Intranasal Anesthetic Effects of Lidocaine and Tetracaine Compared

Intranasal anesthetic effects of lidocaine and tetracaine compared

ALLEN D. NOORILY, MD, RANDALA. OTTO, MD, and SUSAN H. NOORILY, MD, San Antonio, Texas

The quality of nasal anesthesia obtained with two local anesthetic solutions (2% iidocaine in oxymetazoline and I% tetracaine in oxymetazoline] was evaluated in this double-blind, randomized study. Each local anesthetic mixture was applied to the nasal septum of healthy volunteers with medication-soaked pledgets. Measurements of anesthetic effect [sensation threshold and pain perception] were made with Semmes-Weinstein monofllaments [North Coast Medical, San Jose, Calif.]. Measurements were performed before local anesthetic application and at 10 and 70 minutes after local anesthetic application. Subjects had greater increases in sensation threshold with tetracaine than with lidocaine at both 10 and 70 minutes [p = 0.0005 and p = 0.0001, respectively]. Subjects had greater decreases in pain perception with tetracaine than with lidocaine at both time intervals [p = 0.0003 and p < 0.0001, respectively]. Tetracaine mixed with oxymetazoline appears to be a superior topical anesthetic for nasal procedures. [OTOLARYNGOLHEAD NECK SURG 1995;113:370-4.]

Cocaine has been used to provide topical nasal gists for spinal anesthesia but is suitable for infil- anesthesia and vasoconstriction for more than 100 tration, peripheral nerve block, and topical anesthe- years) It was favored by otolaryngologists and an- sia on accessible mucous membranes¢ Tetracaine is esthesiologists because of its availability, low cost, one of the ingredients in Cetacaine, a commercially and inherent vasoconstrictor properties at clinically available topical anesthetic spray. Because tetra- useful doses. 1'2 Recently, however, the routine use of caine is very potent and capable of providing anes- cocaine has been criticized because of increasing thesia for long durations, it would appear to be costs, abuse potential, side effects, and availability desirable as a topical nasal anesthetic. The purpose restrictions. 3'4 For these reasons, alternative topical of this study was to compare the anesthetic effect of anesthetics for intranasal procedures are desirable. tetra/oxy with that of lido/oxy when applied intra- We have shown that no difference exists between nasally. the intranasal anesthetic or vasoconstrictive effects Few controlled clinical studies of topical anes- of cocaine and those of a lidocaine-oxymetazoline thetics have been performed because it is difficult to (lido/oxy) mixture2 The combination of tetracaine design objective techniques to evaluate the quality of and oxymetazoline (tetra/oxy) is another mixture local anesthesia. Semmes-Weinstein monofilaments that has been used as a cocaine substitute. Its quality (North Coast Medical, San Jose, Calif.) have been as a nasal local anesthetic has not been reported. successfully used to measure and compare intrana- Tetracaine is most commonly used by anesthesiolo- sal sensation thresholds and pain perception. The specifics of their use have been described previously From the Departments of Otolaryngology-Headand Neck Sur- and will be only briefly discussed here/ gery (Drs. A. Noorily and Otto) and Anesthesiology (Dr. S. Noorily),The Universityof Texas Health ScienceCenter at San METHODS AND MATERIAL Antonio. The study protocol was reviewed and approved by Presented at the Annual Meeting of the American Academy of the Institutional Review Board at The University of Otolaryngology-Head and Neck Surgery, San Diego, Calif., Sept. 18-21, 1994. Texas Health Science Center at San Antonio. All Received for publication July 28, 1994; accepted March 10, 1995. subjects gave informed consent before enrollment. Reprint requests: Allen D. Noorily, MD, Department of Oto- Fifteen healthy volunteers participated in the study. laryngology-Head and Neck Surgery, The Universityof Texas Subjects ranged in age from 24 to 64 years (mean, Health Science Center at San Antonio, 7703 Floyd Curl Dr., 35.7 years). Subjects with a history of active sinona- San Antonio, TX 78284-7777. Copyright © 1995 by the American Academyof Otolaryngology- sal disease or local anesthetic sensitivity were ex- Head and Neck Surgery Foundation, Inc. cluded. 0194-5998/95/$5.00 + 0 23/1/64767 Each subject participated in two sessions, which 370 Otolaryngology - Head and Neck Surgery Volume 113 Number 4 NOORILY et al. 371

