Legal Considerations of Local Anesthetics in Dental Procedures PDF

394 PART IV Complications, Legal Considerations, Questions, and the Future 137. Rhidian R, Greatorex B. Chest pain in the recovery room, following topical intranasal cocaine solution use. BMJ Rep. 2015. https://doi.org/10.1136/bcr-2015-209698. 138. Latorre F, Klimek L. Does cocaine still have a ro...

394 PART IV Complications, Legal Considerations, Questions, and the Future 137. Rhidian R, Greatorex B. Chest pain in the recovery room, following topical intranasal cocaine solution use. BMJ Rep. 2015. https://doi.org/10.1136/bcr-2015-209698. 138. Latorre F, Klimek L. Does cocaine still have a role in nasal surgery? Drug Saf. 1999;20:9–13. 139. Lachanas VA, Karatzias GT, Pinakas VG, Hatziioannou JK, Sandris VG. The use of tetracaine 0.25% solution in nasal packing removal. Am J Rhinol. 2006;20:483–484. 140. Madineh H, Amani S, Kabiri M, Karimi B. Evaluation of the anesthetic effect of nasal mucosa with tetracaine 0.5% on hemodynamic changes and postoperative pain of septoplasty: a randomized controlled trial. J Adv Pharm Technol Res. 2017;8:116–119. 141. Noorily AD, Noorily SH, Otto RA. Cocaine, lidocaine, tetracaine: which is best for topical nasal anesthesia? Anesth Analg. 1995;81:724–727. 142. Srisawat C, Nakponetong K, Benjasupattananun P, et al. A preliminary study of intranasal epinephrine administration as a potential route for anaphylaxis treatment. Asian Pac J Allergy Immunol. 2016;34:38–43. 143. Higgins TS, Hwang PH, Kingdom TT, et al. Systematic review of topical vasoconstrictors in endoscopic sinus surgery. Laryngoscope. 2011;121:422–432. 144. Giannakopoulos H, Levin LM, Chou JC, et al. The cardiovascular effects and pharmacokinetics of intranasal tetracaine plus oxymetazoline: preliminary findings. J Am Dent Assoc. 2012;143:872–880. 145. Ciancio SG, Hutcheson MC, Ayoub F, et al. Safety and efficacy of a novel nasal spray for maxillary dental anesthesia. J Dent Res. 2013;92(suppl 7):43S–48S. 146. Ciancio SG, Marberger AD, Ayoub F, et al. Comparison of 3 intranasal mists for anesthetizing maxillary teeth in adults: a randomized, double-masked, multicenter phase 3 clinical trial. J Am Dent Assoc. 2016;147:339–347. 147. Hersh EV, Pinto A, Saraghi M, et al. Double-masked, randomized, placebo-controlled study to evaluate efficacy and tolerability of intranasal K-305 (3% tetracaine plus 0.05% oxymetazoline) in anesthetizing maxillary teeth. J Am Dent Assoc. 2016;147:278–287. 148. Evans GD, Yiming L. A phase 3, multi-center, randomized, double-blind, parallel-groups clinical trial comparing the efficacy and safety of intranasally administered K-305 to placebo for anesthetizing maxillary teeth in pediatric patients. 2016. Available at: https:// www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/D evelopmentResources/UCM513665.pdf. Accessed June 6, 2018. 21 Future Trends in Pain Control Although local anesthesia remains the backbone of pain control techniques in dentistry, research continues in both medicine and dentistry with the goal of improving all areas of the local anesthetic experience, from that of the administrator to that of the patient. Much of this research has focused on improvements in the area of local anesthesia—safer needles and syringes; more successful techniques of regional nerve block, such as the anterior middle superior alveolar and palatal anterior superior alveolar nerve blocks (see Chapter 13); and newer drugs, such as articaine hydrochloride. These advances have been discussed in some depth in previous editions of this book and in preceding chapters of this edition: intraosseous anesthesia (see Chapter 15); self-aspirating, pressure, and safety syringes and computer-controlled local anesthetic delivery systems (see Chapter 5); and articaine hydrochloride (see Chapters 4 and 19). These drugs, devices, and techniques have become a part of the mainstream of pain control in the United States and elsewhere. Additionally, phentolamine mesylate (the local anesthesia “off switch”), buffered local anesthetic solutions (the local anesthetic “on switch”) and the tetracaine plus oxymetazoline nasal spray for pulpal anesthesia of maxillary nonmolar teeth (see Chapter 19) have become important adjuncts to the pain control armamentarium in dentistry. Some items discussed in previous editions have not progressed into the dental mainstream: the local anesthetics centbucridine and ropivacaine; the topical anesthetic EMLA (eutectic mixture of local anesthetics); and the technique of electronic dental anesthesia. The reader interested in these items is referred to the fifth edition of this textbook.1 In this chapter we will look at two areas of current local anesthetic research: (1) the search for longer-acting local anesthetics for postsurgical pain management; and (2) a light-activated, light-inactivated local anesthesia—the ability to provide site-specific anesthesia of any desired duration. Longer- and Ultra-Long-Acting Local Anesthetics The most commonly used local anesthetics in dentistry— articaine, lidocaine, mepivacaine, and prilocaine—when combined with a vasoconstrictor such as epinephrine provide pulpal anesthesia of approximately 60 minutes’ duration, with soft tissue anesthesia persisting for approximately 3 to 5 hours. In virtually all instances these drug formulations provide the patient with pain control adequate to receive the dental care—surgical or nonsurgical—painlessly. The aforementioned drugs are also those most frequently used for perioperative pain control during dental surgical procedures such as exodontia, osseous surgery, periodontal surgery, and endodontic procedures, as the duration of the surgical procedure commonly falls within the expected duration of pulpal anesthesia for these drugs. The requirement for postsurgical pain control, however, is somewhat more problematic. In Chapter 16 a pain control regimen for dental surgery patients was described (Box 16.7). It recommends the administration of the longacting local anesthetic bupivacaine (0.5%) with epinephrine (1:200,000), by nerve block, at the completion of the surgical procedure. In combination with timed doses (by the clock) of an appropriate nonsteroidal antiinflammatory drug (e.g., ibuprofen, 600 to 800 mg) virtually all postsurgical pain can be eliminated or minimized. However, following some surgical procedures, primarily in medicine, but occasionally in dentistry, the need for pain control can extend for many days. This need, and the realization that we (in the United States) are in the midst of an “opioid epidemic” (opioid abuse and misuse)2,3 has fostered research into longer- and ultra-long-acting local anesthetics. Three areas will be presented: (1) naturally occurring site-1 selective sodium channel blockers, (2) new local anesthetic delivery systems, and (3) novel adjuvants of local