Reversal Agents in Sedation and Anesthesia Practice for Dentistry

Abstract

Reversal agents are defined as any drug used to counteract the pharmacologic effects of another drug. Several pharmacologic antagonists serve as essential drugs in the contemporary practices of sedation providers and anesthesiologists. Reversal or “antidote” drugs, such as flumazenil and naloxone, are often used in unintentional overdose situations involving significant benzodiazepine- and/or opioid-induced respiratory depression. Within the context of skeletal muscle relaxation, neostigmine and sugammadex are routinely used to reverse the effects of nondepolarizing neuromuscular blocking agents. In addition, the alpha-adrenergic antagonist phentolamine is used in dentistry as a local anesthetic reversal agent, decreasing its duration of action by inducing vasodilation. This review article discusses the pharmacology, uses, practical implications, adverse effects, and precautions needed for flumazenil, naloxone, neostigmine, sugammadex, and phentolamine within the context of sedation and anesthesia practice for dentistry.

Knowledge of reversal agents, or pharmacologic antagonists, is essential for all providers of sedation and general anesthesia. Reversal agents are defined as any drug used to counter the pharmacologic effects of another drug.¹ This article reviews common reversal agents used in contemporary sedation and anesthesia practice for dentistry, specifically flumazenil, naloxone, neostigmine, sugammadex, and phentolamine, and discusses their use in emergency management and routine practice. This article also reviews safety considerations and potential adverse effects for each drug. Several of the key pharmacologic aspects for each reversal agent are summarized in Table 1 while Table 2 presents concise instructions for their use in adult patients.

Table 1. .

Summary of Reversal Agents*

Pharmacology	Flumazenil	Naloxone	Neostigmine	Sugammadex	Phentolamine
Indication for use	Complete or partial reversal of BZD-induced overdose	Complete or partial reversal of opioid-induced overdose	Reversal of nondepolarizing NMBDs	Reversal of rocuronium and vecuronium Rocuronium-induced allergy or anaphylaxis?†	Reversal of local anesthetic At risk for self-injurious behaviors or needed return of normal functions
Contraindications	Hypersensitivity Chronic/continued BZD use Head injury Alcoholism or drug dependency Signs of tricyclic antidepressants overdose	Hypersensitivity	Hypersensitivity Peritonitis Mechanical obstruction of the intestinal or urinary tract	Hypersensitivity Severe renal impairment	Hypersensitivity Severe cardiovascular disease
Pharmacologic effect	BZD receptor competitive antagonist	Opioid receptor competitive antagonist	Acetylcholinesterase inhibitor	Cyclodextrin encapsulates rocuronium or vecuronium	Nonselective α-adrenergic receptor antagonist
Onset, min	1-2	1-2	1	2 (2 mg/kg) 3 (4 mg/kg) 1.5 (16 mg/kg)	50 (maxilla) 70 (mandible)
Duration, min	19-50	5-45	20-30	—	—
Peak effect, min	6-10	5-15	9	—	—
Available formulation(s)	0.1 mg/mL IV	0.02 mg/mL IV 0.4 mg/mL IV 1 mg /mL IV 2 mg/0.1 mL IN2 4 mg/0.1 mL IN	1 mg/mL IV 0.5 mg/mL IV	200 mg/2 mL IV 500 mg/5 mL IV	0.4 mg/mL × 1.7 mL cartridge
Recommended adult dosing	0.2 mg over first 15 s, then 0.2 mg every 1 min as necessary; max dose 1 mg	0.1-0.2 mg increments	0.05 mg/kg lean body weight	2-16 mg/kg actual body weight	0.8 mg (12+ y)
Recommended pediatric dosing	0.01 mg/kg over first 15 s up to max 0.2 mg, then 0.01 mg/kg up to 0.2 mg every 1 min; max 4 additional doses or max 1 mg or 0.05 mg/kg, whichever is lower	0.01 mg/kg IV/IM/ETT	0.03-0.07 mg/kg IV; max 5 mg Add atropine 0.02 mg/kg or glycopyrrolate 0.015 mg/kg IV	Not established for ≤17 y	0.4 mg (6-11 y, ≥ 30 kg) 0.2 mg (6-11 y, 15-30 kg) 0.1 mg (≥10 kg)
Adverse events	Seizures Withdrawal Dysrhythmias Anxiety	Dysrhythmia Hypertension Tachycardia Pulmonary edema N/V Sweating Seizures Pain Dysphoria	N/V Bradycardia Dysrhythmia QT prolongation Bronchospasm Salivation Miosis GI peristalsis	Pain N/V Fever Headache Sore throat Back pain Cough Constipation	Pain Hypertension Bradycardia Headache
Precautions	Prolonged monitoring (2 h)	Prolonged monitoring (2 h)	Anticholinergic crisis	Hypersensitivity Bradycardia Prolonged blockade QT prolongation AV block Cardiac arrest	Tachycardia Dysrhythmia