took place at least 48 hours apart. Seven subjects against the anterior nasal septum. The subject was received lido/oxy during the first session and instructed to remember this stimulus as 10 on the tetra/oxy during the second session. The other eight VAS, to be used for comparison later in the session. subjects received the agents in reverse order. The Fresh anesthetic solutions were prepared within order of drug administration was determined by 30 minutes of use. The lido/oxy mixture was pre- computer-generated pair-wise randomization. Both pared by mixing 5 cm3 of 4% lidocaine with an equal the subjects and the investigators were blinded (both volume of 0.05% oxymetazoline, yielding a final solutions are colorless) to this order. concentration of 2% lidocaine and 0.025% oxymeta- Baseline measurements of sensation thresh- zoline. The tetra/oxy mixture was prepared by dis- old were made before application of local anes- solving 20 mg of tetracaine in 2 cm3 of 0.05% thetic with the Semmes-Weinstein monofilaments. oxymetazoline, yielding a final concentration of 1% Semmes-Weinstein monofilaments are based on the tetracaine and 0.05% oxymetazoline. A cottonoid von Frey hairs, which were developed in 1898. Each pledget (1.3 x 3 cm) was saturated with local anes- monofilament is calibrated to a specific stiffness.7'8 thetic solution. Each pledget absorbed approxi- The tip of the monofilament is placed on the surface mately 0.5 em3 of solution. The medication-soaked to be tested, and pressure is applied until the fila- pledget was placed in the nasal cavity against the ment bends. When the monofilament bends, a stan- septum at time zero and removed, at 10 minutes, dardized force is applied to the surface, in this case Measurements of sensation threshold were re- the nasal septum. The units of the Semmes-Wein- peated at 10 minutes, as previously described. Pain stein monofilaments are expressed as log (10 × force perception was determined in the following manner. in milligrams), where force is the force applied by the The 5.18 filament was pushed against the nasal monofilament when it bends. Most often, the septum until it bent. The subject was asked to mark monofilaments are used to determine the sensation the VAS, rating the pain felt: 0 on the scale indicated threshold for touch and pressure? Because the nasal no pain felt, and 10 indicated the same amount of mucosa has no pressure receptors, application of the pain felt before administration of the anesthetic. monofilaments to the nasal septum measures the Both sensation threshold and pain perception mea- threshold of free nerve endings within the nasal surements were again repeated at 70 minutes. mucosa. A large monofilament can provide a base- Changes in sensation threshold were calculated by line standardized "maximal" painful stimulus to be subtracting the baseline threshold from the thresh- used for comparison purposes after local anesthetic old measured at 10 and 70 minutes. Changes in pain application. perception were measured as the centimeters of line Subjects were asked to close their eyes to prevent on the VAS between 10 and the mark made by the any visual clues. A large filament (5.18; 12.5 gin) was subject. The aforementioned trials were compared gently applied to the nasal ala, vestibule, nasal hairs, by use of a paired t test. and septum to help the subject discriminate between these structures. The nasal ala was gently retracted RESULTS laterally with a blunt-ended, single-pronged retrac- All 15 subjects completed both sessions. No ad- tor to provide easy access to the nasal septum during verse side effects were noted. No significant differ- measurements. The smallest filament (1.65; 0.008 ence was found in the baseline measurements of the gin) was pushed against the anterior nasal septum subjects between the two anesthetic trials. The mean until the filament bent. The subject was then asked change in sensation threshold is shown in Fig. 1. The to state whether the filament could be felt on the tetra/oxy trial showed a significantlygreater increase septum, with any sensation from adjacent structures in sensation threshold than the lido/oxy trial at both ignored. If the subject could not feel the filament, 10 and 70 minutes. The mean change in sensation the next larger filament was applied. This process threshold at 10 minutes for tetra/oxy was 2.27 and was repeated until a filament was felt. The small- for lido/oxy was 1.36 (p = 0.0005), with the units est filament felt was recorded as the sensation representing log (10 × force in milligrams). The threshold. mean change in sensation threshold at 70 minutes Pain perception was rated on a visual analog scale for tetra/oxy was 1.56 and for lido/oxy was 0.57 (VAS). The scale consisted of a 20-cm line with a 0 (p = 0.0001). During the course of the study, one (zero) on one end and a 10 on the other. No anesthetized subject had a threshold shift surpassing intermediate marks were present. Before the local the 6.10 (84.96 gm) filament. When this occurred, anesthetic was applied, the 5.18 filament was pushed larger filaments were not tested for fear of damaging Otolaryngology - Head and Neck Surgery 372 NOORILY et al. October 1995

