Table of Contents

1. Definition
2. Clinical Presentations
3. Management
4. Outcome
5. Footnotes
6. References

1. Definition

   A generalized disorder presenting a clinical picture of CNS hyperirritability, gastrointestinal dysfunction, respiratory distress and vague autonomic symptoms. (1)

   The presence of withdrawal symptoms is evidence of physical dependence. The symptoms occur when the drug of dependence is removed. The symptoms are due to CNS hyperarousal during readaptation to the absence of the drug of dependence. The effects of withdrawal tend to be the opposite to the original effects of the drugs of dependence. (2)

   Neonatal abstinence syndrome can be due to intrauterine exposure to heroin or methadone. Other less potent opiates have been implicated as causes of NAS. In addition, non-opiate central nervous system (CNS) depressants have been considered as causes of NAS. (1)

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2. Clinical Presentations

   Onset of symptoms varies with the drug being used by the mother, the quantity, frequency, and duration of intrauterine exposure, and the timing of the withdrawal (last dose prior to delivery). Thus, withdrawal from methadone, because of its longer half life, tends to appear later when compared to symptoms of withdrawal from heroin. However, in both instances, the newborn appears normal at birth both physically and behaviorally. Symptoms begin to appear during the first 24 to 48 hours of life, although in some instances symptoms may not appear until day 5 to 10. (1),(3),(4)

   Symptoms include the following: (4),(5) :

   • CNS irritability:
     • CNS state: decreased duration of sleep between feedings
     • CNS motor: tremors, increased muscle tone, myoclonic jerks, increased Moro reflex
   • Respiratory distress:
     • increase in respiratory rate
     • nasal flaring
     • nasal stuffiness
     • sneezing
   • Vague autonomic symptoms
     • fever
     • sweating
     • mottling
   • Gastrointestinal dysfunction
     • excessive sucking
     • poor feeding (uncoordinated sucking)
     • regurgitation
     • loose/watery stools

     General comments:

     The effects of fetal exposure to narcotics include the following: (3),(4),(5),(7):

     • decreased birth weight
     • increased weight loss during early neonatal period
     • increased LOS (length of stay)

     Symptoms generally begin during the first 24 hours after birth but can be delayed up to 5 or more days. (1),(2),(3),(4),(6) Some have reported a delay in the onset of symptoms for as long as 7-10 days. Methadone, a long acting narcotic, tends to cause a delay in the onset of NAS symptoms when compared to heroin. (2),(6) While up to 90% of newborns exposed to narcotics during fetal life have some symptoms, only 50 to 75% will require treatment. (8),(9) Newborns exposed to methadone are more likely to experience more severe symptoms and more often require treatment. (3),(4),(10)

     The severity of NAS is not influenced by gestational age, sex of the newborn, race, Apgar score or maternal age. The level of morphine in the newborn's blood does not influence the severity of NAS (9). The blood level of morphine in the mother does not correlate with the severity of NAS (9). However, the maternal blood level of methadone is related to the severity of NAS. The larger the maternal dose of methadone the more likely there are to be symptoms and the symptoms are more likely to be severe. (3),(9),(10)

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3. Management
   1. Scoring system

      Given the vagueness of NAS signs and symptoms, it is difficult to determine when newborns are in need of treatment and once on treatment, when to withdraw the medication. For this reason many use the scoring system developed by Loretta Finnegan, et al. (5)

      The NAS scoring system allows one to semi-objectively measure the degree to which the newborn is experiencing symptoms and once on treatment, the resolution of signs and symptoms. It should be remembered that the NAS scoring system (sometimes referred to as the 'Finnegan Score') should be used as a guide and not as a precise measure of the clinical course. There are no objective data to allow one to understand the normal variation of NAS scores and how to discriminate between normal activity and NAS signs and symptoms.

      One should not base a decision to treat nor should one change the dose on the basis of one or two scores. If at all possible, treatment decisions should be based on daily average scores or a trend in scores over 24 to 48 hours. The NAS scores should not be used to treat NAS as one would treat a diabetic using blood sugar values and urine sugars as a guide.

   2. Non pharmacological treatment (11)
      1. swaddling
      2. frequent small feedings
      3. hypercaloric formula
      4. observation
         • - sleeping habits
         • - temperature stability
         • - weight gain/loss
         • - change in status (symptoms)
   3. Pharmacologic management
      1. Narcotics (1)

         Dosage schedule is based on a solution of morphine sulphate (MS) containing 0.4 mg/mL. of MS. (Paregoric has the same concentration of MS)

         Based on a review of our past experience, we generally begin treatment with MS at a dose of 0.125 - 0.15 mL/kg given q3h when the 24 hour average of NAS scores is above 8-10. Maximal effect is usually seen in 48-72 hours. When the signs and symptoms of NAS begin to decrease (as seen by NAS scores less than 8-10) the dose of MS is decreased 10%. Reductions in the MS dose are usually done no more often than once in a 24 hour period.

         One must be careful not to overdose with MS since narcotics are powerful respiratory depressants.