^*BZD, benzodiazepine; ETT, endotracheal tube; GI, gastrointestinal; IN, intranasal; IV, intravenous; IM, intramuscular; NMBDs, neuromuscular blocking drugs; N/V, nausea and vomiting.

^†Case report finding, not indicated by product monograph.³

Table 2. .

Instructions for Reversal Drugs in Adults*

Drug	Instructions for Use
Flumazenil	1. Inject initial dose of 0.2 mg (2 mL) IV over 15 seconds 2. Assess after 45 seconds 3. Inject second dose of 0.2 mg (2 mL) IV 4. Repeat dose at 60-s intervals as needed (up to a maximum of 4 additional times) to a maximum total dose of 1 mg (10 mL)
Naloxone IV	1. Dilute 0.4 mg into 10 mL (0.04 mg/mL) 2. Inject 1-2 mL every 1-2 min
Naloxone IN	1. Activate EMS 2. Position head back, supporting the neck 3. Insert tip of nozzle into 1 nostril and press plunger firmly to administer 1 dose/spray 4. Position the patient on their side (recovery position or left lateral decubitus) 5. Repeat with a new device after 2 to 3 min if no effect
Neostigmine	1. Confirm TOF ≥0.9 by neuromuscular monitoring device 2. Prepare 0.2 mg of glycopyrrolate with every 1 mg of neostigmine (0.05 mg/kg lean body weight) 3. Inject preparation
Sugammadex	1. Administer 2-16 mg/kg actual body weight
Phentolamine	1. Administer 1 cartridge phentolamine for every 1 cartridge of local anesthetic administered

^*EMS, emergency medical services; IN, intranasal; IV, intravenous; TOF = train-of-four ratio.

BENZODIAZEPINE AND OPIOID REVERSAL DRUGS

Inclusion of the reversal agents flumazenil and naloxone is essential for any emergency drug kit whenever benzodiazepines or opioid agonists are used for sedation or general anesthesia for dentistry. The immediate availability of these specific antagonists ensures that inadvertent overdoses or emergencies involving benzodiazepine or opioid toxicity can be addressed promptly upon recognition. Simply, flumazenil is the antidote for benzodiazepines, and naloxone is the antidote for opioid agonists.

Flumazenil

Flumazenil (Anexate, Romazicon) is a benzodiazepine receptor competitive antagonist effectively used to reduce benzodiazepine-induced unconsciousness, sedation, amnesia, psychomotor impairment, and respiratory depression when these effects become problematic.^4–6 The molecular structure of flumazenil (Figure 1) enables it to act as a γ-aminobutyric acid type A (GABA_A) receptor–negative allosteric modulator. It competitively blocks the benzodiazepine receptor located on GABA-gated chloride ion channels within the central nervous system. This antagonistic action facilitates ion channel closure, preventing the influx of chloride ions and subsequent neuronal hyperpolarization.

Figure 1. .

Schematic of GABA_A receptor depicting competitive antagonism between flumazenil and midazolam at the benzodiazepine (BZD) binding site. Flumazenil acts as a negative allosteric modulator of GABA by facilitating closure of the chloride ion (Cl⁻) channel and preventing the influx of Cl⁻ ions.

