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Methadone withdrawal in newborn infants
BRIEF CLINICAL AND LABORATORY OBSERVATIONS
Articles in this section should require less than three JOURNALpages: text, less than 1,000 words; 1 or 2 illustrations and/or tables; up to 10 references.
Methadone withdrawal in newborn infants B. K. Rajegowda, M.D., Leonard Glass, M.D.,* Hugh E. Evans, M.D., Graciella Mas6, Ph.D., Donald P. Swartz, M.D., and Wiener Leblanc, M.D., N e w York, N.Y.
T K E v A L U E of methadone therapy for heroin addiction was described in 1965 by Dole and Nyswander. 1 This synthetic opiate blocks the euphoric effect of heroin in the addict, eliminates his craving for it, and usually allows him to lead a relatively normal life. Numerous methadone maintenance programs have been established in New York City. Some of these, including the one at Harlem Hospital Center, treat pregnant addicts. There have been limited studies of the effect of maternal methadone administration on the fetus and neonate?, a We have compared withdrawal symptoms in a group of newborn infants of mothers on methadone maintenance therapy with irtfants whose mothers were untreated heroin addicts. From the Department o[ Pediatrics, Obstetrics, and Social Service, Columbia University College o[ Physicians & Surgeons, Harlem Hospital Center. ~Address: 530 Lenox Ave., New York, N. Y. 10037.
MATERIALS AND METHODS The study included 38 newborn infants of mothers who were addicted to heroin and 15 whose mothers were receiving methadone in a maintenance program. All 53 were admitted to the newborn nurseries of Harlem Hospital Center between September, 1971, and February, 1972. The median birth weights of the heroin and methadQne groups were 2,630 and 2,580 Gin., respectively. The median gestational age was 40 weeks, and the range was 34 to 40 weeks in each group. The median 1 and 5 minute Apgar scores were similar in both groups (7 and 9). All 53 survived the neonatal period, and none developed respiratory distress syndrome. 4 Meconjure aspiration with uneventful recovery. occurred in two infants of mothers who were treated with methadone. There were t h r e e full-term infants with hypoglycemia (two consecutive blood glucose determinations of less than 30 rag. per 100 ml. within a 2 hour period) in the methadone group. The number of infants exhibiting major signs of narcotic withdrawal (coarse flapping tremors and irritability) was noted. The severity of tremors and irritability were measured by the grading system of Kahn and associates. 5 Symptoms were considered present only if they were grade I I (marked when the infant was disturbed) or grade I I I (marked at frequent intervals even when the infant was undisturbed). The severity of symptoms was determined daily by two authors jointly and by the nursing staff. In virtually all instances there was unanimity in the assessment of severity of symptoms. Most
Volume 81 Number 3
Brief clinical and laboratory observations
533
Table I. Heroin and methadone withdrawal in newborn infants
Total No. o[ in[ants
No. o[ in[ants studied
Heroin
38
15~
10
Methadone
15
13~
13
Group --
I
No. o[ in[ants with withdrawal symptoms
Duration in days o[ major symptoms median (and range) Tremors I Irritability 5t ~t (2-8) lOt (6-16)
(2-8) 7t (4-12)
ep < 0.005. tP < 0.01.
