E Editorial
Developing Better Local Anesthetics Charles Berde, MD, PhD
S
ince the early reports of cocaine local anesthesia by Koller and Halsted 130 years ago, the local anesthetics used clinically have been almost entirely of 2 chemical classes: aminoesters and aminoamides. These 2 classes of local anesthetics differ in their predominant sites of metabolism, but they are otherwise very similar in their ranges of biological actions. Both bind to a site on voltage-gated sodium channels on the cytoplasmic side of the plasma membrane. Binding of local anesthetics changes the relative stability of resting, open and inactive channel conformations, reducing the fraction of channels capable of opening and conducting inward sodium currents, thereby leading to failure of impulse generation or propagation. In order for a candidate drug to be a useful local anesthetic, suitable receptor chemistry, that is, affinity and efficacy in blocking sodium channels (or other types of channels), is necessary but not sufficient. A candidate local anesthetic must also have suitable physical chemistry, that is, it must diffuse rapidly across a number of barriers (fascia, epineurium, perineurium, endoneurium, myelin, and Schwann cells) to gain access to binding sites on axonal sodium channels.1 For traditional local anesthetics, with binding sites on the cytoplasmic side of the plasma membrane, this physical-chemical requirement for membrane transit necessitates good solubility and rapid diffusion in both hydrophobic and hydrophilic microenvironments. Amphiphilicity is achieved via the presence of a tertiary amine group as a weak base, with pKas sufficiently close to physiologic pH. In this issue of Anesthesia & Analgesia, Banergee et al.2 report an initial preclinical study of a new drug, EN3247, from a chemical class known as a cationic aminoindane, developed to provide selective blockade of nociceptive transmission. Their work follows on an approach pioneered by several groups showing that a membrane-impermeant cationic lidocaine derivative, QX-314,3 could be targeted for selective membrane permeation into small sensory fibers.4,5 Transient receptor potential (TRP) channels are From the Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children’s Hospital; and Department of Anaesthesia, Harvard Medical School, Boston, Massachusetts. Accepted for publication December 5, 2014. Funding: Sara Page Mayo Endowment for Pediatric Pain Research and Treatment and the Boston Children’s Hospital Technology Development Fund. Conflicts of Interest: See Disclosures at the end of the article. Reprints will not be available from the author. Address correspondence to Charles Berde, MD, PhD, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children’s Hospital, 300 Longwood Ave., Boston, MA 02115. Address e-mail to charles.berde@ childrens.harvard.edu. Copyright © 2015 International Anesthesia Research Society DOI: 10.1213/ANE.0000000000000628
718 www.anesthesia-analgesia.org
located predominantly in nociceptive C and A-delta fibers. Opening of TRP channels permits transmembrane flux of a wide range of cations, including QX-314. By combining QX-314 with vanilloids, a class of TRP channel-opening drugs, previous investigators achieved nociceptive-selective local anesthesia.4 Subsequent work showed that lidocaine and other traditional local anesthetics could also open TRP channels and could substitute for vanilloids in facilitating selective entry of QX-314 into nociceptive fibers.5 In vitro high-throughput screening led to selection of EN3247 as a promising candidate for producing prolonged duration nociceptive-selective local anesthesia. Currently available aminoamides and aminoesters are not optimized from the standpoint of efficacy/clinical effectiveness. Motor block and autonomic block complicate the use of epidural analgesia for labor.6 For peripheral nerve blocks involving mixed sensory-motor nerves for postoperative pain, modifications in technique such as adductor canal block instead of femoral block for knee surgery may reduce, but not entirely eliminate, motor impairments7; nevertheless, complete avoidance of motor and proprioceptive impairment is a desirable goal for facilitation of early ambulation. Single-shot peripheral blocks and wound infiltration are useful techniques for postoperative analgesia, but the duration of currently available local anesthetics is too short for covering the expected time course of postoperative pain for many types of surgery. Perineural/plexus and wound catheter infusions can extend the duration of analgesia, and they can permit titrated dosing. Conversely, catheters are sometimes