Flumazenil is intended to be administered intravenously. It is recommended that the first dose (0.2 mg) be given intravenously over 15 seconds, followed by repeated doses (0.1-0.2 mg) every minute as needed. Titration of intravenous (IV) flumazenil to the desired reversal effect or clinical endpoint is strongly recommended to account for the variability in individual patient response. The US Food and Drug Administration (US FDA) monograph states that a “cumulative dose of 1-3 mg” is required for successful reversal of oversedation; however, the US FDA does not take into consideration interpatient variation, concurrent administration of other sedatives, or baseline benzodiazepine dosage.^7,8 The onset of action is 1 to 2 minutes with peak effect in 6 to 10 minutes. More importantly, additional flumazenil may be needed in a dose-dependent manner for complete or partial reversal, depending on sedation depth and the elapsed duration of the clinical effects of benzodiazepine.

In typical 2-compartment modeling, IV flumazenil undergoes rapid redistribution (4-11 minutes) followed by a more delayed elimination half-life (∼54 minutes), which contributes to its highly variable 19- to 50-minute duration of action. As such, it is possible that a patient could become clinically resedated following initial successful reversal. Vigilant patient monitoring is required for 1 to 2 hours or longer following the administration of flumazenil. Although the routine use of flumazenil in clinical practice has been described in the literature, the indications include urgent or emergent reversal of overdose or to facilitate rescue from unintended oversedation.⁹ Its routine use, particularly in an outpatient dental office environment, to speed discharge to an unmonitored setting (ie, transportation, home) is limited by the potential for significant resedation after flumazenil's antagonistic action has subsided. This precaution is valid for virtually all benzodiazepine-induced sedations and general anesthetics. Thus, patients who receive flumazenil require prolonged monitoring during the recovery phase to ensure that they do not resedate and lose upper airway reflexes or respiratory drive.¹⁰ Most national guidelines recommend at least 2 hours of observation following the administration of the last dose of flumazenil.¹¹ Therefore, routine administration of flumazenil to promote faster recovery and discharge cannot be recommended because of the potential for resedation.

Significant discussion persists surrounding flumazenil delivered by off-label intramuscular, submucosal, or sublingual injection routes of administration for emergency management. In their standalone canine study, Heniff et al¹² reported that the mean onset of IV flumazenil (120 ± 24.5 seconds) was faster than the sublingual (262 ± 94.5 seconds) and intramuscular (310 ± 133.7 seconds) routes (P < .005) after midazolam-induced respiratory depression. Published evidence to support the administration of flumazenil by these alternative routes is scant.¹³ Furthermore, additional issues can arise with flumazenil administered via these non-IV routes. Flumazenil is commonly supplied as a 0.1-mg/mL formulation in 5- and 10-mL vials. At that concentration, the volume required to administer 1 to 3 mg of flumazenil would be a minimum of 10 mL. While potentially lifesaving, a large volume of flumazenil administered into the intraoral tissue spaces poses several problematic issues. Injecting a large bolus sublingually or submucosally in patient with an obstructed airway can worsen an ongoing respiratory crisis by initiating bleeding or further reducing airway patency. Sedated patients can bite down upon the syringe during injection and cause medication spillage into the airway, precipitating laryngospasm and/or airway obstruction. While intramuscular administration is considered off-label, any consideration to its use in an urgent or emergent situation should include injection into sites unrelated to the oral cavity or airway such as deltoid or vastus lateralis (outer thigh). Most importantly, basic life support and supportive airway maneuvers (eg, head tilt-chin lift, jaw thrust) should be of primary consideration in a case of benzodiazepine-induced respiratory depression, with prompt pharmacologic reversal being an additional required intervention.⁷

Adverse Effects of Flumazenil. 

As a benzodiazepine antagonist, flumazenil competitively blocks the activity of drugs that bind to the benzodiazepine receptor complex (Figure 1), thus reversing sedative effects, impairment of recall, and psychomotor impairment. As a relative contraindication, clinicians should avoid its use in patients with seizures, with head injury, or who take tricyclic antidepressants. For patients with a history of seizure disorder, flumazenil use can lower the seizure threshold, which can decrease the effectiveness of antiseizure medications. Flumazenil may induce seizures in a patient with a head injury, altered cerebral blood flow, or increased cranial pressure.⁶ Panic attacks may be provoked if flumazenil is administered to patients with anxiety disorders or similar conditions treated with benzodiazepines.⁶ Seizure activity and cardiac ventricular arrhythmias have been produced when the dampening effect of benzodiazepines is reversed, unmasking tricyclic antidepressant toxicity.^7,14

Withdrawal. 

