Intralingual naloxone reversal of morphine-induced respiratory depression in dogs

ORIGINAL CONTRIBUTION intralingual drug administration; naloxone, intralingual

Intralingual Naloxone Reversal of MorphineInduced Respiratory Depression in Dogs A descriptive study was done to determine whether naloxone is efficacious in reversing morphine-induced respiratory depression in dogs when administered intralingually into the ventral lateral surface of the tongue. Mean minute ventilation was depressed to half of resting baseline levels using fixed intravenous doses of morphine sulfate. Intralingually administered naloxone reversed this respiratory depression rapidly within one minute, and resulted in a greater than fourfold increase in mean minute ventilation above established baseline levels. [Maio RE Griener JC, Clark MR, Gifford G, Wiegenstein JG: Intralingual naloxone reversal of morphine-induced respiratory depression in dogs. Ann Emerg Med December 1984;13:1087-1091.] INTRODUCTION

Endotracheally (ET} administered drugs have been advocated for emergency drug administrationJ -a Human and animal studies support the efficacy of this technique. 4-1° Intubation may be difficult to accomplish quickly, however. Intramuscular (IM) or subcutaneous (SC) drug administration suffer the drawbacks of slow absorption and erratic onset of action, even under normal cardiovascular conditions, n-t2 These problems are magnified further by decreased cardiac output and peripheral vasoconstriction. The ventral lateral surface of the tongue is a highly vascular organ.13 Radioactive microsphere studies done in dogs have demonstrated that the tongue maintains its ability to autoregnlate blood flow even in situations of low cardiac output.14,1~ This raises the possibility of using the tongue as a route for emergency drug administration. Uncontrolled animal studies, t6-1s an emergency care manual, i9 anecdotal reports on human subjects, 2o-22 and sources for prehospital care guidelines23, 24 have advocated the tongue as a site for emergency drug administration. The efficacy of naloxone as a narcotic antagonist has been clearly established.2S-29 An anecodotal report discusses the feasibility of intralingually (IL) administered naloxone 22 in heroin abusers. To date, however, no wellcontrolled animal study or well-documented case report substantiates the usefulness of naloxone used by the IL route. The purpose of our pilot study was to design a descriptive experiment to verify and determine pharmacodynamically if naloxone, administered intralingually, is absorbed rapidly and efficiently enough to antagonize morphineinduced respiratory depression in dogs.

Ronald F Maio, DO James C Griener, PharmD Michael R Clark, MD, FACEP Gregory Gifford, MD John G Wiegenstein, MD Lansing, Michigan From the Michigan State University Affiliated Hospitals Emergency Medicine Residency,* and the Department of Pharmacy Services, EW Sparrow Hospital,l- Lansing; and the Section of Emergency Medicine, College of Medicine, Michigan State University,I- East Lansing, Michigan. Received for publication June 16, 1983. Revision received April 6, 1984. Accepted for publication May 24, 1984. Presented at the University Association for Emergency Medicine Annual Meeting in Boston, June 1983. Address for reprints: Ronald F Maio, DO, Emergency Medicine Residency, EW Sparrow Hospital, PO Box 30480, Lansing, Michigan 48909.

MATERIALS A N D M E T H O D S

Four male mongrel dogs were anesthetized with sodium pentobarbital (30 mg/kg) administered intravenously (IV). Animals were intubated and a cuffed plastic endotracheal tube was inserted. The baseline minute ventilation (MV) of each dog was recorded and continuously monitored using the Bourns ventilation monitor (model LS-75) attached to the endotracheal tube. When a stable baseline had been established (our criterion was three continuous oneminute observations within 20% of each other), morphine sulfate was administered IV. Morphine sulfate (15 mg/mL) was given slowly in 0.25-mL to 0.5-mL fixed volumes over one minute until the respiratory depression (defined as 50% of the initial baseline minute ventilation) was achieved. The dose of morphine sulfate required to achieve this ranged from 25 mg to 65

13:12 December 1984

Annals of Emergency Medicine

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INTRALINGUAL NALOXONE Maio et al

Fig. 1. Percentage change of mean ventilation over baseline.

mg (mean, 40 rag). In all experiments morphine respiratory depression was achieved in less than 30 minutes. Once 50% baseline MV was established, 1.0 mL of sterile normal saline solution was administered intralingually into the ventral lateral surface of the tongue. Minute ventilation was again recorded at one, three, and five minutes postinjection. Animals were re-established to 50% MV when necessary (75% of the animals required this). A fixed dose of 1.0 mL (0.4 mg) of n a l o x o n e was i n j e c t e d intralingually on the same side as the previous saline injection, and similar observations made at one, three and five minutes postinjection.