more cumbersome to place compared with single-shot blocks, they can dislodge, they require tethering the patient to a pump, and the pattern of drug spread through a tissue plane on a continuous infusion often differs greatly from the extent of spread of an initial injectate. Controlled release of bupivacaine and other aminoamides from microparticles, liposomes, and other delivery systems has been studied for many years, and one formulation, Exparel®, has come onto the market in the United States, with a currently approved indication for infiltration analgesia only. Liposomal bupivacaine formulations have shown significant variability in efficacy/ clinical effectiveness in volunteer studies8 and clinical trials.9,10 Using rat sciatic blockade, Banergee et al. found that lidocaine-EN3247 combinations showed a very impressive separation of duration of nocifensive block (partial block ranging from 11 hours to several days, depending on concentrations) versus motor block (near complete recovery within 4 hours). In general, block durations in rats are much shorter than analogous block durations in humans. April 2015 • Volume 120 • Number 4
Developing New Local Anesthetics
Thus, based on these findings in rat sciatic nerve, achieving a goal of several days of selective sensory block for infiltration or peripheral nerve block in humans would seem likely. Factors governing drug uptake and distribution for epidural and spinal anesthesia differ from peripheral injection, and separate preclinical studies are needed to define potential neuraxial uses for this new compound. It is plausible that the degree of cephalad spread and time course of action in cerebrospinal fluid of a hydrophilic, cationic local anesthetic such as EN3247 would be considerably different from that of existing tertiary amine local anesthetics. (Consider, e.g., the differing actions of intrathecal morphine, baclofen, and lidocaine.) Currently available local anesthetics are high-risk drugs. For bupivacaine, injection of twice the maximum recommended dose in an intended extravascular location or roughly 30% of the maximum recommended dose via unintended intravascular injection can produce life-threatening cardiotoxicity or seizures. Ropivacaine and levobupivacaine offer only modest improvements in therapeutic index. Cardiotoxicity of existing local anesthetics involves blockade of a specific sodium channel subtype Nav 1.5 found in cardiac myocytes, as well as actions on a number of other non-sodium channel targets. Reduced cardiotoxicity is an attractive feature of the site 1 sodium channel blockers,11 another new class of local anesthetics under clinical development. Studies on systemic toxicity are needed to further define the systemic therapeutic index for EN3247, both alone and in combination with lidocaine. Such studies should be performed using both extravascular and intravascular injection models. A cationic local anesthetic such as EN3247 would be expected to show little entry into cardiac myocytes and very slight transit across the blood-brain barrier, but this must be demonstrated in future toxicologic studies not just assumed. Aminoamides and aminoesters also produce local tissue toxicities to muscle and nerve that are concentration and time dependent.12 Local anesthetic tissue toxicities probably reflect a range of cellular actions aside from sodium channel blockade. Blockade of sodium channels per se is not inevitably cytotoxic because site 1 sodium channel blockers appear devoid of myotoxicity and neurotoxicity.12,13 Banergee and coworkers found that EN3247 produces myotoxicity and neurotoxicity in higher concentrations. While they have identified a concentration range in the rat that does not seem to produce irreversible loss of function, it remains to be determined how this type of tissue toxicity will impact clinical development. One could argue that neurotoxicity confined to small fibers might therefore be less clinically important compared with neurotoxicity from existing local anesthetics that can affect motor and light touch fibers. In highly selected patients with chronic pain or in palliative care, selective small fiber neurotoxicity could conceivably be a desirable therapeutic aim for producing prolonged analgesia. However, there is a theoretical concern that a selective small fiber lesion could generate new forms of neuropathic pain, dysesthesia, or even refractory itching. In patients with disease states that jeopardize nerve integrity or nerve blood flow, there might be a potential for increased vulnerability to a neurotoxic drug at concentrations that would not pose risks for healthy patients.