anesthetics. Naturally Occurring Site-1 Selective Sodium Channel Blockers Tetrodotoxin (TTX), saxitoxin (STX), and neosaxitoxin (NeoSTX) are selective sodium channel blockers that are naturally produced by animals such as the pufferfish (TTX) and shellfish (STX). All are potent neurotoxins commonly known as paralytic shellfish toxins. TTX was “discovered” in 1964 by Narahashi and Moore.4 Although found primarily in pufferfish5 (Fig. 21.1), TTX is also found in certain angelfish,6 octopi,7 cuttlefish, and other sea life. 395 396 PART IV Complications, Legal Considerations, Questions, and the Future A • Fig. 21.1 Pufferfish-tetrodotoxin. (From Gupta PK: Illustrated toxicology, San Diego, 2018, Elsevier.) B • Fig. 21.3 • Fig. 21.2 Red tide-saxitoxin. (© iStock/TriggerPhoto.) STX is produced by marine dinoflagellates and freshwater cyanobacteria, which can form extensive algal blooms, producing the “red tide” (Fig. 21.2).8 Ingestion of shellfish contaminated by such algal blooms is responsible for the human illness known as paralytic shellfish poisoning.9 NeoSTX differs from STX in that it has a hydroxyl group substituted for a hydrogen (Fig. 21.3). Similar to the “traditional” local anesthetics, TTX, STX, and NeoSTX are sodium channel blockers. However, where traditional local anesthetics (e.g., lidocaine) diffuse into the nerve through its lipid membrane to block the sodium channel from its inside, TTX, STX, and NeoSTX interact with the extracellular aspect of the sodium channel (Fig. 21.4). As a result of this, these compounds can act in a synergistic manner with traditional local anesthetics.10,11 Because the traditional amide and ester local anesthetics do not reliably provide analgesia beyond 6 to 12 hours following a single injection, NeoSTX and TTX have received renewed attention in the area of postsurgical pain control.12,13 NeoSTX has been demonstrated to be the most potent of the selective sodium channel blockers in both in vitro and in vivo trials.14,15 It is termed a “site-1 sodium channel blocker,” binding to the outer pore of the sodium channel, Saxitoxin (A) and neosaxitoxin (B). interrupting depolarization of excitable cells and propagation of action potential.12,16 Overdose of traditional local anesthetics—either by direct intravascular administration or by excessive dosage— produces neurologic and myocardial toxicity (see Chapter 18). NeoSTX appears to be devoid of cardiotoxicity.17 Overdose of NeoSTX (and TTX) produces reversible weakness of skeletal and respiratory muscles, which is treatable with respiratory support (assisted or controlled ventilation) until recovery is complete.12 Similar to its effect with traditional local anesthetics, the addition of epinephrine to NeoSTX decreases its blood level, resulting in increased potency and decreased toxicity.18 In that same clinical trial, in human volunteers subcutaneous injection of NeoSTX produced significantly longer effect on the pain threshold compared with bupivacaine. The addition of epinephrine further increased the duration of anesthesia.18 In a phase 1 clinical trial, Lobo et al.19 evaluated the safety and efficacy of NeoSTX alone and NeoSTX combined with 0.2% bupivacaine and epinephrine (NeoSTX-Bup-Epi) and without epinephrine (NeoSTX-Bup). Eighty-four participants completed the trial with no serious adverse events or clinically significant physiologic impairments. The most common adverse events—perioral numbness and tingling—were more frequent with NeoSTX alone and NeoSTX-Bup. All symptoms resolved without intervention. The addition of epinephrine (NeoSTX-Bup-Epi) dramatically reduced symptoms compared with the other NeoSTX combinations (tingling, 0% vs. 70%, P = .004; numbness, 0% vs. 60%, P = .013) at the same dose. The mean peak plasma NeoSTX concentration for NeoSTX-Bup-Epi was reduced at least twofold compared with that for NeoSTX alone and NeoSTX-Bup (67 ± 14 pg/mL, 134 ± 63 pg/mL, and 164 ± 81 pg/mL, respectively, P = .016). NeoSTX-Bup showed a prolonged cutaneous block duration compared with 0.2% bupivacaine, CHAPTER 21 Future Trends in Pain Control 397 Na+ (Sodium channel) Local anesthetic Tetrodotoxin, saxitoxin R-T N R-LA O m m m h C h I Lidocaine, prilocaine, mepivacaine, articaine, bupivacaine h Axoplasm • Fig. 21.4 Na+ channel sites. NeoSTX alone, or placebo at all doses. The median time to near-complete recovery for 10 µg NeoSTX-Bup-Epi was almost fivefold longer than for 0.2% bupivacaine (50 hours vs. 10 hours, P = .007).19 In their conclusions, they stated that “an ideal agent for perioperative use should have (1) very rapid onset of dense blockade, permitting surgery under local or regional anesthesia, (2) persistence of dense and reliable blockade through the first postoperative night, and (3) a prolonged period of partial blockade over the next 2 or 3 days.20 Based on the time course and intensity of block in this phase 1 study, NeoSTX-Bup and NeoSTX-Bup-Epi appear promising for showing these favorable features when used for surgical patients.”19 TTX has also received attention as a long-acting anesthetic with minimal myotoxicity and neurotoxicity.21,22 When administered along with a traditional local anesthetic, TTX has demonstrated significant synergism in multiple animal studies. Individually, TTX or bupivacaine each produced 150 minutes of block in a rat sciatic nerve block. Injected together, the duration was increased to 570 minutes.23 Comment: The site-1 selective sodium channel blockers NeoSTX and TTX provide longer durations of anesthesia than traditional local anesthetics. When TTX is administered in combination with bupivacaine and epinephrine, significant increases in duration are noted. Additionally, these compounds are devoid of cardiotoxicity (NeoSTX) and have minimal myotoxicity and neurotoxicity (TTX). Overdose is noted as various degrees of respiratory depression, which is readily managed through airway maintenance and assisted or controlled ventilation until recovery occurs.