of the newborn infants who were symptomatic at the grade I I or grade I I I level required sedation with phenobarbital (8 mg. per kilogram per day divided into three oral doses). The time of onset and duration of symptoms were recorded in all symptomatic methadone infants and the last ten consecutive symptomatic heroin infants. Pregnant addicts under treatment had received a daily dose of methadone of 80 to 160 mg.; this was taken orally for at least one month prior to delivery. Untreated addicts used 2 to 30 "bags" daily; each "bag" or glassine envelope contains an estimated 10 mg. of heroin. RESULTS
The incidence of irritability and tremulousness was significantly greater in the methadone group (13 of 15 cases) than in the heroin group (15 of 38 cases) (X2 = 8.0, p < 0.005). The time of onset of these symptoms in the two groups was comparable. On the first day of life, ten of the methadone and six of the ten heroin infants who were studied developed symptoms. On the second day, two infants in each group developed symptoms, and on the third day, one of the methadone and two of the heroin infants became symptomatic. Tremors and irritability lasted for a longer period in the methadone group than in the heroin group (Table I). Among the infants with methadone withdrawal symptoms, tremors lasted for a median of ten days, with a range of 6 to 16 days. In the heroin group, tremors lasted for a median of five days, with a range of 2 to 8 days. Irritability lasted for a median of
seven days (range 4 to 12 days) in the methadone group, and a median of three days (range 2 to 8 days) in the heroin group. The two-sample ranks test of Wilcoxon a n d White shows values, respectively, for the methadone and heroin groups as follows6: 216.5 and 59.5 (p < 0.01) for tremulousness and 211 and 65 (p < 0.01) for irritability. Phenobarbital sedation was required for six days (range 4 to 11 days) in the methadone group and for four days (range 2 to 7 days) in the heroin group. DISCUSSION Methadone in the dosage utilized is not only addictive to the fetus, but is associated with a higher incidence and more prolonged duration of withdrawal symptoms than that observed among newborn infants of heroin addicts. This m a y be a reflection of the wide range of heroin consumption, differences in pharmacologic properties of the two drugs, or due to a greater placental passage a n d / o r delayed renal excretion of methadone. Long-term follow-up studies will be necessary before a final judgment can be made about the effect of methadone withdrawal on newborn infants. REFERENCES
1. Dole, V. P., and Nyswander, M. E.: A medical treatment for dioeetylmorphine (heroin) addiction, J. A. M. A. 193: 646, 1965. 2. Annunziato, D.: Neonatal addiction to methadone, Pediatrics 47: 787, 1971. 3. Reddy, A. H., Harper, R. G., and Stern, G.: Observations on heroin and methadone withdrawal in the newborn, Pediairics 48: 353, 1971. 4. Glass, L., Rajegowda, B. K., and Evans, H. E.: Absence of respiratory distress syndrome ir~
53 4
Brief clinical and laboratory observations
premature infants of heroin addicted mothers, Lancet 2: 685, 1971. 5. Kahn, E. J., Neumann, L. L., and Polk, G. A.: The course of the heroin withdrawal syndrome in newborn infants treated with phenobarbital
Relationship of intraventricular gentamicin levels to cure of meningitis Report of a case of Proteus meningitis successfully treated with intraventricular gentamidn Robert C. Moellering, Jr., M.D.,* and Edwin G. Fischer, M . D . , Boston, Mass.
T I-I I s R E P 0 R T describes a p a t i e n t with meningitis caused by a strain of Proteus morganii w h i c h was sensitive to gentamicin. Combined intramuscular and intrathecal g e n t a m i c i n t h e r a p y failed to p r o d u c e adequate g e n t a m i c i n levels in the ventricular fluid a n d resulted in cerebrospinal fluid cultures w h i c h were persistently positive for Proteus morganii. I n t r a v e n t r i c u l a r l y a d m i n istered g e n t a m i c i n p r o d u c e d a d e q u a t e d r u g levels in b o t h v e n t r i c u l a r a n d spinal fluid a n d r a p i d l y sterilized the cerebrospinal fluid. T o our knowledge, this situation has not been d o c u m e n t e d previously with the d e t e r m i n a tion of g e n t a m i c i n levels in both the l u m b a r a n d ventricular cerebrospinal fluid. From the Departments of Medicine and Neurosurgery, Harvard Medical School, and the Infectious Disease Unit, and the Department of Neurosurgery, Mas}aehusetts General Hospital. Supported by United States Public Health Service General Research Suppoit Grant No. RR-05486-08 and by a National Institutes of Health Research Fellowship, NS 02534 (EGF). *Reprint address: MassachusettsGeneral Hospital, Boston, Mass. 02114.