The administration of flumazenil, especially in relatively larger doses, may precipitate acute withdrawal for patients on chronic benzodiazepine therapy, users or abusers of sedative drugs, or those with alcohol use disorders. Autonomic hyperactivity such as hypertension, agitation, or delirium tremens¹⁵ may occur as well as other withdrawal signs and symptoms presented in Table 3. Chronic use of sedatives (ie, benzodiazepines, alcohol) can cause downregulation of inhibitory neurotransmitters such as GABA and upregulation of excitatory neurotransmitters such as glutamate.¹⁵ Abrupt cessation or reversal with flumazenil can lead to an imbalance of excitatory and inhibitory neurotransmitter activity, ultimately producing the signs and symptoms of withdrawal.¹⁵ In addition, dopaminergic and noradrenergic activity can be increased, leading to sympathetic hyperactivity, activation of the hypothalamic-pituitary-adrenal axis, and increased cortisol levels.¹⁵

Table 3. .

Signs and Symptoms of Withdrawal¹⁴

Signs	Symptoms
Tremor	Anxiety
Tachycardia	Agitation
Hypertension	Anorexia
Hyperreflexia	Nausea
Sweating (diaphoresis)	Vomiting
Hyperthermia	Insomnia
Seizures	Nightmares
Delirium	Hallucination (visual, tactile, auditory)

Naloxone

First approved by the US FDA in 1971, naloxone (Narcan) competitively antagonizes m-, k-, and d-opioid receptors with high affinity¹⁶ and is generally indicated for known or suspected opioid overdose. Classic signs of an opioid overdose include respiratory depression, apnea, central nervous system depression, bradycardia, asystole, and miosis. It can be administered by IV, intranasal, or endotracheal routes. IV naloxone dosing can vary depending on the situation, ranging from 0.04 to 0.08 mg for nonemergent oversedation to 0.4 to 2 mg for emergent opioid toxicity. It has a rapid onset of 1 to 2 minutes, with the peak effect occurring in 5 to 15 minutes when given intravenously. Subcutaneous and intramuscular routes are seldom used due to slower onsets than those previously mentioned and are generally not used in urgent and emergent clinical situations. Naloxone is metabolized in the liver primarily by conjugation with glucuronic acid.¹

Naloxone's duration of action depends heavily on the dose given and the route of administration. It has an elimination half-life of 2 hours when given intranasally and 1.2 hours following intramuscular injection. Like flumazenil, patients receiving naloxone require close monitoring to ensure that the opioid effects, namely, central nervous system and respiratory, do not return. Repeated dosing may be indicated as the duration of action of some opioids may exceed that of naloxone. In addition, the administration of naloxone may be complicated in some patient populations. Intranasal administration may not be reliable with patients with nonintact nasal mucosa such as in maxillofacial trauma. Limited absorption via the nasal route can also be prevalent in chronic cocaine users as well.

The opioid crisis, also referred to as the “opioid epidemic,” has prompted health care settings and first responders to have injectable or intranasal naloxone readily accessible to address clinically significant respiratory depression or apnea secondary to inadvertent opioid overdose. Naloxone kits have become more readily available in health clinics, pharmacies, workplaces, and at home.^17–19 In the United States, naloxone distribution programs are increasing,²⁰ while in Canada, the naloxone kits are available without a prescription and often free of charge, resulting from sponsorship by public health programs.¹⁸ Each take-home kit contains 1 to 2 intramuscular naloxone doses of 0.4 mg. A systematic review published in 2016 reported that take-home naloxone programs in North America, Europe, and Australia improved survival rates among program participants. Overall, these kits have reduced overdose-related mortality.¹⁸

Adverse Effects of Naloxone. 