␣ New Local Anesthetic Delivery Systems Another approach to extending the duration of anesthesia provided by traditional local anesthetics is to use new means of delivering the drugs.12 Nanoparticles and liposome microparticles have been used to enhance both the duration and the safety of local anesthetics.12 Clinical trials of third molar pain have shown that the severest pain and the greatest analgesic consumption occur during the first 48 to 72 hours after surgery.24,25 Hersh et al. stated that “a drug that could significantly reduce or eliminate opioid consumption in patients during this time period would be beneficial to the dentist’s armamentarium by providing prolonged analgesia and reducing the need to prescribe opioids. Liposomal bupivacaine may indeed fit this niche.”26 With proprietary DepoFoam technology, as much as 97% of the bupivacaine in the liposomal formulation is packaged within multivesicular liposomal spheres. Each sphere is surrounded by a lipid bilayer that allows controlled release of the drug over time (Fig. 21.5).27,28 The onset of anesthesia is considerably slower than for conventional local anesthetics, at least a couple of hours.26,29,30 Randomized controlled clinical trials comparing liposomal bupivacaine with bupivacaine administered by infiltration postoperatively into surgical sites (total knee arthroplasty, laparoscopic hysterectomy, nephrectomy) have demonstrated the superiority of the liposomal form for pain management, decreased opioid requirement, and decreased occurrence of adverse events.31-38 Liposomal bupivacaine (Exparel) is strictly indicated for postsurgical pain control by infiltration injections around the surgical incision.39 It is not indicated for administration as a nerve block or by intra-articular injection. It should not be used for intraoperative dental local anesthesia because the drug has a slower onset than conventional bupivacaine and a possible 24- to 72-hour duration of lip and tongue anesthesia if administered by inferior alveolar or Gow-Gates nerve blocks.25 If liposomal bupivacaine and other non-bupivacaine “traditional” local anesthetics are administered at the same site, Complications, Legal Considerations, Questions, and the Future 398 PART IV Bupivacaine A B • Fig. 21.5 DepoFoam. (B: ©Pacira Pharmaceuticals Inc. All Rights Reserved. Used Under License.) there may be an immediate release of bupivacaine from the liposomal spheres. The Exparel drug information leaflet states that “the liposomal bupivacaine formulation should not be injected within 20 min into sites where non-bupivacainecontaining local anesthetics, such as lidocaine, have been infiltrated. This increases the risk of damaging the liposomal vesicles and thus potentially increasing free blood levels of bupivacaine to toxic concentrations and/or negating the extended duration of action provided by the liposomes.”39 Comment: Hersh et al.25 stated: The ‘jury is still out’ regarding the use of liposomal bupivacaine after invasive dental surgery. The cost of a 10-mL vial (133 mg of liposomal bupivacaine) is $170, roughly 28 times that of 6 standard (1.7 mL) 0.5% bupivacaine/1:200,000 epinephrine cartridges (an amount of local anesthetic that may be necessary to provide anesthesia/analgesia for the surgical removal of 4 dental impactions). On the flip side, providing postoperative pain control potentially for up to 72 h and reducing the need for opioid consumption would have a positive effect on patient quality of life by reducing or eliminating the known acute side effects of opioids (nausea, vomiting, constipation, psychomotor impairment) and may reduce the chances of opioid abuse in genetically susceptible individuals. Additional randomized, controlled studies following dental impaction surgery, maxillofacial trauma, and periodontal surgery procedures are needed. Animal trials of liposomal STX (sciatic nerve blockade in Sprague Dawley rats) have demonstrated anesthesia of between 13.5 and 48 hours without signs of toxicity.40 Incorporating dexamethasone with the liposomal STX increased the duration of blocks to 7.5 days without signs of toxicity. 40 The shelf life of liposomal local anesthetics is quite short (less than 1 to 2 months), a result of leakage of the drug from the liposomes.12 Proliposomal ropivacaine, in which liposome formation occurs only when it comes into contact with aqueous subcutaneous tissue, is being developed.12 In an in vitro animal (porcine) wound healing study, exposure to saline and plasma effectively transformed the proliposomal oil into a liposomal emulsion. Proliposomal ropivacaine CHAPTER 21 was able to provide 30 hours of sensory anesthesia, in contrast to 6 hours for plain ropivacaine.41 Proliposomal ropivacaine was stable at normal room temperature for more than 24 months.41 In one human study, proliposomal ropivacaine provided anesthesia for between 29 and 36 hours following subcutaneous infiltration. Plain ropivacaine provided anesthesia for between 12 and 16 hours, both without side effects.42␣ Novel Adjuvants of Local Anesthetics The use of adjuvants in local anesthetics is a well-established practice. In dentistry, epinephrine has been added to local anesthetics since the advent of cartridges. In medicine, adjuvants to local anesthetics have included opioids, clonidine, dexamethasone,40 and epinephrine.12 Magnesium has received considerable attention as a local anesthetic adjuvant in recent years. In clinical trials, patients undergoing surgery (arthroscopic rotator cuff repair, elective open thoracic surgery, elective forearm and arm surgery, total abdominal hysterectomy, and laparoscopic cholecystectomy) received bupivacaine or ropivacaine with magnesium (150 mg) by an appropriate nerve block technique.43-47 The addition of magnesium to the local anesthetic increased the duration of pain control in all studies (by 571 minutes following total abdominal hysterectomy46), and patients required less rescue anesthesia (e.g., opioids). No magnesium-associated toxicity was observed in the experimental groups.43-47 Comment. The addition of epinephrine to local anesthetics is considered routine in dentistry, as it increases both the depth and the duration of local anesthesia as well as decreasing the toxicity of the local anesthetic. The addition of magnesium to local anesthetics provides a longer duration of anesthesia, lowers patient pain scores, and, in some studies, lowers opioid requirements when used in combination with bupivacaine.␣ Light-Activated, Light-Inactivated Local Anesthesia Optogenetics is a biological technique involving the use of light to control cells in living tissue, typically neurons, that have been genetically modified to express light-sensitive ion channels. It is a means of neuromodulation using techniques from both optics and genetics to control and monitor the activities of individual neurons in living tissue—even within freely moving animals—and to precisely measure these manipulation effects in real time.48 The use of light to selectively control precise neural activity (action potential) patterns within subtypes of cells in the brain was first described by Francis Crick at the University of California, San Diego in 1999.49 In 2010, optogenetics was chosen as the “Method of the Year” across all fields of science and engineering by the interdisciplinary research journal Nature Methods.50,51 At the same time, optogenetics was highlighted in an article on breakthroughs of the decade in the academic research journal Science.52 Future Trends in Pain Control 399 Primarily a research tool in animals, optogenetics applications include (1) the identification of particular neurons and neural networks, (2) the precise temporal control of interventions, and (3) cellular biology/cell signaling