April 2015 • Volume 120 • Number 4
Table 1. Desirable Features of New Local Anesthetics Selective block of nociceptive fibers Prolonged duration
Improved systemic safety Improved local tissue safety
For surgical anesthesia No
For analgesia Yes
No (or at least with motor and proprioceptive recovery within 8 hours) Yes
Yes
Yes
Yes
Yes
While a nocifensive-selective local anesthetic would seem ideal for postoperative analgesia and labor analgesia, how would it be experienced as a surgical local anesthetic in awake or lightly sedated patients? (This evokes memories of residency, with attending physicians saying to patients “it’s just pressure, right?”) By administering EN3247 in combination with lidocaine, there is the attractive possibility that complete block of all nerve fibers for surgical anesthesia is achieved over a suitable time frame for surgery, with selective block of nociception over a much longer timeframe for postoperative analgesia (Table 1). Banergee et al. examined the impact of a wide range of concentrations of both lidocaine and EN3247 on the characteristics and time course of rat sciatic block. Similar studies would be needed in a range of human studies to predict the median duration and degree of variability of nonselective versus nociceptiveselective block using a range of injection sites. Regional anesthesia is currently undergoing a revolution. The importance of opioid-sparing approaches14 that permit rapid recovery, early mobilization, and acute rehabilitation after surgery is well established, and local anesthetics for infiltration and peripheral nerve blockade are key elements of an opioid-sparing multimodal approach to postoperative pain management and acute rehabilitation. Improvements in ultrasound guidance are ongoing, if not quite at a “Moore’s law” pace, and hold the promise that block failures due to needle malpositioning should become increasingly less common. I would argue that advances in regional anesthesia are now more limited by the pharmacology of existing local anesthetics than by technical barriers to optimal needle positioning. Better drugs having a range of features outlined in Table 1 could have an enormously positive impact on patient comfort, perioperative outcomes, including rehabilitation, and on the progression from acute to chronic pain. Compared with the 1980s and 1990s, the rate of introduction of new drugs in the field of anesthesiology as a whole has declined dramatically. Among analgesics (especially opioids), a high percentage of recent new approvals by the Food and Drug Administration involve old chemical entities in new delivery vehicles. In this context, it is therefore extremely heartening to see creative work sponsored by a major pharmaceutical company toward developing a new chemical entity as a local anesthetic. While more work needs to be done before proceeding into clinical trials, Banergee et al. are to be commended for taking a very promising and innovative step toward developing a better local anesthetic. E
www.anesthesia-analgesia.org
719
E EDITORIAL DISCLOSURES
Name: Charles Berde, MD, PhD. Contribution: This author conceived and wrote this editorial. Attestation: Charles Berde attests to the content of this editorial. Conflicts of Interest: Dr. Berde and his coinventors (Dr. Daniel Kohane, Dr. Gary Strichartz, Dr. Robert Langer) hold issued patents on multiple approaches to prolonged duration local anesthesia. He is the holder of an investigator-initiated Investigational New Drug (IND) application for clinical development of a site 1 sodium channel blocker, neosaxitoxin, as a prolonged duration local anesthetic. In the event of future commercial development, Dr. Berde, his coinventors, and Boston Children’s Hospital could potentially receive royalties. He has consulted to CVSHealth on opioid safety and to Cubist on design of a pediatric trial of an opioid antagonist. This manuscript was handled by: Jianren Mao, MD, PhD. REFERENCES 1. Hille B. Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J Gen Physiol 1977;69:497–515 2. Banergee M, Baranwal A, Saha S, Saha A, Priestley T. EN3427: a novel cationic aminoindane with long-acting local anesthetic properties. Anesth Analg 2015;120:941–9 3. Strichartz GR. The inhibition of sodium currents in myelinated nerve by quaternary derivatives of lidocaine. J Gen Physiol 1973;62:37–57 4. Binshtok AM, Bean BP, Woolf CJ. Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature 2007;449:607–10 5. Binshtok AM, Gerner P, Oh SB, Puopolo M, Suzuki S, Roberson DP, Herbert T, Wang CF, Kim D, Chung G, Mitani AA, Wang GK,