The Journal of Pediatrics September 1972
or chlorpromazine, J. PEDIATR. 75: 495, 1969. 6. Mainland, D.: Elementary medical statistics, ed. 2, Philadelphia, 1963, W. B. Saunders Company, p. 283.
CASE REPORT Meningitis due to Proteus morganli developed in a 16-month-old boy following the removal of a nonfuncfioning, infected ventriculoatrial shunt. The shunt had been inserted at another hospital when the child was 8 months of age following a ventriculogram which showed a mild symmetrical enlargement of the ventricles without any obstruction. Following removal of the shunt it was demonstrated that the shunt was unnecessary. Intramuscular gentamicin resulted in defervescence and marked reduction in cerebrospinal fluid pleocytosis but hypoglycorrhachia and positive eerebrospinal fluid cultures for Proteus persisted as shown in Fig. 1. Additional daily instillation by barbotage of 1 mg. of gentamicin for six days and 2 mg. for two days also failed to eradicate the infection. Following the first of five daily intraventricular doses of, gentamicin (2 rag. per dose), all ventricular and lumbar cerebrospinal fluid cultures were negative. Cerebrospinal fluid cultures remained negative two weeks after discontinuing therapy. There has been no clinical evidence of recurrent meningitis during the three months since discharge. Bacteriologic studies and gentamicin levels. The gram negative organism isolated from the cerebrospinal fluid was Proteus morganii, and by disk sensitivity testing, was resistant to ampicillin, chloramphenicoI, colistin, streptomycin, and tetracycline. It was sensitive only to cephalothin, gentamicin, and kanamycin. This sensitivity pattern remained unchanged on all isolates obtained throughout the course of therapy. Minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) determined by the tube dilution method for several antibiotics against this organism were as follows: gentamicin--MIC 4 /zg per milliliter, MBC 8" /zg per milliliter; kanamycin~M}C 31 /~g per milliliter, MBC 62 /~g per milliliter; cephalothin - - M I C 31 /xg per milliliter, MBC 62 /~g per milliliter; chloramphenicol--MIC and MBC >250 /zg per milliliter. Gentamicin levels were determined using the agar diffusion method described b y Winters and
Articles in this section should require less than three JOURNALpages: text, less than 1,000 words; 1 or 2 illustrations and/or tables; up to 10 references.
Methadone withdrawal in newborn infants B. K. Rajegowda, M.D., Leonard Glass, M.D.,* Hugh E. Evans, M.D., Graciella Mas6, Ph.D., Donald P. Swartz, M.D., and Wiener Leblanc, M.D., N e w York, N.Y.
T K E v A L U E of methadone therapy for heroin addiction was described in 1965 by Dole and Nyswander. 1 This synthetic opiate blocks the euphoric effect of heroin in the addict, eliminates his craving for it, and usually allows him to lead a relatively normal life. Numerous methadone maintenance programs have been established in New York City. Some of these, including the one at Harlem Hospital Center, treat pregnant addicts. There have been limited studies of the effect of maternal methadone administration on the fetus and neonate?, a We have compared withdrawal symptoms in a group of newborn infants of mothers on methadone maintenance therapy with irtfants whose mothers were untreated heroin addicts. From the Department o[ Pediatrics, Obstetrics, and Social Service, Columbia University College o[ Physicians & Surgeons, Harlem Hospital Center. ~Address: 530 Lenox Ave., New York, N. Y. 10037.