pathways. One area of interest is its use in the management of cardiac dysrhythmias. Although still in the development stage, optogenetics was applied on atrial cardiomyocytes to terminate dysrhythmias found to occur in atrial fibrillation, with light.53 A recent study explored the possibilities of optogenetics as a means of correcting dysrhythmias and resynchronizing cardiac pacing. Channelrhodopsin-2 was introduced into cardiomyocytes in ventricular areas of hearts of transgenic mice, and in vitro photostimulation studies were performed. Photostimulation led to increased activation of cells, thus increasing ventricular contractions, resulting in increased heart rates. In addition, this approach has been applied in cardiac resynchronization therapy as a new biological pacemaker as a substitute for electrodebased cardiac resynchronization therapy.54 More recently, optogenetics has been used in the heart to defibrillate ventricular arrhythmias with local epicardial illumination,55 a generalized whole heart illumination,56 or with customized stimulation patterns based on arrhythmogenic mechanisms to lower defibrillation energy.57 Optogenetic tools have also been proposed as a strategy for restoring vision58 as well as for treating Parkinson disease or epilepsy through deep brain optical stimulation.59 Optogenetics and pain modulation—the ability to instantaneously turn on and turn off anesthesia and to specifically target precise areas for treatment. In a 180-degree turn from the earlier discussion of longer- and ultra-long-acting local anesthetics used almost exclusively for the management of postsurgical pain, most traditional local anesthetics provide pulpal anesthesia of sufficient duration to permit completion of virtually all dental procedures painlessly. However, soft tissue anesthesia—usually unnecessary and almost always unwanted—persists for many hours following completion of the dental treatment. Additionally, injectable local anesthetics are not targeted to a specific site; rather they affect a generalized area. The traditional local anesthetics (e.g., articaine, bupivacaine, lidocaine, mepivacaine, prilocaine) lack specificity for motor neurons versus sensory neurons and for different sensory modalities (e.g., touch sensation), and the duration and intensity of the anesthesia cannot be regulated.60 A new option, developed by researchers at the University of California, Berkeley, the University of Munich, and the University of Bordeaux,61 involves a novel local anesthetic that can be switched on and off with the use of different wavelengths of light, potentially allowing much finer control of exactly which nerves it blocks.62 Chemically, quaternary ammonium–azobenzene–quaternary ammonium (QAQ) resembles lidocaine. QAQ exists in two forms, cis and trans. In the active trans form, the molecule is a straight chain, but exposure to 380-nm light converts it to the cis form, which is bent like an L (Fig. 21.6). 400 PART IV Complications, Legal Considerations, Questions, and the Future Quaternary ammonium Azobenzene Acrylamide O HN 380 nm + N O N HN NH N N+ O N O TRANS QAQ • Fig. 21.6 500 nm or ∆ N HN CIS QAQ The cis and trans forms of quaternary ammonium–azobenzene–quaternary ammonium. 500 nm light activates 380 nm light inactivates • Fig. 21.7 Light-activated, light-inactivated local anesthetic quaternary ammonium–azobenzene–quaternary ammonium. Redrawn from Gitlin JM. Light-switched local anaesthetic lets scientists turn pain nerve on and off. Available at: https://www.arstechnica.com/science/2012/02/light-switched-local-anaestheticlets-scientists-turn-pain-nerves-on-and-off. Accessed June 19, 2018. In the dark, QAQ slowly reverts to the trans form; however, this can also be achieved much more rapidly by illumination with 500-nm light (Fig. 21.7). Once inside a cell, in its trans form QAQ blocks many different ion channels, whereas the cis form is inactive. The difficulty researchers have found has been in getting QAQ into the cell itself. Being a fairly large molecule, QAQ does not normally cross cell membranes. To demonstrate the effectiveness of photoswitching, researchers had to inject QAQ into the cells they were testing. Although this might be thought of as a factor limiting its potential clinical usefulness, this lack of membrane permeability actually confers on QAQ the potential to be a very selective local anesthetic. Because QAQ is selective for pain-sensing neurons, it may block nociception without affecting motor axons or other sensations. Moreover, because QAQ blockade can be precisely modulated by a change in light wavelength or intensity, it may be possible to phototitrate the analgesic effect at will.63 Comment. The ability to provide location-specific pain control without additional involvement of motor nerves CHAPTER 21 would be a welcome addition to the management of patients with chronic pain syndromes. Further, as most dental treatments are not associated with postoperative pain, the ability to “switch off” anesthesia at the end of treatment would be appreciated by most dental patients. Although still very early in their development, optogenetics and light-activated/ light-inactivated compounds hold promise for a new means of managing perioperative pain. References 1. Malamed SF. Future considerations. 5th ed. Handbook of Local Anesthesia. St Louis: CV Mosby; 2004. 2. Olsen Y. The CDC guideline on opioid prescribing. Rising to the challenge. J Am Med Assoc. 2016;315:1577–1579. 3. National Institute on Drug Abuse. Opioid overdose crisis. Available at: http://www.drugabuse.gov/drugs-abuse/opioids/opioid-overdosecrisis. Accessed June 18, 2018. 4. Narahashi T, Moore JW, Scott WR. Tetrodotoxin blockage of sodium conductance increase in lobster giant axons. J Gen Physiol. 1964;47:965–974. 5. Lago J, Rodriguez LP, Blanco L, et al. Tetrodotoxin, an extremely potent marine neurotoxin: distribution, toxicity, origin and therapeutical uses. Mar Drugs. 2015;13:6384–6406. 6. Narahishi T. Tetrodotoxin: a brief history. Proc Jpn Acad Ser B Phys Biol Sci. 2008;84(5):147–154. 7. Bane V, Lehane M, Dikshit M, et al. Tetrodotoxin: chemistry, toxicity, source, distribution and detection. Toxins. 2014;6:693– 755. 8. Wiese M, D’Agostino PM, Mihail TK, et al. Neurotoxic alkaloids: saxitoxin and its analogs. Mar Drugs. 2010;8:2185–2211. 9. Centers for Disease Control and Prevention. Epidemiologic notes and reports paralytic shellfish poisoning—Massachusetts and Alaska, 1990. 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Assessment of liposome bupivacaine infiltration versus continuous femoral nerve block for postsurgical analgesia following total knee arthroplasty: a retrospective cohort study. Curr Med Res Opin. 2016;32:1727–1733. 36. Cien AJ, Penny PC, Horn BJ, et al. Comparison between liposomal bupivacaine and femoral nerve block in patients undergoing primary total knee arthroplasty. J Surg Orthop Adv. 2015;24:225–229. 