720 www.anesthesia-analgesia.org
Bean BP, Woolf CJ. Coapplication of lidocaine and the permanently charged sodium channel blocker QX-314 produces a long-lasting nociceptive blockade in rodents. Anesthesiology 2009;111:127–37 6. Jones L, Othman M, Dowswell T, Alfirevic Z, Gates S, Newburn M, Jordan S, Lavender T, Neilson JP. Pain management for women in labour: an overview of systematic reviews (Review). Cochrane Library Database Syst Rev 2012;3:CD009234 7. Jenstrup MT, Jæger P, Lund J, Fomsgaard JS, Bache S, Mathiesen O, Larsen TK, Dahl JB. Effects of adductor-canal-blockade on pain and ambulation after total knee arthroplasty: a randomized study. Acta Anaesthesiol Scand 2012;56:357–64 8. Ilfeld BM, Malhotra N, Furnish TJ, Donohue MC, Madison SJ. Liposomal bupivacaine as a single-injection peripheral nerve block: a dose-response study. Anesth Analg 2013;117:1248–56 9. Bupivacaine Liposome Injectable Suspension (EXPAREL®) National Drug Monograph VA Pharmacy Benefits Management Service. June 2013. Available at www.pbm.va.gov. Accessed November 29, 2014 10. Bagsby DT, Ireland PH, Meneghini RM. Liposomal bupivacaine versus traditional periarticular injection for pain control after total knee arthroplasty. J Arthroplasty 2014;29:1687–90 11. Wylie MC, Johnson VM, Carpino E, Mullen K, Hauser K, Nedder A, Kheir JN, Rodriguez-Navarro AJ, Zurakowski D, Berde CB. Respiratory, neuromuscular, and cardiovascular effects of neosaxitoxin in isoflurane-anesthetized sheep. Reg Anesth Pain Med 2012;37:152–8 12. Epstein-Barash H, Shichor I, Kwon AH, Hall S, Lawlor MW, Langer R, Kohane DS. Prolonged duration local anesthesia with minimal toxicity. Proc Natl Acad Sci U S A 2009;106:7125–30 13. Sakura S, Bollen AW, Ciriales R, Drasner K. Local anesthetic neurotoxicity does not result from blockade of voltage-gated sodium channels. Anesth Analg 1995;81:338–46 14. Kehlet H. Postoperative opioid sparing to hasten recovery: what are the issues? Anesthesiology 2005;102:1083–5
anesthesia & analgesia
Developing Better Local Anesthetics Charles Berde, MD, PhD
S
ince the early reports of cocaine local anesthesia by Koller and Halsted 130 years ago, the local anesthetics used clinically have been almost entirely of 2 chemical classes: aminoesters and aminoamides. These 2 classes of local anesthetics differ in their predominant sites of metabolism, but they are otherwise very similar in their ranges of biological actions. Both bind to a site on voltage-gated sodium channels on the cytoplasmic side of the plasma membrane. Binding of local anesthetics changes the relative stability of resting, open and inactive channel conformations, reducing the fraction of channels capable of opening and conducting inward sodium currents, thereby leading to failure of impulse generation or propagation. In order for a candidate drug to be a useful local anesthetic, suitable receptor chemistry, that is, affinity and efficacy in blocking sodium channels (or other types of channels), is necessary but not sufficient. A candidate local anesthetic must also have suitable physical chemistry, that is, it must diffuse rapidly across a number of barriers (fascia, epineurium, perineurium, endoneurium, myelin, and Schwann cells) to gain access to binding sites on axonal sodium channels.1 For traditional local anesthetics, with binding sites on the cytoplasmic side of the plasma membrane, this physical-chemical requirement for membrane transit necessitates good solubility and rapid diffusion in both hydrophobic and hydrophilic microenvironments. Amphiphilicity is achieved via the presence of a tertiary amine group as a weak base, with pKas sufficiently close to physiologic pH. In this issue of Anesthesia & Analgesia, Banergee et al.2 report an initial preclinical study of a new drug, EN3247, from a chemical class known as a cationic aminoindane, developed to provide selective blockade of nociceptive transmission. Their work follows on an approach pioneered by several groups showing that a membrane-impermeant cationic lidocaine derivative, QX-314,3 could be targeted for selective membrane permeation into small sensory fibers.4,5 Transient receptor potential (TRP) channels are From the Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children’s Hospital; and Department of Anaesthesia, Harvard Medical School, Boston, Massachusetts. Accepted for publication December 5, 2014. Funding: Sara Page Mayo Endowment for Pediatric Pain Research and Treatment and the Boston Children’s Hospital Technology Development Fund. Conflicts of Interest: See Disclosures at the end of the article. Reprints will not be available from the author. Address correspondence to Charles Berde, MD, PhD, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children’s Hospital, 300 Longwood Ave., Boston, MA 02115. Address e-mail to charles.berde@ childrens.harvard.edu. Copyright © 2015 International Anesthesia Research Society DOI: 10.1213/ANE.0000000000000628