Adverse events with naloxone administration are most commonly related to an abrupt release of catecholamines resulting from sudden increases in pain previously mediated by opioid analgesia.¹ As a result, hypertension, tachycardia, and in extreme cases ventricular arrhythmias and flash pulmonary edema can result.¹

Opioid Withdrawal. 

Caution should be exercised for the administration of naloxone to patients with opioid use disorders and chronic opioid users, as reversal may precipitate acute opioid withdrawal. Signs and symptoms can include hypertension, vomiting, agitation, irregular cardiac rhythms, diaphoresis, confusion, pulmonary edema, and/or seizures due to sudden catecholamine release in an opioid-dependent patient, as described earlier. In contrast to the typical 8-hour onset, 3-day peak, and 10-day course for acute withdrawal associated with abstinence for opioid dependency, naloxone-precipitated opioid withdrawal occurs in minutes, peaks at ∼30 minutes, and subsides within 1 hour.²¹ Drug craving (ie, the urge to use opioids) does not occur in naloxone-precipitated opioid withdrawal.²¹ Naloxone can be used in patients with opioid use disorders who exhibit signs and symptoms of acute opioid overdose, provided that they are appropriately monitored and managed for opioid withdrawal. Opioid use disorder may be treated with behavioral cognitive therapy, long-acting opioids such as methadone, or opioid partial agonist-antagonists such as buprenorphine (Suboxone, Subutex) and extended-release naltrexone (Vivtrol).

NEUROMUSCULAR BLOCKADE REVERSAL DRUGS

Reversal drugs that are routinely used during general anesthesia for dentistry counteract nondepolarizing neuromuscular blockade often used in intubation, emergent laryngospasm management, and surgical procedures requiring paralysis and muscular flaccidity. For this purpose, neostigmine is still commonly used, and sugammadex is now available internationally.

Neostigmine

Neostigmine is a reversible acetylcholinesterase inhibitor used to reverse the effects of nondepolarizing neuromuscular blocking drugs (NMBDs). By inactivating the enzyme acetylcholinesterase, neostigmine impairs the normal breakdown and thus the rate of degradation of acetylcholine, leading to drastically increased concentrations of acetylcholine within the neuromuscular synaptic cleft. The increased quantity of acetylcholine molecules competitively displaces the nondepolarizing NMBD molecules at the postsynaptic nicotinic receptors, reestablishing normal neuromuscular function and reversing paralysis. Neuromuscular paralysis reversal depends on the degree of blockade prior to administering neostigmine. Four visual or tactile muscle contractions at the adductor pollicis, or other anatomic sites used for muscle paralysis monitoring, following train-of-four (TOF) electrical stimulation of the ulnar nerve (ie, TOF ≥0.9) is required before administering neostigmine. The TOF ratio estimates the degree of neuromuscular blockade. A series of four 2-Hz pulses is administered to observe muscle twitches. The TOF ratio is the amplitude between the fourth to first twitch.³ The full dose of neostigmine is 0.05 mg/kg based on lean body weight. Accordingly, if there is minimal residual neuromuscular blockade, the neostigmine dose should be reduced by half of the appropriate dose. The surge in acetylcholine concentration precipitating unwanted parasympathetic vagal response requires concurrent administration of an antimuscarinic anticholinergic agent, namely, atropine 0.02 mg/kg or glycopyrrolate 0.004 mg/kg. A meta-analysis supports the preference for the coadministration of glycopyrrolate because of its superior efficacy and reduced side effect profile when compared with atropine use for NMBD reversal.³ The classic and recommended dose for this drug pairing was 0.2 mg of glycopyrrolate for every 1 mg of neostigmine, given concomitantly, noting that the maximum dose was 1 mg glycopyrrolate and 5 mg neostigmine. The pairing ratio of 0.2 mg glycopyrrolate to 1 mg neostigmine for NMBD reversal has become common practice. The onset of action is ∼1 minute with a peak effect at 9 minutes. The plasma half-life of neostigmine ranges from 45 to 60 minutes.²² It is eliminated unchanged in the urine (50%) and metabolized by plasma cholinesterase and the liver (30%).²²

Adverse Effects of Neostigmine. 