402 PART IV Complications, Legal Considerations, Questions, and the Future 37. Hutchins JL, Kesha R, Blanco F, et al. Ultrasound-guided subcostal transverse abdominis plane blocks with liposomal bupivacaine vs. non-liposomal bupivacaine for postoperative pain control after laparoscopic hand-assisted donor nephrectomy: a prospective randomised observer-blinded study. Anaesthesia. 2016;71:930–937. 38. Hutchins J, Delaney D, Vogel RI, et al. Ultrasound guided subcostal transverse abdominis plane (TAP) infiltration with liposomal bupivacaine for patients undergoing robotic assisted hysterectomy: a prospective randomized controlled study. Gynecol Oncol. 2015;138:609–613. 39. Pacira Pharmaceuticals. Exparel drug package insert. Available at: https://www.exparel.com/prescribinginformation. Accessed 23 February 2019. 40. Epstein-Barash H, Shichor I, Kwon AH, et al. Prolonged duration local anesthesia with minimal toxicity. Proc Natl Acad Sci U S A. 2009;106:7125–7130. 41. Davidson EM, Haroutounian S, Kagan L, et al. A novel proliposomal ropivacaine oil: pharmacokinetic-pharmacodynamic studies after subcutaneous administration in pigs. Anesth Analg. 2016;122:1663–1672. 42. Ginosar Y, Haroutounian S, Kagan L, et al. Proliposomal ropivacaine oil: pharmacokinetic and pharmacodynamic data after subcutaneous administration in volunteers. Anesth Analg. 2016;122:1673–1680. 43. Lee AR, Yi HW, Chung IS, et al. Magnesium added to bupivacaine prolongs the duration of analgesia after interscalene nerve block. Can J Anaesth. 2012;59:21–27. 44. Ammar AS, Mahmoud KM. Does the addition of magnesium to bupivacaine improve postoperative analgesia of ultrasoundguided thoracic paravertebral block in patients undergoing thoracic surgery? J Anesth. 2014;28:58–63. 45. Mukherjee K, Das A, Basunia SR, et al. Evaluation of magnesium as an adjuvant in ropivacaine-induced supraclavicular brachial plexus block: a prospective, double-blinded randomized controlled study. J Res Pharm Pract. 2014;3:123–129. 46. Rana S, Verma RK, Singh J, et al. Magnesium sulphate as an adjuvant to bupivacaine in ultrasound-guided transversus abdominis plane block in patients scheduled for total abdominal hysterectomy under subarachnoid block. Indian J Anaesth. 2016;60:174–179. 47. Al-Refaey K, Usama EM, Al-Hefnawey E. Adding magnesium sulfate to bupivacaine in transversus abdominis plane block for laparoscopic cholecystectomy: a single blinded randomized controlled trial. Saudi J Anaesth. 2016;10:187–191. 48. Deisseroth K, Feng G, Majewska AK, et al. Next-generation optical technologies for illuminating genetically targeted brain circuits. J Neurosci. 2006;26:10380–10386. 49. Crick F. The impact of molecular biology on neuroscience. Philos Trans R Soc B. 1999;354:2021–2025. 50. Primer on Optogenetics, Pastrama E. Optogenetics: controlling cell function with light. Nat Methods. 2010;8:24–25. 51. Editorial. Method of the year 2010. Nat Methods. 2010;8(1). 52. Staff News. Insights of the decade. Stepping away from the trees for a look at the forest. Introduction. Science. 2010;330:1612– 1613. 53. Bingen BO, Engels MC, Schalij MJ, et al. Light-induced termination of spiral wave arrhythmias by optogenetic engineering of atrial cardiomyocytes. Cardiovasc Res. 2014;104:194–205. 54. Nussinovitch U, Gepstein L. Optogenetics for in vivo cardiac pacing and resynchronization therapies. Nat Biotechnol. 2015;33: 750–754. 55. Nyns ECA, Kip A, Bart CI, et al. Optogenetic termination of ventricular arrhythmias in the whole heart: towards biological cardiac rhythm management. Eur Heart J. 2017;38:2132– 2136. 56. Bruegmann T, Boyle PM, Vogt CC, et al. Optogenetic defibrillation terminates ventricular arrhythmia in mouse hearts and human simulations. J Clin Invest. 2016;126:3894–3904. 57. Crocini C, Ferrantini C, Coppini R, et al. Optogenetics design of mechanistically-based stimulation patterns for cardiac defibrillation. Sci Rep. 2016;6:35628. 58. Busskamp V, Roska B. Optogenetic approaches to restoring visual function in retinitis pigmentosa. Curr Opin Neurobiol. 2011;21:942–946. 59. Gradinaru V, Mogri M, Thompson KR, et al. Optical deconstruction of parkinsonian neural circuitry. Science. 2009;324:354– 359. 60. Roberson DP, Binshtok AM, Blasl F, et al. Targeting of sodium channel blockers into nociceptors to produce long-duration analgesia: a systematic study and review. Br J Pharmacol. 2011;164: 48–58. 61. Mourot A, Fehrentz T, Le Feuvre Y, et al. Rapid optical control of nociception with an ion-channel photoswitch. Nat Methods. 2012;9:396–402. 62. Gitlin JM. Light-switched local anaesthetic lets scientists turn pain nerve on and off. Available at: https://www.arstechnica.com/ science/2012/02/light-switched-local-anaesthetic-lets-scientiststurn-pain-nerves-on-and-off. Accessed June 19, 2018. 63. Mourot A, Tochitsky I, Kramer RH. Light at the end of the channel: optical manipulation of intrinsic neuronal excitability with chemical photoswitches. Front Mol Neurosci. 2013;6:5. 22 Frequently Asked Questions Local Anesthetics Question Why is it said that intravascular administration of local anesthetics is dangerous when emergency department physicians frequently administer lidocaine intravenously to treat potentially fatal cardiac dysrhythmias? Intravenous administration of local anesthetics is potentially hazardous at all times and in all patients. However, intravenous local anesthetics, such as lidocaine and procainamide, do have an important place in the management of prefatal ventricular dysrhythmias, such as premature ventricular contractions and ventricular tachycardia. Several factors, including weighing the risk versus the benefit, must be considered whenever local anesthetics are to be administered “safely” intravenously. 1. The patient’s physical status. Patients receiving intravenously administered lidocaine or other antidysrhythmic drugs have potentially life-threatening cardiac dysrhythmias. The myocardium is highly irritable (usually secondary to ischemia), which is often the primary cause of the dysrhythmia. Local anesthetics are myocardial depressants. By depressing the myocardium, lidocaine decreases the incidence of dysrhythmias. However, patients with normal cardiac rhythms receiving intravenous local anesthetics will also have their myocardium depressed; their cardiac function may be impaired by the local anesthetic in this circumstance. 