718 www.anesthesia-analgesia.org
located predominantly in nociceptive C and A-delta fibers. Opening of TRP channels permits transmembrane flux of a wide range of cations, including QX-314. By combining QX-314 with vanilloids, a class of TRP channel-opening drugs, previous investigators achieved nociceptive-selective local anesthesia.4 Subsequent work showed that lidocaine and other traditional local anesthetics could also open TRP channels and could substitute for vanilloids in facilitating selective entry of QX-314 into nociceptive fibers.5 In vitro high-throughput screening led to selection of EN3247 as a promising candidate for producing prolonged duration nociceptive-selective local anesthesia. Currently available aminoamides and aminoesters are not optimized from the standpoint of efficacy/clinical effectiveness. Motor block and autonomic block complicate the use of epidural analgesia for labor.6 For peripheral nerve blocks involving mixed sensory-motor nerves for postoperative pain, modifications in technique such as adductor canal block instead of femoral block for knee surgery may reduce, but not entirely eliminate, motor impairments7; nevertheless, complete avoidance of motor and proprioceptive impairment is a desirable goal for facilitation of early ambulation. Single-shot peripheral blocks and wound infiltration are useful techniques for postoperative analgesia, but the duration of currently available local anesthetics is too short for covering the expected time course of postoperative pain for many types of surgery. Perineural/plexus and wound catheter infusions can extend the duration of analgesia, and they can permit titrated dosing. Conversely, catheters are sometimes more cumbersome to place compared with single-shot blocks, they can dislodge, they require tethering the patient to a pump, and the pattern of drug spread through a tissue plane on a continuous infusion often differs greatly from the extent of spread of an initial injectate. Controlled release of bupivacaine and other aminoamides from microparticles, liposomes, and other delivery systems has been studied for many years, and one formulation, Exparel®, has come onto the market in the United States, with a currently approved indication for infiltration analgesia only. Liposomal bupivacaine formulations have shown significant variability in efficacy/ clinical effectiveness in volunteer studies8 and clinical trials.9,10 Using rat sciatic blockade, Banergee et al. found that lidocaine-EN3247 combinations showed a very impressive separation of duration of nocifensive block (partial block ranging from 11 hours to several days, depending on concentrations) versus motor block (near complete recovery within 4 hours). In general, block durations in rats are much shorter than analogous block durations in humans. April 2015 • Volume 120 • Number 4
Developing New Local Anesthetics
Thus, based on these findings in rat sciatic nerve, achieving a goal of several days of selective sensory block for infiltration or peripheral nerve block in humans would seem likely. Factors governing drug uptake and distribution for epidural and spinal anesthesia differ from peripheral injection, and separate preclinical studies are needed to define potential neuraxial uses for this new compound. It is plausible that the degree of cephalad spread and time course of action in cerebrospinal fluid of a hydrophilic, cationic local anesthetic such as EN3247 would be considerably different from that of existing tertiary amine local anesthetics. (Consider, e.g., the differing actions of intrathecal morphine, baclofen, and lidocaine.) Currently available local anesthetics are high-risk drugs. For bupivacaine, injection of twice the maximum recommended dose in an intended extravascular location or roughly 30% of the maximum recommended dose via unintended intravascular injection can produce life-threatening cardiotoxicity or seizures. Ropivacaine and levobupivacaine