The most significant adverse effect reported with neostigmine coadministered with an anticholinergic (ie, glycopyrrolate or atropine) was parasympathetic-mediated postoperative nausea and vomiting.²³ In contrast to these reports, a meta-analysis by Cheng et al²⁴ found that neostigmine in combination with glycopyrrolate or atropine did not significantly increase the risk of postoperative vomiting within 24 hours (relative risk 0.91, confidence interval [0.70-1.18]; P = .48). Atropine reduces postoperative nausea and vomiting (PONV) by the central effects attributed to its tertiary amine structure, enabling it to cross the blood-brain barrier, whereas glycopyrrolate's quaternary amine cannot do so.²⁵ Furthermore, using multiple logistic regression analysis, these authors found no significant increase in vomiting risk with large doses of neostigmine.²⁴ In practice, clinicians commonly perform PONV prophylaxis by routinely administering other antiemetics such as the serotonin 5-HT3 receptor antagonist ondansetron.

Acute Cholinergic Crisis. 

Acute cholinergic syndrome or crisis results from a sudden excess of acetylcholine concentration in the synaptic cleft of the neuromuscular junction, which may result from neostigmine use. Symptoms of muscarinic and nicotinic toxicity (Table 4) include cramps, hypersalivation, lacrimation, muscular weakness, paralysis, muscular fasciculation, diarrhea, and blurry vision.²⁶ Parasympathetic effects, such as nausea, vomiting, gut peristalsis, secretions, bronchospasm, and miosis have been experienced with neostigmine.²⁶ Cardiovascularly, the most pronounced effect is clinically significant bradycardia if neostigmine is administered without a muscarinic antagonist. Offsetting these adverse effects is achieved by coadministration of an antimuscarinic (eg, glycopyrrolate or atropine), which is common practice.

Table 4. .

Muscarinic and Nicotinic Toxicity²⁴

Muscarinic Effects of Acetylcholine	Nicotinic Effects of Acetylcholine
Eye miosis and blurry vision	Voluntary muscle fasciculation, flaccid paralysis
Nausea, vomiting, diarrhea	Tachycardia that progresses to bradycardia
Bronchoconstriction, bronchorrhea
Hypersecretions in tracheobronchial and gastrointestinal systems
Bradycardia
Urinary frequency and urgency

Sugammadex

Sugammadex (Bridion) is a relatively novel drug that uses a gamma-cyclodextrin molecule, essentially a sugar structure that resembles a hollow, truncated cone (Figure 2), which encapsulates nondepolarizing steroidal NMBDs in a 1:1 ratio, rendering them otherwise inert. These include the nondepolarizing agents that have “-onium” in the suffix of the drug name: pancuronium, pipecuronium, rocuronium, and vecuronium. Sugammadex does not have clinical effects on the benzylisoquinoline class of nondepolarizing drugs, such as cisatracurium or mivacurium, because of its unique structural selectivity. It has the greatest affinity for rocuronium but will also sequester vecuronium.

Figure 2. .

Molecular structure of sugammadex.

It is recommended to adjust the dose of sugammadex according to ideal body weight and the intensity of neuromuscular blockade induced by rocuronium.²⁵ A study by Lee et al²⁷ induced and maintained patients under anesthesia using propofol and opioids. Their test group was administered rocuronium 1.2 mg/kg, followed 3 minutes later by sugammadex 16 mg/kg. For comparison, the control group was administered succinylcholine 1 mg/kg and then allowed to recover spontaneously. Their results demonstrated that the rocuronium-sugammadex group recovered (ie, TOF ≥0.9) in 6.2 minutes versus 10.9 minutes for the control group. They stated in their conclusions that faster recovery from muscular blockade could be achieved by immediate reversal of rocuronium using sugammadex in emergent “cannot intubate, cannot ventilate” situations.²⁷ Pharmacokinetically, the sugammadex-NMBD complex is excreted unchanged via the kidneys (75%-90%).²²