2. The form of lidocaine used. Lidocaine for intravenous use in the management of ventricular dysrhythmias, socalled cardiac lidocaine, is prepared in single-use ampules or prefilled syringes. These ampules and syringes contain only lidocaine and sodium chloride. The typical dental cartridge of lidocaine contains lidocaine, distilled water, a vasoconstrictor, sodium bisulfite, and sodium chloride. Intravenous injection of these ingredients, in and of itself, might precipitate unwanted cardiovascular responses rather than terminate them. 3. The rate of injection. Lidocaine for antidysrhythmic use is titrated slowly intravenously to achieve a therapeutic blood level in the myocardium. The accepted therapeutic blood level of lidocaine is between 1.8 and 5 µg/mL. To achieve this, lidocaine is administered intravenously slowly and is titrated until ventricular dysrhythmias on the electrocardiogram are eliminated—typically, a dose between 1.0 and 1.5 mg/kg. In the typical dental practice, a 1.8-mL cartridge of lidocaine (36 mg) is deposited in 15 seconds or less. The rate at which the drug is administered intravenously has a significant bearing on its peak blood level. Overly rapid intravenous administration results in lidocaine blood levels that quickly approach the overdose range, whereas a more slowly administered dose results in blood levels well within the therapeutic range for terminating dysrhythmias. 4. Risk versus benefit. An overdose reaction is possible anytime lidocaine is administered intravenously. Even under controlled conditions in a hospital, adverse reactions related to overly high blood levels do develop.1-6 The risk from intravenous administration of local anesthetics must always be weighed against the potential benefit to be gained from their use. For high-risk patients with a specific life-threatening dysrhythmia, the benefit clearly outweighs the risk. For dental patients seeking relief from intraoral pain, intravenous local anesthetic administration confers no benefit yet adds many risks.␣ Question What should I do when a patient claims to be allergic to a local anesthetic? Believe the patient! Do not use any form of local anesthetic (including topical anesthetic preparations) on this patient until you are able to definitively determine whether a true, documented, reproducible allergy exists. Seek to determine what actually happened to the patient to prompt such a claim and how his or her “reaction” was managed. (A detailed discussion of this situation is given in Chapter 18.)␣ Question Are any local anesthetics safer than others? Some appear to be implicated more than others in adverse reactions. No. When used properly, all currently available local anesthetic formulations are extremely safe and effective. 403 404 PART IV Complications, Legal Considerations, Questions, and the Future “Used properly” is the key phrase. Aspiration (twice) before injection (to minimize the risk from intravascular administration) and slow administration of the drug are vital. To determine potential contraindications to specific local anesthetics or additives, the patient’s medical history must be obtained and a physical evaluation completed before their use. The maximum dose of a drug should be determined for a given patient and not exceeded. Tables for the most commonly used local anesthetics are found in Chapters 4 and 18. The figures cited are maximum recommended doses. The stated maximum recommended dose should be decreased in patients with certain medical complications and in older individuals. Most systemic reactions to local anesthetics are entirely preventable. Overdose reactions that have led to death or significant morbidity frequently result from the administration of too large a dose to a younger, lighter-weight, well-behaved patient requiring multiple quadrants of dental care or, much less commonly, after “accidental” intravenous administration. Psychogenic reactions, by far the most common adverse response to the administration of a local anesthetic, may be virtually eliminated through enhanced rapport with the patient, use of an atraumatic injection technique (see Chapter 11), placement of the patient in a supine position during injection, and ample doses of empathy.␣ Question Do some local anesthetics have a greater risk of producing nerve damage (e.g., paresthesia)? Discussion in dental circles regarding 4% local anesthetic formulations and the reported incidence of paresthesia has ebbed and flowed since the introduction of articaine into Canada in 1985 and the United States in 2000. Such concern started in 1995 with the publication of an article by Haas and Lennon7 that stated the incidence of paresthesia following administration of all local anesthetic solutions was 1 in 785,000. For 0.5%, 2%, and 3% local anesthetics, the calculated risk was 1 in 1,125,000, and for 4% local anesthetics, it was 1 in 485,000. Discussion of paresthesia associated with nonsurgical dental treatment is presented in Chapters 17 and 20. A meta-analysis comparing articaine hydrochloride with lidocaine (lignocaine) hydrochloride reported that articaine is more likely than lidocaine to achieve anesthetic success in the posterior first molar area, and that there is no difference in postinjection adverse events.8 A 2011 review of the articaine literature (116 articles reviewed) concluded that “although there may be controversy regarding its safety and advantages in comparison to other local anaesthetics, there is no conclusive evidence demonstrating neurotoxicity or significantly superior anesthetic properties of articaine for dental procedures.”9 For an in-depth look at all aspects of the local anesthetic articaine hydrochloride, the reader is referred to the article “Articaine 30 years later.”10␣ Question How do I select an appropriate local anesthetic for a given patient and procedure? Two factors are particularly important: 1. The duration of pain control required to complete the procedure painlessly, and the possible need for posttreatment pain control (e.g., after surgical procedures). Box 4.1 lists currently available local anesthetic formulations by their approximate duration of action—for both soft tissue and pulpal anesthesia. 2. The patient’s physical status (e.g., American Society of Anesthesiologists [ASA] classification), hypersensitivity, methemoglobinemia, or sulfur allergy, which may preclude the use of specific drugs. For most patients the duration of desired pain control is the ultimate deciding factor in local anesthetic selection, because usually there are no contraindications to the administration of any particular agent.␣ Question What local anesthetics should be available in my office? It is suggested that a number of local anesthetics be available at all times. The nature of the dental practice will dictate the number and types of local anesthetics needed. In a typical dental practice, selection of a local anesthetic formulation is based on the desired duration of pulpal anesthesia; for example, less than 30 minutes, approximately 60 minutes, in excess of 90 minutes. One local anesthetic preparation from each group, as necessitated by the nature of the doctor’s practice, should be available. For example, the pediatric dentist has little need or desire for long-acting local anesthetics such as bupivacaine, whereas the oral and maxillofacial surgeon may have little need for shorter-acting drugs such as mepivacaine plain, but a greater need for bupivacaine. Remember that not all patients have similar local anesthetic requirements, and the same patient may require a different local anesthetic for a dental procedure of a different duration. Amide local anesthetics are preferred to ester local anesthetics because of their decreased incidence of allergy.