MATERIALS AND METHODS The study included 38 newborn infants of mothers who were addicted to heroin and 15 whose mothers were receiving methadone in a maintenance program. All 53 were admitted to the newborn nurseries of Harlem Hospital Center between September, 1971, and February, 1972. The median birth weights of the heroin and methadQne groups were 2,630 and 2,580 Gin., respectively. The median gestational age was 40 weeks, and the range was 34 to 40 weeks in each group. The median 1 and 5 minute Apgar scores were similar in both groups (7 and 9). All 53 survived the neonatal period, and none developed respiratory distress syndrome. 4 Meconjure aspiration with uneventful recovery. occurred in two infants of mothers who were treated with methadone. There were t h r e e full-term infants with hypoglycemia (two consecutive blood glucose determinations of less than 30 rag. per 100 ml. within a 2 hour period) in the methadone group. The number of infants exhibiting major signs of narcotic withdrawal (coarse flapping tremors and irritability) was noted. The severity of tremors and irritability were measured by the grading system of Kahn and associates. 5 Symptoms were considered present only if they were grade I I (marked when the infant was disturbed) or grade I I I (marked at frequent intervals even when the infant was undisturbed). The severity of symptoms was determined daily by two authors jointly and by the nursing staff. In virtually all instances there was unanimity in the assessment of severity of symptoms. Most
Volume 81 Number 3
Brief clinical and laboratory observations
533
Table I. Heroin and methadone withdrawal in newborn infants
Total No. o[ in[ants
No. o[ in[ants studied
Heroin
38
15~
10
Methadone
15
13~
13
Group --
I
No. o[ in[ants with withdrawal symptoms
Duration in days o[ major symptoms median (and range) Tremors I Irritability 5t ~t (2-8) lOt (6-16)
(2-8) 7t (4-12)
ep < 0.005. tP < 0.01.
of the newborn infants who were symptomatic at the grade I I or grade I I I level required sedation with phenobarbital (8 mg. per kilogram per day divided into three oral doses). The time of onset and duration of symptoms were recorded in all symptomatic methadone infants and the last ten consecutive symptomatic heroin infants. Pregnant addicts under treatment had received a daily dose of methadone of 80 to 160 mg.; this was taken orally for at least one month prior to delivery. Untreated addicts used 2 to 30 "bags" daily; each "bag" or glassine envelope contains an estimated 10 mg. of heroin. RESULTS
The incidence of irritability and tremulousness was significantly greater in the methadone group (13 of 15 cases) than in the heroin group (15 of 38 cases) (X2 = 8.0, p < 0.005). The time of onset of these symptoms in the two groups was comparable. On the first day of life, ten of the methadone and six of the ten heroin infants who were studied developed symptoms. On the second day, two infants in each group developed symptoms, and on the third day, one of the methadone and two of the heroin infants became symptomatic. Tremors and irritability lasted for a longer period in the methadone group than in the heroin group (Table I). Among the infants with methadone withdrawal symptoms, tremors lasted for a median of ten days, with a range of 6 to 16 days. In the heroin group, tremors lasted for a median of five days, with a range of 2 to 8 days. Irritability lasted for a median of
seven days (range 4 to 12 days) in the methadone group, and a median of three days (range 2 to 8 days) in the heroin group. The two-sample ranks test of Wilcoxon a n d White shows values, respectively, for the methadone and heroin groups as follows6: 216.5 and 59.5 (p < 0.01) for tremulousness and 211 and 65 (p < 0.01) for irritability. Phenobarbital sedation was required for six days (range 4 to 11 days) in the methadone group and for four days (range 2 to 7 days) in the heroin group. DISCUSSION Methadone in the dosage utilized is not only addictive to the fetus, but is associated with a higher incidence and more prolonged duration of withdrawal symptoms than that observed among newborn infants of heroin addicts. This m a y be a reflection of the wide range of heroin consumption, differences in pharmacologic properties of the two drugs, or due to a greater placental passage a n d / o r delayed renal excretion of methadone. Long-term follow-up studies will be necessary before a final judgment can be made about the effect of methadone withdrawal on newborn infants. REFERENCES
1. Dole, V. P., and Nyswander, M. E.: A medical treatment for dioeetylmorphine (heroin) addiction, J. A. M. A. 193: 646, 1965. 2. Annunziato, D.: Neonatal addiction to methadone, Pediatrics 47: 787, 1971. 3. Reddy, A. H., Harper, R. G., and Stern, G.: Observations on heroin and methadone withdrawal in the newborn, Pediairics 48: 353, 1971. 4. Glass, L., Rajegowda, B. K., and Evans, H. E.: Absence of respiratory distress syndrome ir~
53 4
Brief clinical and laboratory observations
premature infants of heroin addicted mothers, Lancet 2: 685, 1971. 5. Kahn, E. J., Neumann, L. L., and Polk, G. A.: The course of the heroin withdrawal syndrome in newborn infants treated with phenobarbital
Relationship of intraventricular gentamicin levels to cure of meningitis Report of a case of Proteus meningitis successfully treated with intraventricular gentamidn Robert C. Moellering, Jr., M.D.,* and Edwin G. Fischer, M . D . , Boston, Mass.