RESULTS Percentage changes in mean ventilation observed in four dog experiments are compared to baseline levels (Figure 1). The pretreatment baseline observations for mean MV for the dogs studied was 2.44 _+ 1.01 L/min. The mean MV post IV injection of morphine decreased to 51% of previous baseline levels. With administration of 1.0 mL normal saline (IL), mean minute ventilation increased to within 15% of baseline levels. When 1.0 mL naloxone was injected (IL), mean MV increased 447% above the 50% mean minute ventilation and 223% above the mean baseline MV. Mean observations (N=4) made at one, three, and five minutes following IL sterile normal saline and naloxone injections are shown (Tables 1 and 2). The onset of effect of the IL naloxone appeared to occur rapidly, within one minute of the injection (Figures 2 and 3). The peak effect in these experiments appeared to plateau between three and five minutes (Figures 2 and 3). To measure the effect of the saline injection (noxious stimuli) on the results, the overall percentage change was calculated as follows: IL naloxone % change IL saline % change mean baseline MV The results of the calculation are shown (Tables 2 and 3), and are plotted as a graph (Figures 2 and 3).

DISCUSSION Many clinical situations involve pa16/1088

500-

q~ r-

400"

09 G~ fl3

*P<.O25 tNS :~P<.005 *Note: P values are based on Student one-tailed t test.

300-

~g 200r(D

100500

w

Baseline

IV Morphine

tients with severe peripheral vascular constriction, making direct venous access difficult. This problem is compounded in children, obese patients, dialysis patients, and drug abusers. Case reports and animal studies support the efficacy of endotracheal drug administration, 4-10 yet difficulties can occur in intubation. Frequently naloxone must be administered to patients with scarcity of peripheral veins. Under these conditions, the IM or SC routes would appear adequate; however, these routes provide less rapid and less predictable systemic absorption.llA2, 3° The tongue has been advocated as a site for emergency drug administration. 16-24 Two primary observations support its use. The first is that anatomically the tongue (and specifically the lateral ventral surface) is highly vascular, 13 with an abundance of capillary beds. Theoretically this may allow for rapid systemic uptake and absorption of therapeutic agents required in emergency situations. Recent radioactive microsphere studies in dogs have shown that the tongue maintains its high blood flow properties even in cardiac arrest, regardless of the type of cardiopulmonary resuscitation administered34A s These studies imply that the tongue effectively autoregulates blood flow even at low perfusion presAnnals of Emergency Medicine

IL Saline

IL IL Naloxone Naloxone (Compared to (Compared to Baseline) 50% MV)

sure, making it a site at which drug absorption may continue even in the face of profound hypotension. A second reason supporting use of the tongue is that it is easily accessible. The primary step in afiy resuscitation is assurance of an airway. Initial maneuvers include clearing the mouth and making sure the tongue does not occlude the airway. Therefore the tongue is immediately available as a potential route for drug administration. Prehospitai care guide!ines for Los Angeles C o u n t y suggest the intralingual route for various pediatric emergencies and for anaphylaxis in adults.23, 24 This method of drug administration is advocated when intravenous or endotracheal administration is not feasible. An array of various e m e r g e n c y drugs has been advocated using the int r a l i n g u a l r o u t e in a n i m a l s and man. 16-2~ Specifically epinephrine, when administered intralingually in anesthetized dogs, had a faster onset, a greater peak effect, and a longer duration of action than did IM injections. ~7 The effects of epinephrine, aminophylline, m e t a r a m i n o l bitartrate, and m e p h e n t e r m i n e sulfate given intralingually have been compared to femoral vein injections in anesthetized rhesus monkeysJ 8 With 13:12 December 1984

TABLE 1. 50% M e a n M V (2: = •.22 + .49) (N = 4) I

3

5

IL Saline

Time (min)

£ = 2.19

£ = 2.06

2 = 1.98

IL N a l o x o n e

2 = 4.52

Y< = 5.76

£ = 6.11

190%

302%

340%

Overall % C h a n g e *

*(IL N a l o x o n e % -

IL Saline %)

5O% ,t MV The time 1, 3, 5 minutes represent selected time intervals after injections of normal saline and naloxone. They represent the mean (2) of the four animals at these time intervals.

