Naloxone Use in Newborns Sydney Segal, Walter R. Anyan, Jr, Reba M. Hill, Ralph E. Kauffman, Howard Mofenson, Albert W. Pruitt, Henry R. Shinefield, Harvey S. Singer and Miles M. Weinberger Pediatrics 1980;65;667 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/65/3/667 PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 1980 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275. Downloaded from pediatrics.aappublications.org by guest on August 29, 2014 Committee on Drugs Naloxone Use in Newborns* Naloxone hydrochloride (Narcan) is a pure narcotic antagonist that is the drug of choice in the treatment of central nervous system and cardiorespiratory It has depression virtually no produces in greater the when doses, administered in contrast to approved a dosage form of 0.02 mg/ml use in newborns that scription of pressed naloxone in newborn merits information endogenous long-term the management of clarification. regarding In opiate of was whose the de- addition, receptors and opioids raises questions concerning the safety of naloxone in neonates. A review available published and taming to naloxone the Committee on following commentary unpublished data per- use in the newborn infant Drugs forms the basis for and recommendations. by the The potent narcotic antagonist activity of naloxone is well documented in infants and children as well as in adults. Naloxone has been effectively used to reverse respiratory depression in infants and children analgesia.’2 Additional which naloxone was who received narcotics for cases have been reported in successfully and safely used to treat were * children This tee who statement Ofl Fetus Maternal tricians and PEI)IATRICS American and has and been Newborn Fetal Gynecologists. (ISSN Academy poisoned approved and Medicine, the 0031 4005). of Pediatrics. by the the with American Copyright narcotic Academy’s Committee on College 0 CommitObstetrics: of Obste- 1980 by as methadone the diphenoxylate hydrochloride,57 hydrochloride and pro- hydrochloride (Darvon)? Most of the controlled clinical trials to study the safety and efficacy of naloxone in treating respirapoxyphene tory have depression been carried overt clinical pression at narcotic in evidence birth. The effect include the assessment of respiratory the narcotic-exposed out on full-term, healthy received morphine during labor, but vary or who of respiratory parameters from study newborn infants meperidine showed or used to Apgar score, various scales, and physiologic function. Not only no CNS deto detect study. These neurobehavioral measurements do the methods of assessment vary from study to study, but naloxone dose and route of administration are different. This makes comparison of the studies difficult and, not surprisingly, results Several significant fants who with and are controlled differences received respect ventilatory to inconsistent. trials have shown statistically between narcotic-exposed innaloxone and those who did not alveolar response CO2 tension.” The onstrated significantly EFFICACY postoperatively such whose mothers hydrochloride receive narcotic analgesics during labor are born with narcotic-induced respiratory this drug was marketed for general preuse. Three years after its introduction, the depression; of FDA in a concentration designed for mothers and who recent even agonist drugs. and therefore hydrochloride and levallorphan tartrate, mixed agonist-antagonist activity. 1975 naloxone specifically role narcotic activity no narcotic effect than recommended nalorphine which have In due to agonist agonists (Lomotil),’4 Pco2,” tidal volume,9” to breathing an increased infants in one improved study” sucking and shortened time for habituation stimuli after receiving naloxone, 200 times the usual recommended dose). of 43 higher newborns, “alertness sound” than the naloxone-treated scores” and greater the studies was there or central nervous control infants.’2 evidence system also dembehavior to auditory gig/kg IM (20 In one series infants “response In none of significant depression had to of these respiratory as reflected by Apgar scores. With the possible exception of one study,” capillary pH and Pco2 also did not differ significantly between naloxone-treated and control group infants. Several uncontrolled studies have claimed beneficial effects due to naloxone based on subjective, nonquantitative observations such as increase increased Only in depth of activity, and one controlled respiration, increased clinical improved crying.2” trial (P. Lynd, AMERICAN ACADEMY OF PEDIATRICS Downloaded from pediatrics.aappublications.org by guest on August 29, 2014 tone, J. J. 667 Piecoro, and R. A. Beargie, unpublished data) has tion of sensory information attempted to look at the efficacy of naloxone in treating newborns with overt clinical evidence of respiratory and/or central nervous system depression at delivery. Eleven infants with presumed nar- tuitary function. There that naloxone is capable cotic-induced dents to thermal endorphin-mediated