␣ Question Do topical anesthetics really work? Absolutely, if the topical anesthetic preparation is applied to mucous membrane for an adequate length of time.11 The American Dental Association recommends a 1-minute application.12 The US Food and Drug Administration recommends application for a minimum of 1 minute. Gill and Orr13 recommend application for 2 to 3 minutes. Topical anesthetics containing benzocaine are not absorbed from their site of application into the cardiovascular system; therefore the risk of overdose is minimal when benzocaine-containing topical anesthetic preparations are used. CHAPTER 22 On May 23, 2018, the US Food and Drug Administration issued a warning to consumers not to use teething products containing benzocaine in infants and children younger than 2 years because of the risk of inducing methemoglobinemia when the product is administered in too large of a dose.14 Many dental topical anesthetics include benzocaine, but when applied appropriately to isolated areas in small amounts (see the following paragraph)—as is done in dental offices—this risk is minimal. Because of the rapid absorption of some topically applied local anesthetics such as lidocaine, it is recommended that their use be restricted to the following situations: 1. locally, at the site of needle puncture before injection; 2. for scaling or curettage, over not more than one quadrant at a time. Pressurized sprays of topical anesthetics cannot be recommended unless they release a metered dose of the drug, not a steady uncontrolled dose.15 Sterilization of the spray nozzle must be possible if a spray is used. Many pressurized topical anesthetic sprays are available in metered form with disposable spray nozzles.␣ Vasoconstrictors Question Are there any contraindications to the use of vasoconstrictors in dental patients? Yes. Use of local anesthetics with vasoconstrictors should be avoided or kept to an absolute minimum in the following cases16-18: 1. patients with blood pressure in excess of 200 mmHg systolic or 115 mmHg diastolic 2. patients with uncontrolled hyperthyroidism 3. patients with severe cardiovascular disease a. less than 6 months after myocardial infarction b. less than 6 months after cerebrovascular accident c. with daily episodes of angina pectoris or unstable (preinfarction) angina d. with cardiac dysrhythmias despite appropriate therapy e. after coronary artery bypass surgery less than 6 months ago 4. patients who are undergoing general anesthesia with halogenated agents 5. patients receiving nonspecific β-blockers, monoamine oxidase inhibitors, or tricyclic antidepressants Patients in categories 1 to 3d are classified as ASA 4 class risks and are normally not considered candidates for elective or emergency dental treatment in the office. (See Chapters 3 and 10 for more detailed discussions, and also see the next question.)␣ Question Often medical consultants recommend against inclusion of a vasoconstrictor in a local anesthetic for a cardiovascular risk patient. Why? And what can I do to achieve effective pain control? Frequently Asked Questions 405 As indicated, there are several instances in which it is prudent to avoid the use of vasoconstrictors in local anesthetics. Most of these situations (e.g., severely elevated, untreated high blood pressure; severe cardiovascular disease) are also absolute contraindications to elective dental care because of greater potential risk to the patient. If a dental patient with cardiovascular disease is deemed treatable (ASA class 2 or 3), then local anesthetics for pain control are indicated. The patient’s physician often states that although local anesthetics can be used, use of epinephrine should be avoided.␣ Question When should use of epinephrine be avoided? One of the few valid reasons for avoiding use of epinephrine is the patient with cardiac rhythm abnormalities that are unresponsive to medical therapy. The presence of dysrhythmias (especially ventricular) usually indicates an irritable or ischemic myocardium. Epinephrine, exogenous or endogenous, further increases myocardial irritability, thereby predisposing this patient to a greater frequency of dysrhythmias or to more significant types of dysrhythmias, such as ventricular tachycardia or ventricular fibrillation. In these patients, use of epinephrine-containing local anesthetics should be avoided, if at all possible. However, many cardiologists today do not even consider the ischemic myocardium a valid reason for excluding vasoconstrictors from local anesthetics, provided the dose of epinephrine administered is minimal (volume of drug and concentration of epinephrine [1:200,000 preferred]) and intravascular administration is avoided. It is my recommendation that with a patient who is deemed able to tolerate the stresses involved in the planned dental treatment, a vasoconstrictor should be included in the local anesthetic if there is a valid reason for its inclusion (e.g., depth or duration of anesthesia, need for hemostasis). As Bennett has stated, “the greater the medical risk of a patient, the more important effective control of pain and anxiety becomes.”19␣ Question Why do many physicians still recommend against the use of epinephrine (and other vasoconstrictors) in cardiovascular risk patients? Most physicians never, or at best rarely, use epinephrine in their practice. The only physicians who do so on a regular basis are anesthesiologists, emergency medicine specialists, and surgeons. As used in medicine, epinephrine is almost always used in emergency situations. At those times, the dose is considerably higher than that used in dentistry. The average emergency dose of intramuscularly or intravenously administered epinephrine (used in a 1:1000 or 1:10,000 concentration) for anaphylaxis or cardiac arrest is 0.3 to 1 mg, whereas one dental cartridge with 1:100,000 epinephrine contains only 0.018 mg. 406 PART IV Complications, Legal Considerations, Questions, and the Future It is therefore understandable that many physicians, lacking intimate knowledge of the practice of dentistry, think of epinephrine in terms of the doses used in emergency medicine and not in the much more dilute forms used for anesthesia in dentistry. An example follows. In a hospital situation, a patient with a serious cardiovascular problem (ASA class 4) who requires a surgical procedure (e.g., emergency appendectomy) may be considered too great a risk for general anesthesia. Many anesthesiologists opt to use a regional local anesthetic (spinal) block with an intravenous antianxiety agent (midazolam) for sedation in place of general anesthesia. The local anesthetic usually contains epinephrine in a 1:100,000 or 1:200,000 concentration, added primarily to decrease the rate at which the local anesthetic is absorbed into the cardiovascular system, but also to minimize bleeding and prolong the duration of clinical action.