The selection of sugammadex dose is dependent on actual body weight and the depth of the nondepolarizing neuromuscular blockade.²⁸ The 2-mg/kg dose is recommended for a moderate block (ie, reappearance of the second twitch); the 4-mg/kg dose is recommended for a deep block (ie, no twitch response).²⁸ The 16-mg/kg dose is reserved for emergent situations when immediate reversal is required for patient who has received rocuronium 1.2 mg/kg approximately 3 minutes prior.²⁸ Any bolus would be administered over 10 seconds.²⁸ No dose adjustments are required for special populations such as patients with cardiac, pulmonary, and/or mild or moderate renal disease. No dose adjustments are necessary for geriatric patients unless severe renal impairment is present.²⁸

Adverse Effects of Sugammadex. 

Sugammadex has minimal adverse effects overall, as it is stable and biologically inert. However, unintended drug interactions may occur whereby it encapsulates other drugs that include opioids, hydrocortisone, verapamil, and atropine.²² Rocuronium could be displaced by coadministration of these agents, and then some level of neuromuscular blockade could be reinitiated.²² The mechanism for this possible drug interaction is unclear. There are a few reports of vagal responses occurring following administration of sugammadex. Although poorly understood, it is for this reason that atropine or glycopyrrolate should be made readily available.

Hypersensitivity and Anaphylaxis. 

There are anecdotal reports of anaphylaxis and significant cardiovascular events with sugammadex. Hypersensitivity, allergy, and anaphylaxis have been rarely reported in the literature.^22,28–30 These anecdotal reports suggest the allergic response is an immunoglobulin E–mediated reaction that results in elevated serum tryptase levels and/or a positive reaction to a skin-prick test.^22,28 In a randomized, double-blind, placebo-controlled, parallel-group, repeat-dose study, 375 subjects were randomized to receive 3 doses of sugammadex (0 mg/kg, 4 mg/kg, and 16 mg/kg) by IV administration.²⁸ The incidence of anaphylaxis among these healthy volunteer subjects was 0.3% (n = 1 in the 16-mg/kg group on the first dose). This subject experienced conjunctival edema, urticaria, erythema, swelling of the uvula, and reduction in peak expiratory flow within 5 minutes of dose administration.²⁸ In other reports, urticaria, rash, erythema, flushing and skin eruption, hypotension, hospitalization, and respiratory support have been observed.²⁸

Interestingly, there has been 1 case report involving a 33-year-old patient who experienced rocuronium-induced anaphylaxis while undergoing laparoscopic surgery and rapidly stabilized following the administration of sugammadex.²⁹ In that case, the anaphylaxis was unresponsive to epinephrine, crystalloid fluids, and prolonged cardiopulmonary resuscitation.²⁹

Dysrhythmias. 

A few reports of QTc interval prolongation, atrioventricular block, and even cardiac arrest after sugammadex exist. It is postulated that the maintenance anesthetic agents propofol or sevoflurane could have been contributory; however, the mechanism for this vagal effect is not yet fully understood.^22,28

LOCAL ANESTHETIC REVERSAL DRUGS

In dentistry, the so-called “reversal” of soft-tissue anesthesia may be desired in pediatrics, special care dentistry, or certain circumstances when normal oral function is immediately necessary. Rather than structurally encapsulating a local anesthesia molecule or competitively inhibiting intracellular sodium channels, the intended aim of local anesthesia reversal is to abbreviate the duration of action of anesthetic action and restore function to the affected area by causing vasodilation. Individual characteristics of local anesthetics, such as pKa, pH, lipid solubility, or protein binding, are left unaffected by the resulting vasodilation.