depression were compared mothers received group cotics (Apgar score less greater appeared intralingually. than 7). The activity, in all infants who 10 to 15 tg naloxone heart rate, respiratory and infants capillary during other parameters. poorly or not causes pneumonia, of depression undefined pression, ending The other at all and infants reto have including central and asphyxia with emergency three appeared system prolonged section. de- labor Two of the principal parameters used in this study, ie, Apgar score and respiratory rate, have been shown by other investigators to be crude and nondiscriminating measures of respiratory depression.’5 No data are available regarding use of naloxone in premature infants. The single published administered study to the reverse potential pression of the of the mother just prior narcotic-induced neonate is difficult to the poorly controlled conditions Naloxone is not recommended for to the parturient for this indication. use of naloxone to delivery to respiratory de- to interpret due of the study.’6 administration immediate short-term to be negligible. Even does not detectable safety have narcotic adverse effects. of naloxone The administration a narcotic-dependent has not toxicity of in excessive agonist activity However, the been naloxone doses it or other long-term investigated. of naloxone to the infant mother may precipitate acute withdrawal syndrome in the infant. It therefore, important for the physician to ascertain whether the mother may be narcotic-dependent prior to using naloxone in her infant. 668 PEDIATRICS may function as Endogenous opioids functions involving stimuli’8 and may interfere clinical analgesia.’9’#{176} increases plasma corticosteroid not known, the observations must be answered before narcotic-exposed neonates with Naloxof proluteinizin male that nal- concentra- tion and theoretically might influence or endorphin-mediated stress responses.2’ the relationships of these observations naloxone in the depressed and stressed Central nervous sion in the newborn many factors tion of narcotic enkephalin Although to the use of newborn are do raise questions routine use of naloxone can be recommended. system infant other than analgesics it is imperative be immediately that in depression are present ation. Naloxone should resuscitative measures adjunctive onstrate and respiratory depresmay be attributable to intrapartum to the mother. administraTherefore, that customary resuscitation efforts initiated when signs of neonatal therapy significant to ensure adequate oxygennot be used in lieu of such but should be reserved for in selected depression, infants who demwho have been ex- posed to intrapartum narcotics, and who are receiving or have received assisted ventilation and are not able to maintain effective spontaneous sponse likely after 2 to 3 doses, the not due to narcotic effect. response to repeated narcotic in 30 to and dose naloxone, of an newborn action is, should preferably either through peripheral vein Recent information regarding opiate receptors and endogenous opioid substances (endorphins and enkephalins) suggests that opiate receptors probably have physiologic roles and enkephalin and endorphin polypeptides neurotransmitters.’7 important regulatory For example, response of ro- ventilation despite other resuscitative efforts. The recommended dose of naloxone is 0.01 mg/kg. This dose may be repeated in three to five minutes if there is no immediate response. If there is no re- SAFETY The appears and endorphins. nociceptive evidence physiologic COMMENT aspiration nervous following cesarean inand in the the hypothalamic-pi- one reduces enkephalin-mediated secretion lactin and growth hormones and increases ing and follicle-stimulating hormone rats.21’22 Preliminary data in mice indicate oxone blood gases the first six hours of life. Eight of the 1 1 naloxone-treated fants seemed to respond rapidly to naloxone showed no difference from the control infants monitored sponded 6) whose and a received narbirth (Apgar eleven depressed received Temperature, color, cry, monitored than a group of seven infants no narcotics during labor of seven infants whose mothers but who appeared normal at scores rate, were to effects of enkephalins naloxone increases and is experimental of blocking the important may play integra- dose may exposed, since is relatively be administered an umbilical venous in order to obtain Although the drug or subcutaneously, is most is an initial need 90 minutes, depending of the narcotic to has been of naloxone response. muscularly delayed stricted support the depression If there the short. to on which be the the duration Naloxone intravenously, catheter or an immediate of a may be given intraabsorption may be and erratic in the stressed and vasoconinfant. There is not clear-cut evidence to the routine administration of naloxone to infants who during central labor nervous have but been show system exposed to narcotic no overt or respiratory Vol. 65 No. 3 March 1980 Downloaded from pediatrics.aappublications.org by guest on August 29, 2014 analgesia clinical signs depression. of CONCLUSIONS AND RECOMMENDATIONS Naloxone should be therapy in selected infants reserved for adjunctive who have not initiated 1. or established ventilation, high independent significantly are probability 2. When respirations depressed, of being naloxone the 0.02 mg/mi recommended 3. Rumack 4. following and have 5. a narcotized. 