         1. Advantages
            • oral administration
            • inhibition of bowel motility
            • low level of sedation improves effectiveness of sucking
            • increases nutrient consumption
            • effective in treating seizures secondary to withdrawal
         2. Disadvantages
            • large dose required
            • long withdrawal period
            • Paragoric contains (Not recommended)
              • 44-46% alcohol
              • anise oil
              • benzoic acid
      2. Phenobarbital (1),(3),(11)
         1. Advantages
            • non-specific CNS depression
            • controls irritability and insomnia
         2. Disadvantages
            • little to no effect on G. I. symptoms
            • not effective in treating seizures secondary to withdrawal
            • impairs suck reflex
            • large dose required to achieve desired effect(s) and toxicity/efficacy levels are quite close. Need to monitor levels using blood samples
            • contains 14-25% alcohol
         3. Dosage
            • Requires a loading dose with the objective being a serum phenobarbital level of 18-22 mcg/mL. Maintenance dose is 2-6 mg/kg/day given once a day.
      3. Diazepam
         1. Advantages
            • safe rapid suppression of symptoms
         2. Disadvantages
            • interferes with sucking reflex
            • marked sedation
            • contraindicated if patient is hyperbilirubinemic
            • ethyl alcohol 10%
            • propylene glycol 40%
            • elimination may continue for more than 4 weeks
            • questionable efficacy (in the one clinical trial, diazepam did not appear to be better than placebo in ameliorating the clinical signs and symptoms of NAS). (12)

            Both because of the disadvantages enumerated and the lack of evidence of efficacy, Diazepam should not be considered in the treatment of NAS.

      4. Chlorpromazine (1), (12)
         1. Advantages
            • decreases CNS symptoms
            • very efficacious for G. I. symptoms
         2. Disadvantages (13)
            • contraindicated in newborns with elevated bilirubin
            • prolonged excretion (reported to be as long as 18 months)

            Chlorpromazine is very effective and was used extensively in the 1970’s for treatment of NAS. However, it is rarely used today given the problems with excretion and hyperbilirubinemia.

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4. Outcome

   Intrauterine exposure to narcotics causes passive addiction (NAS) as well as smaller birthweight and head circumference. The specific effects of prenatal narcotic (and other drugs, i.e., cocaine) exposure is difficult to evaluate because of the complicating factors of multiple drug exposure, cigarettes, alcohol and generally high risk social environment. Despite the host of negative factors there is little evidence that the prenatal exposure results in cognitive deficits for the affected newborns.

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Less potent opiates:

• propoxyphene hydrochloride (Darvon)
• codeine
• pentazocine (Talwin)

Non-opiate central nervous system (CNS) depressants:

• alcohol
• barbiturates
• bromide
• chlordiazepoxide
• diazepams
• ethchlorvynol
• diphenhyramine
• imipramine

Symptoms	Frequency (%)
COMMON
Tremors
- - Mild/disturbed	96
- - Mild/undisturbed	95
- - Marked/disturbed	77
- - Marked/undisturbed	67
High-pitched cry	95
Continuous high-pitched cry	54
Sneezing	83
Increased muscle tone	82
Frantic sucking of fists	79
Regurgitation	74
Sleeps less than 3 hr after feeding	65
Sleeps less than 2 hr after feeding	66
Sleeps less than 1 hr after feeding	58
Respiratory rate greater than 60/min	66
Poor feeding	65
Hyperactive Moro reflex	62
Loose stools	51
LESS COMMON
Sweating	49
Excoriation	43
Mottling	33
Nasal stuffiness	33
Frequent yawning	30
Fever less than 101oF (39.3oC)	29
Respiratory rate greater than 60/min and retractions	28
Markedly hyperactive Moro reflex	15
Projectile vomiting	12
Watery stools	12
Fever less than 101oF (39.3oC)	3
Dehydration	1
Generalized convulsions	1

Taken from: Finnegan L. Neonatal abstinence syndrome: assessment and pharmacotherapy. Neonatal Therapy: An update, F. F. Rubaltelli and B. Granti, editors. Elsevier Science Publishers B. V. (Biomedical Division). 1986: 122-146 (4).

Maternal dose of methadone:

Methadone treatment of the mother is preferred by the obstetrician because it allows for a smoother pregnancy and delivery and decreases the likelihood of maternal withdrawal during labor and delivery. Thus, it is preferable to have a larger, more mature newborn who is addicted to the methadone than a small and potentially compromised newborn less severely addicted to heroin.

Frequent small feedings:

Actually, one should attempt to disturb the NAS newborn as infrequently as possible. Thus, it would be preferable to feed less often using large feedings. However, the newborn undergoing withdrawal has a less effective suck and large feedings are not possible. Nutrition can be a significant problem and the solution is to opt for frequent small feedings.

Hypercaloric formula:

Some advocate using a hypercaloric formula or enhanced breast milk if weight gain is inadequate. An increased caloric formula is usually not necessary if the nursing care is adequate. In addition, hypercaloric formula may exacerbate the diarrhea seen as part of the clinical picture of withdrawal.

Observation:

Signs and symptoms of NAS are non-specific and can mimic sepsis or other neurologic or gastrointestinal problems. One must be very disciplined when caring for babies with NAS. During the first few days of life daily examinations are essential and periodic (every other day to every other week examinations) thereafter. Compounding the problem is the treatment consisting of some form of narcotic which can mask pain, discomfort, and other signs of neurologic or gastrointestinal disease.