T I-I I s R E P 0 R T describes a p a t i e n t with meningitis caused by a strain of Proteus morganii w h i c h was sensitive to gentamicin. Combined intramuscular and intrathecal g e n t a m i c i n t h e r a p y failed to p r o d u c e adequate g e n t a m i c i n levels in the ventricular fluid a n d resulted in cerebrospinal fluid cultures w h i c h were persistently positive for Proteus morganii. I n t r a v e n t r i c u l a r l y a d m i n istered g e n t a m i c i n p r o d u c e d a d e q u a t e d r u g levels in b o t h v e n t r i c u l a r a n d spinal fluid a n d r a p i d l y sterilized the cerebrospinal fluid. T o our knowledge, this situation has not been d o c u m e n t e d previously with the d e t e r m i n a tion of g e n t a m i c i n levels in both the l u m b a r a n d ventricular cerebrospinal fluid. From the Departments of Medicine and Neurosurgery, Harvard Medical School, and the Infectious Disease Unit, and the Department of Neurosurgery, Mas}aehusetts General Hospital. Supported by United States Public Health Service General Research Suppoit Grant No. RR-05486-08 and by a National Institutes of Health Research Fellowship, NS 02534 (EGF). *Reprint address: MassachusettsGeneral Hospital, Boston, Mass. 02114.
The Journal of Pediatrics September 1972
or chlorpromazine, J. PEDIATR. 75: 495, 1969. 6. Mainland, D.: Elementary medical statistics, ed. 2, Philadelphia, 1963, W. B. Saunders Company, p. 283.
CASE REPORT Meningitis due to Proteus morganli developed in a 16-month-old boy following the removal of a nonfuncfioning, infected ventriculoatrial shunt. The shunt had been inserted at another hospital when the child was 8 months of age following a ventriculogram which showed a mild symmetrical enlargement of the ventricles without any obstruction. Following removal of the shunt it was demonstrated that the shunt was unnecessary. Intramuscular gentamicin resulted in defervescence and marked reduction in cerebrospinal fluid pleocytosis but hypoglycorrhachia and positive eerebrospinal fluid cultures for Proteus persisted as shown in Fig. 1. Additional daily instillation by barbotage of 1 mg. of gentamicin for six days and 2 mg. for two days also failed to eradicate the infection. Following the first of five daily intraventricular doses of, gentamicin (2 rag. per dose), all ventricular and lumbar cerebrospinal fluid cultures were negative. Cerebrospinal fluid cultures remained negative two weeks after discontinuing therapy. There has been no clinical evidence of recurrent meningitis during the three months since discharge. Bacteriologic studies and gentamicin levels. The gram negative organism isolated from the cerebrospinal fluid was Proteus morganii, and by disk sensitivity testing, was resistant to ampicillin, chloramphenicoI, colistin, streptomycin, and tetracycline. It was sensitive only to cephalothin, gentamicin, and kanamycin. This sensitivity pattern remained unchanged on all isolates obtained throughout the course of therapy. Minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) determined by the tube dilution method for several antibiotics against this organism were as follows: gentamicin--MIC 4 /zg per milliliter, MBC 8" /zg per milliliter; kanamycin~M}C 31 /~g per milliliter, MBC 62 /~g per milliliter; cephalothin - - M I C 31 /xg per milliliter, MBC 62 /~g per milliliter; chloramphenicol--MIC and MBC >250 /zg per milliliter. Gentamicin levels were determined using the agar diffusion method described b y Winters and