anaesthesia was of little importance in day case surgery due to prolonged nerve block and negative side effects especially when using long acting local anaesthetics. Since prilocaine and 2-chloroprocaine, two short acting local anaesthetics with a known low incidence of side effects, were recently introduced into clinical practice a reevaluation of spinal anaesthesia in a day case setting according to EMB guidelines still has to be done.

Prolonged sensory-selective nerve blockade

Sensory-selective local anesthesia has long been a key goal in local anesthetic development. For example, it allows women to be pain-free during labor without compromising their ability to push. Here we show that prolonged sensory-selective nerve block can be produced by specific concentrations of surfactants-such as are used to enhance drug flux across skin-in combination with QX-314, a lidocaine derivative that has relative difficulty penetrating nerves. For example, injection of 25 mM QX-314 in 30 mM octyltrimethylammonium bromide (OTAB) lasted up to 7 h. Sensory selectivity was imparted to varying degrees by cationic, neutral, and anionic surfactants, and also was achieved with another lidocaine derivative, QX-222. Simultaneous injection of OTAB at a s.c. injection site remote from the sciatic nerve did not result in prolonged sensory-specific nerve blockade from QX-314, suggesting that the observed effect is due to a local interaction between the surfactant and the lidocaine derivative, not a systemic effect.

Somatic paravertebral block decreases opioid requirements in children undergoing appendectomy

Somatic paravertebral block (SPVB) appears to provide effective and prolonged nerve block in children; however, study of its use in this population is limited. We compared SPVB with no block in children undergoing appendectomy. Thirty-six children aged 3-16 yr undergoing open appendectomy were involved in this prospective randomized controlled study. Anesthesia was induced with propofol and maintained with isoflurane in N(2)O/oxygen. All subjects received fentanyl, acetaminophen and ketorolac during anesthesia. Group I (SPVB) subjects received a right SPVB at T(11), T(12), and L(1) using 0.2% ropivacaine 0.25 mL.kg(-1) with epinephrine 1:200,000 preoperatively. Group II (Control) had only bandaids applied to skin. Both groups were given morphine 0.05 mg.kg(-1) iv every 2 hr if pain scores reached 5/10 on a visual analogue scale. Acetaminophen was administered postoperatively every 6 hr to both groups. Time to first dose of morphine, total dose of morphine in 24 hr, and any adverse effects up to 24 hr after surgery were recorded. Group I (SPVB) subjects required significantly less morphine than Group II (Control) patients (0.12 +/- 0.07 vs 0.34 +/- 0.15 mg.kg(-1), respectively; P < 0.001), and time to their first dose was significantly longer (7.1 +/- 4.4 vs 2.5 +/- 1.6 hr, respectively; P < 0.001). Incidence of vomiting was 11% with Group I and 27% with Group II (P = 0.21). No other adverse effects were observed in either group. In children undergoing appendectomy, SPVB provides better pain relief than no block and reduces opioid requirements. Side effects were not statistically different between groups.

Calcium Chloride Prolongs the Effects of Lidocaine and Bupivacaine in Rat Sciatic Nerve

Elevated extracellular calcium ion has been shown to shift the voltage dependence of Na+- and K+-ion channels rightward, making the nerve less excitable. We hypothesized that calcium chloride (CaCl2) when used as an adjuvant prolongs and intensifies the block by local anesthetics (LAs). We investigated the effects of LAs combined with calcium in rat sciatic nerve blockade and in cultured rat GH3 cells expressing Na+ channels. Furthermore, we tested for histologic changes due to CaCl2. We anesthetized rats with sevoflurane, exposed the sciatic nerves, and injected 0.2 mL of 1% lidocaine or 0.1% bupivacaine, alone or coadministered with 0.625%, 1.25%, 2.5%, or 5% CaCl2 (n = 8-10 per group). We assessed the complete-block time and complete-recovery time of proprioception, motor function, and nocifensive reaction. To elucidate the mechanism of nerve block, we performed electrophysiology experiments in cultured rat GH3 cells. Sciatic nerves were harvested at day 7 and stained with hemotoxylin/eosin. The addition of CaCl2 overall prolonged the duration of blockade by lidocaine or bupivacaine. Adding 10 mM CaCl2 to 300 microM lidocaine caused a right shift of the steady-state Na+-channel inactivation curve, indicating that the CaCl2 reduced the potency of lidocaine. Rat sciatic nerves treated with 1% lidocaine coadministered with 5% CaCl2 showed microscopic signs of neurotoxicity. The mechanism of prolonged nerve block of CaCl2 coadministered with LAs seems to be a raised threshold for nerve excitation. Major histopathologic changes at higher concentrations of CaCl2 are evident, and therefore, clinical application as an adjuvant to LAs seems unlikely.

722. Effect of Prolonged Peripheral Nerve Block on Phantom Limb Syndrome: A Prospective Study in 46 Patients

722. Effect of Prolonged Peripheral Nerve Block on Phantom Limb Syndrome: A Prospective Study in 46 Patients

722: Effect of Prolonged Peripheral Nerve Block on Phantom Limb Syndrome: A Prospective Study in 46 Patients

722: Effect of Prolonged Peripheral Nerve Block on Phantom Limb Syndrome: A Prospective Study in 46 Patients

Effect of Prolonged Peripheral Nerve Block on Phantom Limb Syndrome: A Prospective Study in 46 Patients

Effect of Prolonged Peripheral Nerve Block on Phantom Limb Syndrome: A Prospective Study in 46 Patients

Tetrodotoxin for prolonged local anesthesia with minimal myotoxicity

Conventional local anesthetics such as bupivacaine cause considerable myotoxicity and neurotoxicity, whereas tetrodotoxin (TTX) does not. Tetrodotoxin combined with bupivacaine or vasoconstrictors produces long-duration nerve blockade. To assess whether these prolonged blocks can be produced without increased myotoxicity, Sprague-Dawley rats were injected with bupivacaine, TTX, and both, or TTX plus epinephrine. Median durations of thermal nociceptive blockade were, respectively, 188, 401, 882, and 972 min. On dissection 4 days later, all tissues appeared macroscopically pristine. Muscle injury was at most mild to moderate in all animals, and the muscle injury scores for the combination formulations were not higher than for bupivacaine alone. Similarly, in differentiated cells from a myoblast cell line (C2C12), TTX caused either no or minimal worsening of cell viability from bupivacaine at 2 or 7 days. Epinephrine did not worsen TTX's relatively minimal cytotoxicity. Tetrodotoxin may thus be useful in producing prolonged nerve block with minimal myotoxicity and perhaps neurotoxicity.