TABLE 2. M e a n baseline M V (2 = 2.44 +_ 1.01) (N = 4) 1

3

5

IL Saline

Time (min)

£ = 2.19

~ = 2.06

£ = 1.98

IL N a l o x o n e

2 = 4.52

£ = 5,76

:~ = 6.11

96%

152%

169%

overall % Change*

*(IL N a l o x o n e % - IL Saline %) B a s e l i n e £ MV The time 1, 3, 5 minutes represent selected time intervals after injections of normal saline and naloxone. They represent the mean (2) of the four animals at these time intervals.

both methods maximum response was reached in less than 35 seconds. Rappolt 22 advocates the use of naloxone via the -intralingual route in dealing with narcotic overdoses. This technique was used in the successful treatment of more than 50 patients without any specific adverse side effects. He does not state whether this was the only route used, however, nor does he cite any specific case information. In our study, the respiratory depressant effects of morphine sulfate were reversed using saline administered intralingually. A similar but larger response was observed in a study using endotrachea!ly administered saline in rabbits 4 (107% versus 85% of mean baseline ventilation in our study). The most probable explanation for this effect is that it represents the painful or noxious stimuli of the injection. Intralingual administration of naloxone, however, resulted in a significant increase (P < .025) in respiration when compared to baseline levels. The one-minute, three-minute, fiveminute, and mean minute ventilation of both the 50% MV and baseline MV showed consistent impressive 13:12 December 1984

changes, implying that the observed changes were not just secondary to the noxious stimuli alone. Naloxone has been shown to have a respiratory stimulant effect.2r Our results are consistent with this effect; one-minute, three-minute, five-minute, and mean baseline minute ventilation all exceeded experimental baseline values. Mice pretreated with morphine have shown an increase in the antagonist effect of naloxone. 31 Two hypotheses have been advanced to explain this observation. Enhanced tissue distribution of naloxone to the b r a i n secondary to morphine treatment has been advanced as one possible reason by Lange et al.31,32 Other investigators explain this phenomenon as increased receptor sensitivity to naloxone in morphine-treated animals. 33-3s The increased receptor affinity for naloxone, combined with enhanced naloxone distribution to brain tissue, appears to account for the profound increase in mean minute ventilation. We may infer that for this to occur, naloxone is absorbed rapidly and efficiently into circulation. The onset of naloxone reversal of depressed minute ventilation in our Annals of Emergency Medicine

study occurred within one m i n u t e post IL injection, which is similar to the onset of effect time observed by Nicholas et al in their study of stimUlant drugs given IL.18 Knowing that naloxone's onset of effect occurs within one m i n u t e does allow one to weigh the utility of the method for clinical purposes and to make appropriate decisions. The plateau of naloxone reversal in our study occurred between three and five minutes (Tables 1 and 2). It is impossible to say whether this was a true plateau, however, for observations were not made beyond these specified time intervals. The lack of a sustained duration of action would limit the clinical utility of this dosing method because narcotic effects might outlast the antagonist effects of naloxone. A similar argument can be made against the antagonist effects of IV naloxone. Because we did not study whether gradual, slow (depot type) absorption occurred, further work on the duration of action and effective blood levels achieved following IL naloxone seems warranted. Previous animal studies using endotracheally administered drugs were not designed using the randomized double blind crossover technique. 4-10 While our study suffers the same design flaw, our results correlate with results of endotracheally administered naloxone in the rabbit, making them of comparative value. 4 Laboratory studies done on IL drug administration have used either the dog or monkey as the animal mode1.13,17,18 Due to the scarcity and prohibitive cost of the latter, dogs were selected as our experimental species. Interspecies differences in tongue physiology have not been addressed in previous studies of IL injection; however, microsphere studies done in dogs have shown that the tongue maintains its blood flow even in low-perfusion s t a t e s . 14,15