2.5 ...... ,~ T I [] Lido/oxyI l:::: ~ ] [] Tetra/oxyI l'~ 2.

m .:..:..:.:..;.S'.%'- P < 0.000 Lo ;~,..g.g.¢""~'~

'r" ~:.~:-~'-~ Error bar = ] 0.5 ~,~..:.~..~"///////,//j- 'i""~~.,'-.~y//////.//7~ 'i standard error I .,.,:.;."'~'4'~ i F~!~ °f the mean I

10 70 Time (minutes)

Fig. 1. Means(+_SEMlforthechangeinsensationthresholdsasmeasuredbytheSemmes-Weinstein filaments at 10 and 70 minutes after application of either tetra/oxy or Udo/oxy.

the nasal septal mucosa. The threshold shift was decreasing availability, toxicity, and habit-forming recorded as 6.10 for this subject, although the true potential. 1-4 threshold may have been higher. Few other local anesthetics have been widely used The mean change in pain perception is shown in to provide topical nasal anesthesia. Lidocaine and Fig. 2. The tetra/oxy trial showed a significantly tetracaine are the most commonly chosen alterna- greater decrease in pain perception than the tives to cocaine but must be mixed with a vasocon- lido/oxy trial at both 10 and 70 minutes. The mean strictor to provide optimal surgical conditions. Our change in pain perception at 10 minutes for tetra/oxy previous study demonstrated that the combination was 16.8 cm and for lido/oxy was 8.3 cm of lidocaine and oxymetazoline was as efficacious as (p = 0.0003). The mean change in pain perception cocaine in providing intranasal anesthesia and va- at 70 minutes for tetra/oxy was 12.4 cm and for soconstriction? Other studies have shown that lido/oxy was4.2 cm (p < 0.0001). oxymetazoline and cocaine have similar vasocon- A sample size determination before the study was strictive effects when applied intranasally.9,1° The begun estimated that 43 subjects were needed to purpose of this study was to compare tetracaine, in show a 30% difference between treatment groups. low doses, with lidocaine as a topical nasal anes- An interval analysis after the first 15 subjects showed thetic. The results of the study indicate that tetra/oxy a significant difference between tetracaine and is, in fact, a better nasal anesthetic than lido/oxy. lidocaine, and therefore the study was concluded at Tetracaine was a commonly used topical anes- this point. thetic in the past because it appeared to be most effective in anesthetizing structures deep to the DISCUSSION superficial mucous membranes. A 1956 report in the Otolaryngologists, facial plastic surgeons, and an- Journal of the American Medical Association" dis- esthesiologists rely on local anesthetics to perform cussed fatalities that occurred after the topical ap- many intranasal procedures? With the increased use plication of local anesthetic to mucous membranes, of functional endoscopic sinus surgery, the number and most of these cases involved tetracaine. The of intranasal procedures performed with local an- toxic reactions to tetracaine were described as being esthesia will probably increase. For many years, more severe than those to other local anesthetics. In cocaine was the preferred topical local anesthetic most of the tetracaine fatalities, the dose exceeded agent used for intranasal procedures, but a replace- the recommended maximum dose of 100 mg. In two ment has been sought because of its increasing cost, follow-up articles, it was demonstrated that tetra- Otolaryngology - Head and Neck Surgery Volume 113 Number 4 NOORILY et al. 373

2 0 ...... i ...... ] [] Lido/o×y l I [] retra/oxy [

15 ......