Narcotics are powerful respiratory depressants:

It is wise to invoke a mandatory order to stop treatment if two consecutive scores are 2 or less. If the NAS score is 2 or less there is not likely to be much need for additional treatment and if the patient is being overdosed, discontinuing treatment is essential. If the scores are 2 or less, it would be prudent to watch such an infant very closely.

Inhibition of bowel motility:

One of the best treatments for the diarrhea resulting from NAS is to administer a narcotic. Since the clinical picture of NAS includes poor feeding (uncoordinated suck and regurgitation), inadequate nutrition and poor fluid balance are the most serious problems for patients with NAS. Nutrition and fluid balance are further compromised in the newborn due to the lack of reserves at that time of their life.

Paragoric contains (Not recommended):

Because of the alcohol content and other ingredients in paregoric, we recommend using a saline solution containing 0.4mg/mL of morphine sulfate which is equivalent to the morphine concentration in paragoric.

Disadvantages of phenobarbital:

While phenobarbital is the most effective treatment for non-narcotic addiction, the disadvantages of using it for NAS are of sufficient significance to consider it as a last resort. Phenobarbital has almost no effect on the G. I. symptoms of diarrhea and poor suck, two potential life-threatening aspects of NAS. Phenobarbital is not effective in treating the seizures caused by narcotic withdrawal. It is difficult to maintain the newborn in a therapeutic range without pushing the serum levels of phenobarbital to toxicity. Finally, the need to monitor serum levels adds a negative dimension to its use for treatment of NAS. Having said this, the author recognizes that in 1983 the AAP suggested phenobarbital as the drug of choice.

The negative effects of phenobarbital on cognitive development is another deterrent, especially if treatment continues for more than a few weeks. If treatment were to persist beyond the first month of life, concern for cognitive development would be more realistic.

References

1. Finnegan L. Management of neonatal abstinence. Adapted from: Current Therapy in Neonatal-Perinatal Medicine, N. Nelson (Ed). B. C. Decker, Inc., Publisher, Ontario, Canada, 1985, pp. 262-270.
2. Goodman and Gilman’s: The Pharmacological Basis of Therapeutics 9th edition, 1996, McGraw Hill, New York. Joel Gl. Hardman and Lee E. Limbird, Editors in Chief. pp
3. Finnegan L. Influence of maternal drug dependence on the newborn. in Kacew S, Lock S (eds): Toxicologic and Pharmacologic Principles in Pediatrics, New York, Hemisphere Publishing Corp., 1988, pp. 183-198.
4. Finnegan L. Neonatal abstinence syndrome: assessment and pharmacotherapy. Neonatal Therapy: An update, F. F. Rubaltelli and B. Granti, editors. Elsevier Science Publishers B. V. (Biomedical Division). 1986, pp. 122-146.
5. Finnegan L, Connaughton J, Kron R, Emich J. Neonatal abstinence syndrome: Assessment and Management. Addictive Diseases: an International Journal 1975;2:141-158.
6. Zelson C, Lee S, Casalino M. Neonatal narcotic addiction: Comparative effects of maternal intake of heroin and methadone. N Engl J Med 1973; 289:1216-1220.
7. Doberczak T, Kandall S, Wilets I. Neonatal opiate abstinence syndrome in term and preterm infants. J Pediatrics 1991;118:933-937.
8. Rosen T, Pippenger C. Pharmacologic observations on the neonatal withdrawal syndrome. J Pediatrics 1976;88:1044-1048.
9. Zelson C. Acute management of neonatal addiction. Addictive Diseases: an International Journal 1975;2:159-168.
10. Xylina Bean. Maternal Substance Abuse (Chapter 26), in Schaffer and Avery’s: Diseases of the Newborn, Taeusch HW, Ballard R A, Avery M E (eds), W. B. Saunders Company, Philadelphia, 1991, pp. 243-253.
11. Kron RE, Litt M, Phoenix MD, Finnegan LP. Neonatal narcotic abstinence: Effects of pharmacotherapeutic agents and maternal drug usage on nutritive sucking behavior. J Pediatrics 1976; 88:637-641.
12. Kaltenbach K, Finnegan L. Prenatal narcotic exposure: Perinatal and developmental effects. NeuroToxicology 1989;10:597-604.
13. Brooks-Gunn J, McCarton C, Hawley T. Effects of in utero drug exposure on children’s development. Arch Pediatr Adolesc Med 1994;148:33-39.
14. Hofkosh D, Pringle JL, Wald HP, Switala J, Hinderliter S, Hamel S. Early interactions between drug-involved mothers and infants: Within-group differences. Arch Pediatr Adolesc Med 1995; 149: 665-672.
15. Chiriboga CA, Vibbert M, Malouf R, Suarez MS, Abrams EJ, Heagarty MC, Brust JCM, Hauser WA. Neurological correlates of fetal cocaine exposure: Transient hypertonia of infancy and early childhood. Pediatrics 1995;96:1070-1077.

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