In keeping with the doses used in previous studies on endotracheally administered naloxone in the rabbit, we used 1.0 mL of 0.4 mg naloxone (Natcan).4 The largest animal used in this study weighed 15.4 kg, making the mg/kg dose much larger than it would be in a 70-kg man. Thus prior to making any dosing recommendations in human beings, further studies using equivalent doses in animals appear warranted. Due to the lack of a readily available assay for naloxone blood levels, 1089/17

INTRALINGUAL NALOXONE Maio et al

Fig. MV Fig. MV

2. Percentage change over 50% (L/min). 3. Percentage change of baseline (L/min).

pharmacokinetic studies on the peak levels and time to peak level have not been done for alternative dosing methods. To date, the only available technique for measuring naloxone reversal of morphine-induced respiratory depression is the pharmacodynamic parameter of minute ventilation. The P values generated (Figure 1) are based on the raw value changes in this parameter. The large percentage changes in MV (Figure 1} should be kept in proper perspective, for percentage tends to inflate small differences observed in treatment groups. All the animals treated with naloxone, however, had an MV that exceeded their pretreatment baseline MV (Table 3). These results are consistent with the results of ET-administered naloxone. 4 Other potential limitations to this dosing method include the volume injected and the effect this route may have on tongue tissue and nerves. Bullough zl has advocated using volumes up to 2 cc for IL injection and leaving the needle in the tongue if repeat injections are required. In our study the total volume injected was 2 cc, and no apparent tissue necrosis or bleeding was observed. Further investigation should be undertaken to determine whether IL naloxone causes any specific tissue or nerve damage to the tongue. T h e r a p e u t i c agents that require large bolus volumes are not candidates for this dosing route; however, s i m i l a r a r g u m e n t s can be m a d e against IM, SC, or ET routes of administration. Severe facial trauma or surgical disturbance of oral a n a t o m y would preclude IL drug use. CONCLUSION Our study demonstrates that morphine-induced respiratory depression in the dog can be reversed rapidly and easily using intralingually administered naloxone. This implies that in certain specific situations IL injection may provide an advantageous alternative r o u t e w h e n c o n v e n t i o n a l routes cannot be achieved. Before any recommendations for human use of IL naloxone can be made, however, more thorough investigations directed specifically to milligram per kilogram equivalent studies, the effect of glossal 18/1090

600" 500' "E"

SL = IL Saline NAL = IL Naloxone DIF = Di (IL

400-

E ¢--~

300"

0o'-1 2000 100 t Ot

300 -

J

SL NAL DIF 1

SL NAL DIF SL NAL DIF 3 5 Time Post IL Injection (min)

SL = IL Saline NAL = IL Naloxone DIF = Difference (IL N A L - IL SL)

200. ~ v

09

"b

100-

ml II m

SL NAL DIF 1 3

SL NAL DIF SL NALr DIF 3 5 Time Post IL Injection (min)

physiology in hypoperfusion states, and complications that may occur with h u m a n subjects, must be performed. The authors thank Stan Kanaval, Veterinary Facilities Coordinator of Michigan State University's College of Veterinary Medicine, and James Cooley, Supervisor, ,Department of Respiratory Therapy, Lansing General Osteopathic Hospital, Lansing, Michigan, for their assistance.

REFERENCES 1. Redding JS, Asuncion JS, Pearson JW: Effective routes of drug administration Annals of Emergency Medicine

during cardiac care. Anesth Analg 1967;46:253-258."2. Standards for cardiopulmonary resuscitation and emergency cardiac care. JAMA 1974;227:883-868. 3. Elam JO: The intrapulmonary route for GPR drugs, in Safar P {ed): Advances in Cardiopulmonary Resuscitation. New York, Springer Verlag, 1977, p 132. 4. Greenberg MI, Roberts JR, Baskin SI: Endotracheal naloxone reversal of morphine-induced respiratory depression in rabbits. Ann Emerg Med 1980;9:289-292. 5. Barsan WG, Otten EJ, Ward JT: Blood levels of diazepam after intratracheal administration in dogs. Ann Emerg Med 13:12 December 1984

TABLE 3. Effect of IL naloxone on morphine-induced respiratory depression (mean +- SD)