6. is administered preparation dose is 0.01 to the neonate, should be used. mg/kg. The initial The dose may be repeated in three to five minutes if there is no response. The dose may need to be repeated in 30 to 90 minutes, depending on the degree of depression of the infant, because of the relatively short duration of action of naloxone. Naloxone should be given tion to the mother just prior to delivery fants of precipitate infant. narcotic-dependent withdrawal 5. Naloxone mothers in the physically should newborns. cotic-exposed not be used COMMITTEE Sydney Walter Reba Ralph Howard Albert Henry Harvey Miles in- as this may dependent routinely in nar- ON DRUGS Segal, MD, Chairman R. Anyan, Jr, MD M. Hill, MD E. Kauffman, MD Mofenson, MD W. Pruitt, MD R. Shinefield, MD S. Singer, MD M. Weinberger, MD REFERENCES 1. Fisher nistic CG, Cook effects of DR: The naloxone respiratory in infants. and Anesth narcotic Analg Data Welfare, file, Food US and Department I)rug of Health, Administration, Education Bureau MIJ, Rosen Gerhardt neonatal J 2:228, T, Bancalari narcotic J Pediatr M: Reversal of narcotic Br Med J 2:1098, by naloxone. Rosen M: 1977 E, Cohen respiratory Effects depression: of H, et al: Use depression naloxone 1. Intravenous in the de1976 on nat- of naloxone to newborn in- fant. 90:1009, 1977 Bonta BW, Gagliardi JV, Williams V, et al: Naloxone reversal of mild neurobehavioral depression in normal newborn infants after routine obstetric analgesia. J Pediatr 94:102, 1979 13. Wolochowicz-J#{243}zwick Z, Norek W: Evaluation of antidepressive effect of naloxone in newborns (Polish). Anesth Reanim Inten Tenap 9:269, 1977 14. Clark RB, Beard AG, Barclay DI: Naloxone in the newborn 15. and of Drugs infant. Anesth Rev 2:9, 1975 Gerhardt T, Bancalari E, Cohen H, et al: Respiratory de- pression at birth: Value of Apgar score and ventilatory measurements in its detection. J Pediatr 90:971, 1977 16. Clark RB, Beard AG, Greifenstein FE, et al: Naloxone in the parturient and her infant. South Med J 69:570, 1976 17. Snyder SH: Opiate receptors in the brain. N Engi J Med 296:266, 1977 18. Kosterlitz HW, Hughes J: Possible physiological significance of enkephalin, an endogenous ligand of opiate receptors, Bonica ii, Albe-Fessard D (eds): in Advances in Pain Research and Therapy, Vol 1. New York, Raven Press, 1976, p 641 19. Levine JD, Gordon NC, Fields HL: The mechanism of placebo analgesia. Lancet 2:654, 1978 20. Stephenson JBP: Reversal of hypnosis-induced analgesia by naloxone. Lancet 2:991, 1978 21. Bruni JF, Van Vugt D, Marshall S, et al: Effects of naloxone, morphine, and methionine enkephalin on serum prolactin, luteinizing hormone, follicle stimulating hormone, thyroid stimulating hormone, and growth hormone. Life Sci 21:461, 1977 22. Shaar CJ, Frederickson RCA, Dininger NB, et al: EnkephaIm analogues and naloxone modulate the release of growth hormone 23. on Hogg in the neonate PC, Hogg MIJ, pethidine-induced oxone. Br Med antago53:849, 1974 2. 10. JM, pression Wiener 12. adminto 9. Evans reverse to reverse the fetal and neonatal effects of maternally istered narcotic analgesics. 4. Naloxone should not be administered 8. I 1. intravenously if possible. is not recommended for administra- 3. Naloxone 7. BH, Temple AR: Lomotil poisoning. Pediatrics 53: 495, 1974 Snyder R, Mofenson HC, Greensher J: Toxicity from Lomotil: Accidental ingestion by a 22-month-old child. Clin Pediatr 12:47, 1973 Buchner LH, Cimino JA, Raybin HW, et al: Naloxone versal of methadone poisoning. NY State J Med 72:2305, 1972 Sesso AM, Rodzvilla JP: Naloxone therapy in a seven month old with methadone poisoning. Clin Pediatr 14:388, 1975 Simons PS: The treatment of methadone poisoning with naloxone (Narcan) J Pediatn 83:846, 1973 Lovejoy FH, Mitchell AA, Goldman P: The management of propoxyphene poisoning. J Pediatn 85:98, 1974 and prolactin: Evidence for regulation Sci 21:853, dogenous opioid peptide in brain. Life Gibson A, Ginsburg M, Hall M, et naloxone and normorphine on plasma in normal and stressed mice. J Physiol AMERICAN ACADEMY OF al: The influence of corticosteroid leveLs 270:28, 1977 PEDIATRICS Downloaded from pediatrics.aappublications.org by guest on August 29, 2014 by an en1977 669 Naloxone Use in Newborns Sydney Segal, Walter R. Anyan, Jr, Reba M. Hill, Ralph E. Kauffman, Howard Mofenson, Albert W. Pruitt, Henry R. Shinefield, Harvey S. Singer and Miles M. 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All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275. Downloaded from pediatrics.aappublications.org by guest on August 29, 2014