I11 , ? ?, .E lo ...... T ...... ! P < 0.0005

5 ...... T ...... V////////k, I~3.'~.Jf;~.~gg~.j~.~.~.~.~//////////J ~ F/////////~ I Standard error I

?.~:~ ".,~:::~ i .~:~:~:~:~.~:y .fi F/'///////4 ::, o - H 10 70 Time (minutes)

Fig. 2. Means (_+SEM) for the change in pain perception as measured by the 5.18 Semmes- Weinsfein filament at 10 and 70 minutes after application of either tetra/oxy or lido/oxy.

caine, when applied topically to the mucous mem- anesthetics. Small amounts of tetracaine absorbed branes of the pharynx and trachea, is absorbed sys- systemically would be easily metabolized in the temically such that blood levels are comparable with plasma, making the topical administration of tetra- those after intravenous injection. 1243 Vasoconstric- caine safe as long as doses are kept below the toxic tors did not retard the absorption of local anesthetic range. Although the maximal safe dosage of tetra- from the mucous membranes tested, but absorption caine for topical use has never been clearly defined, of local anesthetic from the nasal mucosa was not the 5 mg of tetracaine applied to the nasal septum evaluated. ~4 As a result of these reports, the use of of the study subjects is a very small dose and was tetracaine as a topical anesthetic fell into disfavor. found to be very effective. Interestinglyl the recommended alternative topical In addition to finding that tetracaine provided anesthetic at that time was believed to be cocaine. superior nasal anesthesia to lidocaine, it also has the More recently, tetracaine has been combined with advantage of an increased duration because of the adrenaline and cocaine as a topical anesthetic in a drug's high degree of protein binding (76%). In this mixture known as TAC. TAC is most commonly study intranasal tetracaine appeared to provide an- used by emergency department physicians to close esthesia for greater than 70 minutes, although dura- skin lacerations in pediatric patients, obviating the tion of anesthetic action was not specifically evalu- need for local injections. 1~,~6There have been reports ated. A long duration of action is desirable for nasal of morbidity associated with the use of TAC in this procedures, which often last for more than 1 hour setting, especially when the solution is applied near and leave the patient with some postoperative dis- mucous membranes. 17,~8 comfort. It is known that intranasal anesthetics are ab- One disadvantage of tetracaine is that it has a sorbed systemically to some degreeJ 9 Ester local longer latency period than many other local anes- anesthetics are rapidly hydrolyzed by pseudocholin- thetics because of its high pKa (8.5). The slower esterase in the plasma and partly by the liver. When onset of action of tetracaine was apparent in this a toxic level of an ester local anesthetic is achieved, study, although this aspect was not specifically evalu- any systemic reaction should be brief unless the ated. In contrast, both lidocaine and cocaine have enzyme is saturated or "atypical," in which case short latency periods. This difference does not ap- toxic reactions will be prolonged. Tetracaine is me- pear to detract from the benefits of tetracaine when tabolized at a slower rate than other ester local used intranasally; despite a longer latency, tetra/oxy Otolaryngology - Head and Neck Surgep/ 374 NOORILY et al. October 1995

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Although the concentration of oxymetazoline was 6. Covino BG. Clinical pharmacology of local anesthetic agents. not constant during the study, it is unlikely that this In: Cousins MJ, Bridenbaugh PO, eds. Neural blockade in affected the results. Tetracaine crystals can be dis- clinical anesthesia and management of pain. 2nd ed. Philadelphia: J.B. Lippincott Co., 1988:86-121. solved in other vasoconstrictor solvents, such as 7. Levin S, Pearsall G, Ruderman RJ. Von Frey's method of epinephrine, but the potential cardiovascular effects measuring pressure sensibility in the hand: an engineering of this combination must be recognized. analysis of the Weinstein-Semmes pressure aesthesiometer. We did not directly compare tetra/oxy with co- J Hand Surg 1978;3:211-6. caine in this study. Because our previous study found 8. Halar EM, Hammond MC, LaCava EC, Camann C, Ward J. Sensory perception threshold measurement: an evaluation of no difference between cocaine and lido/oxy when semiobjective testing devices. Arch Phys Med Rehabil 1987; applied intranasally, an indirect comparison can be 68:499-507. made regarding cocaine and tetra/oxy. The methods 9. Wight RG, Cochrane T. A comparison of the effects of two of sensation measurement and pain perception used commonly used vasoconstrictors on nasal mucosal blood flow were identical in both studies. The results suggest and nasal airflow. Acta Otolaryngol (Stockh) 1990;109:137- 41. that the sensation threshold shifts and the reduc- 10. Bende M, Loth S. Vascular effects of topical oxymetazoline tions in pain perception are greater in the tetra/oxy on human nasal mucosa. J Laryngol Otol 1986;100:285-8. group than those obtained in the previous study's 11. Adriani J, Campbell D. Fatalities following topical applica- cocaine group. The average change in sensation tion of local anesthetics to mucous membranes. 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