offer only modest improvements in therapeutic index. Cardiotoxicity of existing local anesthetics involves blockade of a specific sodium channel subtype Nav 1.5 found in cardiac myocytes, as well as actions on a number of other non-sodium channel targets. Reduced cardiotoxicity is an attractive feature of the site 1 sodium channel blockers,11 another new class of local anesthetics under clinical development. Studies on systemic toxicity are needed to further define the systemic therapeutic index for EN3247, both alone and in combination with lidocaine. Such studies should be performed using both extravascular and intravascular injection models. A cationic local anesthetic such as EN3247 would be expected to show little entry into cardiac myocytes and very slight transit across the blood-brain barrier, but this must be demonstrated in future toxicologic studies not just assumed. Aminoamides and aminoesters also produce local tissue toxicities to muscle and nerve that are concentration and time dependent.12 Local anesthetic tissue toxicities probably reflect a range of cellular actions aside from sodium channel blockade. Blockade of sodium channels per se is not inevitably cytotoxic because site 1 sodium channel blockers appear devoid of myotoxicity and neurotoxicity.12,13 Banergee and coworkers found that EN3247 produces myotoxicity and neurotoxicity in higher concentrations. While they have identified a concentration range in the rat that does not seem to produce irreversible loss of function, it remains to be determined how this type of tissue toxicity will impact clinical development. One could argue that neurotoxicity confined to small fibers might therefore be less clinically important compared with neurotoxicity from existing local anesthetics that can affect motor and light touch fibers. In highly selected patients with chronic pain or in palliative care, selective small fiber neurotoxicity could conceivably be a desirable therapeutic aim for producing prolonged analgesia. However, there is a theoretical concern that a selective small fiber lesion could generate new forms of neuropathic pain, dysesthesia, or even refractory itching. In patients with disease states that jeopardize nerve integrity or nerve blood flow, there might be a potential for increased vulnerability to a neurotoxic drug at concentrations that would not pose risks for healthy patients.
April 2015 • Volume 120 • Number 4
Table 1. Desirable Features of New Local Anesthetics Selective block of nociceptive fibers Prolonged duration
Improved systemic safety Improved local tissue safety
For surgical anesthesia No
For analgesia Yes
No (or at least with motor and proprioceptive recovery within 8 hours) Yes
Yes
Yes
Yes
Yes
While a nocifensive-selective local anesthetic would seem ideal for postoperative analgesia and labor analgesia, how would it be experienced as a surgical local anesthetic in awake or lightly sedated patients? (This evokes memories of residency, with attending physicians saying to patients “it’s just pressure, right?”) By administering EN3247 in combination with lidocaine, there is the attractive possibility that complete block of all nerve fibers for surgical anesthesia is achieved over a suitable time frame for surgery, with selective block of nociception over a much longer timeframe for postoperative analgesia (Table 1). Banergee et al. examined the impact of a wide range of concentrations of both lidocaine and EN3247 on the characteristics and time course of rat sciatic block. Similar studies would be needed in a range of human studies to predict the median duration and degree of variability of nonselective versus nociceptiveselective block using a range of injection sites. Regional anesthesia is currently undergoing a revolution. The importance of opioid-sparing approaches14 that permit rapid recovery, early mobilization, and acute rehabilitation after surgery is well established, and local anesthetics for infiltration and peripheral nerve blockade are key elements of an opioid-sparing multimodal approach to postoperative pain management and acute rehabilitation. Improvements in ultrasound guidance are ongoing, if not quite at a “Moore’s law” pace, and hold the promise that block failures due to needle malpositioning should become increasingly less common. I would argue that advances in regional anesthesia are now more limited by the pharmacology of existing local anesthetics than by technical barriers to optimal needle positioning. Better