Weight (kg)

Dog 1

Dog 2

Dog 3

Dog 4

11.4

15.4

11.4

9.1

Baseline MV (L/min)

3.30 _+ 0.11

2.44 _+ 0.09

3.00 _+ 0.09

1.02 _+ 0.17

MV Post Morphine

1.61 _+ 0.03

1.21 _+ 0.06

1.54 _+ 0.06

0.53 _ 0.15

MV Post IL Saline (1.0 mL)

2.04 _+

.06

2.49 +_ 0.12

3.15 _+ 0.35

0,61 + 0.02

MV Post IL Naloxone (0.4 mg/mL)

4.14 _+ 0.39

4.45 _+ 0.32

9.50 + 2,54

3.70 + 1.10

1982;11:242-247. 6. Roberts JR, Greenberg MI, Baskin SI: Endotracheal epinephrine in cardiorespiratory collapse. JACEP 1974;8:515-519. 7. Greenberg MI, Roberts JR, Baskin SI: Use of endotracheally administered epinephrine in a pediatric patient. A m J Dis Child 1982;135:767-768. 8. Greenberg MI, Roberts JR, Krusz JC, et al: Endotracheal epinephrine in a canine a n a p h y l a c t i c shock model. JACEP 1979;8:500-503. 9. Roberts JR, Greenberg MI, Knaub M, et al: Comparison of the pharmacological effects of epinephrine administered by the intravenous and endotracheal routes. JACEP 1978;7:260-264. 10. Greenberg MI, Mayeda DV, Chrzanowski R, et al: Endotracheal administration of atropine sulfate. Ann Emerg Med 1982;11:546-548. 11. Greenblatt DJ, Koch-Weser J: Intramuscular injection of drugs. N Engl J Med 1976;295:542-546. 12. Alper PR: Legitimate indications for intramuscular injections. Arch Intern Med 1978;138:1705-1710. 13. Hunsuck EE, Cutright DE: Microcirculation of the perioral regions in the Macaca rhesus. Oral Surg 1970;29:776785. 14. Luce JM, Ross BK, O'Quin RJ: Regional blood flow during cardiopulmonary resuscitation in dogs using simultaneous and nonsimultaneous compression and ventilation. Circulation 1983;67:258-263. 15. Koehler RC, Chandra N, Guerce AD: Augmentation of cerebral perfusion by simultaneous chest compression and lung inflation with abdominal binding after

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Annals of Emergency Medicine

Med 1976;85:765-768. 26. Fischer CG, Cook DR: The respiratory and narcotic antagonistic effects of naloxone in infants. Anesth Analg (Cleve) 1974;53:849-852. 27. Stephen GW, Cooper LV, Harvey D: The effect of narcotic and narcotic antagonistic drugs in the newborn rabbit. Br J Anaesth 1976;48:635-638. 28. Evans JM, Hogg MIJ, Rosen J: Reversal of narcotic depression in the neonate by naloxone. Br Med J 1976;2:1098-1100. 29. Vongnecker DE, Grazis PA, Eggers GWN: Naloxone for antagonism of morphine-induced respiratory depression. Anesth Analg (Cleve) 1973;52:447-453. 30. McGuigan MA, Mitchell AA: Prolonged action of intramuscular naloxone (letter). Br Med 1 1977;:580. 31. Lange DG, Fujimoto JM, Roerig S, et al: Enhanced naloxone distribution to the brain by morphine pretreatment in mice. Drug Metab Dispos 1977;5:167-173. 32. Takemori AE, Oka T, Nishiyama N: Alternation of analgesic receptor antagonist interaction induced by morphine. Pharmacol Exp Ther 1973;186:261-265. 33. Tulunay FC, Takemori AE: The increased efficacy of narcotic antagonism induced by various narcotic analgesics. Pharmacol Exp Ther 1974;190:395-400. 34. Tullunay FC, Takemori AE: Further studies on the alteration of analgesic receptor antagonist interaction induced by morphine. J Pharmacol Exp Ther 1974; 190:401-407. 35. Evans JM, Hogg MIJ, Lann JN, et al: Degree and duration of reversal by naloxone of effects of morphine in conscious subjects. Br Med J 1974;2:589-591..

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