Phentolamine

Phentolamine mesylate (OraVerse) is a nonselective α-adrenergic antagonist used to clinically “reverse” the effects of local anesthesia in dental procedures. Phentolamine does not provide pharmacologic antagonism of any local anesthesia molecule. Instead, the action of this direct-acting α-antagonist increases vasodilation of the submucosal and other intraoral tissues primarily by blocking the α₁ vasoconstriction produced by epinephrine or levonordefrin. This effectively facilitates absorption of the local anesthetic into the systemic vasculature and clearance away from its site of administration. While it does not provide true pharmacologic reversal in terms of antagonistic action within sodium ion channels directly, phentolamine effectively reduces a local anesthetic's duration of action. Indications for its use include the prevention of self-inflicted soft-tissue trauma in young children or patients with cognitive impairments as well as reducing prolonged local anesthesia to facilitate ease of eating, drinking, or speaking.² According to the manufacturer, normal sensation returns in ∼50 minutes for the upper lip and ∼70 minutes for the lower lip. To administer this reversal agent, practitioners deposit phentolamine into the same anatomic area using the same techniques for the local anesthetic injections. The dose administered is determined by a 1:1 cartridge ratio to the local anesthetic. Maximum recommended doses are listed for adult and pediatric patients in Table 1.

Adverse Effects of Phentolamine. 

Overall, phentolamine's safety profile is favorable when used to shorten the duration of action of intraoral local anesthetics. Cardiovascular effects, namely, compensatory tachycardia in response to systemic vasodilation and hypotension, may occur if the drug is inadvertently injected intravascularly. The common adverse effects reported by a national, prospective, noninterventional, study (ORAPAES: OraVerse Post-Authorization Efficacy Study) included injection site pain, hypertension, bradycardia, and headache.² These effects were reported when the drug was administered submucosally. Caution is recommended in patients who have coronary artery disease or insufficiency or other significant cardiovascular risk. Increasing the rate at which local anesthesia is absorbed into systemic circulation may also contribute to local anesthesia toxicity due to an increase in serum concentration.

CONCLUSION

Reversal agents are a key part of sedation and anesthesia practice in dental settings. The benzodiazepine antagonist flumazenil and the opioid antagonist naloxone are typically reserved for emergent use or to rescue a patient from unintended levels of deeper sedation. For both agents, prolonged postoperative monitoring is required to assess for potential resedation that may manifest after their reversal actions wane. It is important to consider both absolute and relative contraindications before use to avoid significant complications. Sugammadex and neostigmine are paralytic reversal agents commonly used to antagonize the effects of nondepolarizing NMBDs. Lastly, phentolamine is uniquely used to cause local vasodilation, reversing the effects of local anesthetic. It can be deployed after dental care for pediatric or special needs populations. Safe and effective use of these reversal drugs requires keen understanding of each agent's particular pharmacodynamic and pharmacokinetic profiles along with full appreciation of their respective indications, contraindications, and potential adverse effects.

CONTINUING EDUCATION QUESTIONS

This continuing education (CE) program is designed for dentists who desire to advance their understanding of pain and anxiety control in clinical practice. After reading the designated article, the participant should be able to evaluate and utilize the information appropriately in providing patient care.

The American Dental Society of Anesthesiology (ADSA) is accredited by the American Dental Association and Academy of General Dentistry to sponsor CE for dentists and will award CE credit for each article completed. You must answer 3 of the 4 questions correctly to receive credit.

Submit your answers online at www.adsahome.org. Click on “On Demand CE.”

CE questions must be completed within 3 months and prior to the next issue.

1. All of the following are correct statements about flumazenil EXCEPT:

   1. it assists in psychomotor recovery.

   2. it can lower the seizure threshold.

   3. it competitively binds directly to the GABA receptor.

   4. it structurally resembles midazolam.

2. All of the following are correct statements about naloxone EXCEPT:

   1. it can precipitate opioid withdrawal in minutes.

   2. it comes in a formulation for intranasal delivery.

   3. it does require prolonged monitoring after use.

   4. it reverses fentanyl and midazolam.

3. Which statement about neostigmine is TRUE?

   1. Dose calculation should be based on lean body weight.

   2. Glycopyrrolate is coadministered with neostigmine to prevent tachycardia.

   3. Neostigmine has potent antiemetic effects.

   4. Neostigmine is an acetylcholine inhibitor.

4. Which statement about sugammadex is TRUE?

   1. A dose of 16 mg/kg can reverse rocuronium 1.2 mg/kg.

   2. Displacement drug interactions may occur with local anesthetics.

   3. It undergoes significant metabolism by the liver.

   4. Succinylcholine-induced paralysis is reversed by sugammadex.