drugs having a range of features outlined in Table 1 could have an enormously positive impact on patient comfort, perioperative outcomes, including rehabilitation, and on the progression from acute to chronic pain. Compared with the 1980s and 1990s, the rate of introduction of new drugs in the field of anesthesiology as a whole has declined dramatically. Among analgesics (especially opioids), a high percentage of recent new approvals by the Food and Drug Administration involve old chemical entities in new delivery vehicles. In this context, it is therefore extremely heartening to see creative work sponsored by a major pharmaceutical company toward developing a new chemical entity as a local anesthetic. While more work needs to be done before proceeding into clinical trials, Banergee et al. are to be commended for taking a very promising and innovative step toward developing a better local anesthetic. E
www.anesthesia-analgesia.org
719
E EDITORIAL DISCLOSURES
Name: Charles Berde, MD, PhD. Contribution: This author conceived and wrote this editorial. Attestation: Charles Berde attests to the content of this editorial. Conflicts of Interest: Dr. Berde and his coinventors (Dr. Daniel Kohane, Dr. Gary Strichartz, Dr. Robert Langer) hold issued patents on multiple approaches to prolonged duration local anesthesia. He is the holder of an investigator-initiated Investigational New Drug (IND) application for clinical development of a site 1 sodium channel blocker, neosaxitoxin, as a prolonged duration local anesthetic. In the event of future commercial development, Dr. Berde, his coinventors, and Boston Children’s Hospital could potentially receive royalties. He has consulted to CVSHealth on opioid safety and to Cubist on design of a pediatric trial of an opioid antagonist. This manuscript was handled by: Jianren Mao, MD, PhD. REFERENCES 1. Hille B. Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J Gen Physiol 1977;69:497–515 2. Banergee M, Baranwal A, Saha S, Saha A, Priestley T. EN3427: a novel cationic aminoindane with long-acting local anesthetic properties. Anesth Analg 2015;120:941–9 3. Strichartz GR. The inhibition of sodium currents in myelinated nerve by quaternary derivatives of lidocaine. J Gen Physiol 1973;62:37–57 4. Binshtok AM, Bean BP, Woolf CJ. Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature 2007;449:607–10 5. Binshtok AM, Gerner P, Oh SB, Puopolo M, Suzuki S, Roberson DP, Herbert T, Wang CF, Kim D, Chung G, Mitani AA, Wang GK,
720 www.anesthesia-analgesia.org
Bean BP, Woolf CJ. Coapplication of lidocaine and the permanently charged sodium channel blocker QX-314 produces a long-lasting nociceptive blockade in rodents. Anesthesiology 2009;111:127–37 6. Jones L, Othman M, Dowswell T, Alfirevic Z, Gates S, Newburn M, Jordan S, Lavender T, Neilson JP. Pain management for women in labour: an overview of systematic reviews (Review). Cochrane Library Database Syst Rev 2012;3:CD009234 7. Jenstrup MT, Jæger P, Lund J, Fomsgaard JS, Bache S, Mathiesen O, Larsen TK, Dahl JB. Effects of adductor-canal-blockade on pain and ambulation after total knee arthroplasty: a randomized study. Acta Anaesthesiol Scand 2012;56:357–64 8. Ilfeld BM, Malhotra N, Furnish TJ, Donohue MC, Madison SJ. Liposomal bupivacaine as a single-injection peripheral nerve block: a dose-response study. Anesth Analg 2013;117:1248–56 9. Bupivacaine Liposome Injectable Suspension (EXPAREL®) National Drug Monograph VA Pharmacy Benefits Management Service. June 2013. Available at www.pbm.va.gov. Accessed November 29, 2014 10. Bagsby DT, Ireland PH, Meneghini RM. Liposomal bupivacaine versus traditional periarticular injection for pain control after total knee arthroplasty. J Arthroplasty 2014;29:1687–90 11. Wylie MC, Johnson VM, Carpino E, Mullen K, Hauser K, Nedder A, Kheir JN, Rodriguez-Navarro AJ, Zurakowski D, Berde CB. Respiratory, neuromuscular, and cardiovascular effects of neosaxitoxin in isoflurane-anesthetized sheep. Reg Anesth Pain Med 2012;37:152–8 12. Epstein-Barash H, Shichor I, Kwon AH, Hall S, Lawlor MW, Langer R, Kohane DS. Prolonged duration local anesthesia with minimal toxicity. Proc Natl Acad Sci U S A 2009;106:7125–30 13. Sakura S, Bollen AW, Ciriales R, Drasner K. Local anesthetic neurotoxicity does not result from blockade of voltage-gated sodium channels. Anesth Analg 1995;81:338–46 14. Kehlet H. Postoperative opioid sparing to hasten recovery: what are the issues? Anesthesiology 2005;102:1083–5
anesthesia & analgesia