␣ Question Why is the use of vasoconstrictors in local anesthetics recommended for cardiac risk patients? Pain is stressful to the body. During stress, endogenous catecholamines (e.g., epinephrine, norepinephrine) are released from their storage sites into the cardiovascular system at a level approximately 40 times greater than the resting level. (See Chapter 3 for a review of the pharmacology of this group of drugs.) Release of epinephrine and norepinephrine into the cardiovascular system increases the workload of the heart; thus the myocardial oxygen requirement increases. In patients with compromised (partially occluded) coronary arteries, if this increased myocardial oxygen requirement is not met, ischemia develops, leading to the onset of dysrhythmias, anginal pain (if ischemia is transient), or myocardial infarction (if ischemia is prolonged). Increased cardiac workload may also lead to acute exacerbation of heart failure (acute pulmonary edema). Elevated catecholamine levels can produce a dramatic increase in blood pressure; this can precipitate another life-threatening situation (e.g., a hemorrhagic stroke [cerebrovascular accident, “brain attack”]). Therefore the goal is to minimize endogenous catecholamine release during dental therapy. The stress-reduction protocol is designed to accomplish this. A local anesthetic without a vasoconstrictor provides pulpal anesthesia of shorter duration than the same drug with a vasoconstrictor. Profound pain control of adequate duration is less likely to be achieved when a vasoconstrictor is excluded from a local anesthetic solution. If the patient experiences pain during treatment, an exaggerated stress response will be observed. With proper use (aspiration twice and slow injection) of a local anesthetic with minimum volume and concentration of an exogenous vasoconstrictor (e.g., 1:200,000, 1:100,000), pain control of longer duration is virtually guaranteed and an exaggerated stress response avoided or minimized. Levels of catecholamine in the blood are elevated when exogenous epinephrine is administered, but these levels are usually not clinically significant. An often repeated and essentially true statement is that the cardiovascularly impaired patient is more at risk from endogenously released catecholamines than from exogenous epinephrine administered in a proper manner.␣ Question Can I administer a local anesthetic with a vasoconstrictor even if a physician has advised against it? Yes. A medical consultation is a request for advice from you to a person with more knowledge of the matter being discussed. You are not obligated to heed this advice if you feel it may be inaccurate. If doubt persists in your mind concerning the proper treatment protocol following this initial consultation, additional opinions should be sought, preferably from a specialist in the “area” of concern, such as a cardiologist, an anesthesiologist, or a dental expert in local anesthesia. Of course, for some patients, exogenous catecholamines may prove too great a risk; in these cases, plain local anesthetic solutions should be administered. It must always be remembered that the primary responsibility for the care and well-being of a patient rests solely in the hands of the person who performs the treatment, not the one who gives advice. An incident concerning a medical consultation is worth relating. A periodontal graduate student was planning four quadrants of osseous surgery on a patient whose medical history was within normal limits, except for a torticollis for which she was receiving imipramine, a tricyclic antidepressant. A written consultation was sent to the patient’s physician requesting that the patient stop being treated with imipramine before the surgical procedure was performed. The response was that the patient could not stop taking the drug because it had taken longer than 1 year to get her medical condition stabilized. Moreover, it was recommended that use of epinephrine be avoided during this patient’s surgery. It was decided to contact the physician directly to discuss the matter and to attempt to explain the importance of the use of epinephrine during an osseous surgical procedure. In the ensuing conversation, it was agreed that epinephrine could be used, but in a limited dose, and that the patient was to be monitored (vital signs) throughout the procedure. The surgery proceeded and was completed without incident. The lesson to be learned from this episode is that the wording of the original consult was too constricting, or indeed might have been construed as threatening, to the physician. Whenever possible, there should be direct contact and discussion between both parties explaining their needs, as this is more likely to lead to a satisfactory compromise and to better and safer patient management.␣ Question If epinephrine is used in cardiac risk patients, is there a maximum dose? CHAPTER 22 Yes. Bennett19 recommends, and others agree, that the maximum dose of epinephrine in a cardiac risk (ASA 2,3) patient should be 0.04 mg. This equates to roughly the following: • one cartridge of epinephrine 1:50,000 • two cartridges of epinephrine 1:100,000 • four cartridges of epinephrine 1:200,000 I cannot recommend use of epinephrine 1:50,000 for pain control purposes. (Further information on dental management of the cardiovascular risk patient is available.20-22)␣ Question What about epinephrine-containing gingival retraction cord? Racemic epinephrine gingival retraction cord should never be used for cardiovascular risk patients, and it is my opinion that it should not be used in any patient. Gingival retraction cord contains 8% racemic epinephrine. Half of this is the levorotatory form, which provides a concentration of active epinephrine of 4% (or 40 mg/mL). This is 40 times the concentration used in the management of anaphylaxis or cardiac arrest. Absorption of epinephrine through mucous membrane into the cardiovascular system is normally rapid but is even more so with active bleeding, such as that occurring after subgingival tooth preparation. Levels of epinephrine in the blood rise rapidly, leading to cardiovascular manifestations of epinephrine overdose (p. 346). This increase in cardiovascular activity may prove to be life threatening in patients with preexisting clinically evident or subclinical cardiovascular disease.␣ Question If I elect not to use a vaso