Neonatal Abstinence Syndrome Medication

Updated: May 17, 2023
  • Author: Ashraf H Hamdan, MD, MBBCh, MSc, MRCP, FAAP; Chief Editor: Santina A Zanelli, MD  more...
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Medication Summary

Medications used in patients with neonatal abstinence syndrome (NAS) should be considered when supportive measures fail to ameliorate the infant's withdrawal. This may be manifested early on as difficulty with feeding, extreme irritability, and poor sleeping. If a scoring system is used, pharmacological treatment is commonly started when the average of 3 scores is 8 or more on the Finnegan scale [41] or 4 or more on the Lipsitz scale.

The optimal treatment for neonatal abstinence syndrome has not been established. This is reflected in the considerable heterogeneity in the pharmacologic treatment of neonatal abstinence syndrome among different institutions. Many pharmacological agents have been used to treat neonatal abstinence syndrome. However, few randomized trials have compared the efficacy of the various pharmacological treatments. For opioid related neonatal abstinence syndrome, morphine and methadone are given as substitutes. Nonmorphine treatments (eg, phenobarbital, chlorpromazine, diazepam, clonidine) provide symptomatic relief.

Opioids are currently considered the first-line therapy. Second-line therapy has been phenobarbital. Phenobarbital has been effective for the treatment of opioid withdrawal seizures. Clonidine has been shown to be an effective and safe second-line medication for the treatment of NAS symptoms refractory to opioid therapy. [89]

Agthe et al studied 80 infants exposed in utero to methadone or heroin and subsequently had NAS to determine if oral clonidine, an alpha2-adrenergic receptor agonist, would reduce the duration of opioid detoxification. [90] Each infant received oral diluted tincture of opium (dosage according to standardized algorithm) and either oral clonidine (1 mcg/kg q4h) or placebo. Duration of opioid therapy was measured.

Results showed that the median length of therapy was 27% shorter in the clonidine group (11 d) versus placebo (15 d). Seven infants in the clonidine group required restarting opium after initial discontinuation, versus none in the placebo group, although total length of treatment was significantly less in the clonidine group. Higher opium doses were required by 40% of infants in the placebo group versus 20% in the clonidine group. Treatment failures occurred in 12.5% of the infants in the placebo group versus none in the clonidine group. The addition of clonidine to standard opioid therapy reduced the duration of pharmacotherapy for NAS.

A US survey reported that opioid medications are the most commonly used medications for the treatment of both opioid and polydrug withdrawal. [91] Diluted tincture of opium is recommended by the American Academy of Pediatrics for the treatment of neonatal abstinence syndrome due to opioid withdrawal. [64] Diluted tincture of opium is a 25-fold dilution of deodorized tincture of opium. Deodorized tincture of opium is equivalent to anhydrous morphine 10 mg/mL, whereas diluted tincture of opium is equivalent to anhydrous morphine 0.4 mg/mL. As a tincture, opium contains a high amount of alcohol. Diluted tincture of opium (Paregoric) contains 45% alcohol. The Institute for Safe Medication Practices considers this a high alert medication because of the confusion if abbreviated as DTO because the abbreviation could mean deodorized or diluted tincture of opium.

Many neonatal units use proprietary oral or intravenous morphine solutions, and methadone is also used. A study comparing duration of treatment of NAS between methadone and morphine showed that methadone was associated with a shorter length of treatment. However, due to the small sample size, the researchers recommended a larger multicenter randomized trial. [76]

A study showed chlorpromazine to be efficacious, with no adverse effects in neonates with neonatal abstinence syndrome and shorter treatment time when compared with morphine. A large multicenter trial was recommended by the author to confirm the safety and efficacy of chlorpromazine. [92]

Buprenorphine is the first prescription drug approved under the 2000 US Drug Addiction Treatment Act for office based treatment of addiction to narcotics. [93] Buprenorphine has numerous characteristics that make it an attractive agent in the treatment of neonatal abstinence syndrome. Buprenorphine has a ceiling effect for respiratory depression. It does not have the cardiovascular liability associated with methadone and has an established safety profile in adults. Finally, abuse liability is limited, which makes consideration of outpatient treatment for neonatal abstinence syndrome a possibility for carefully screened caregivers.

A pilot study showed that the treatment of NAS with sublingual buprenorphine is feasible, has an acceptable safety margin, and may represent a novel treatment. [94] A Cochran review found that among infants with NAS, treatment with sublingual buprenorphine resulted in a shorter duration of treatment and shorter length of hospital stay than treatment with oral morphine, with similar rates of adverse events. [81]

Currently, many infants are exposed to polydrug abuse. Unfortunately, evidence from randomized studies is insufficient to determine the best management for these patients. In 2 randomized trials, phenobarbital (rather than diazepam or paregoric) was best at controlling symptoms in infants exposed to polydrugs. The results of another study suggested that the combination of phenobarbital with diluted tincture of opium may be more effective than diluted tincture of opium alone because the combination was associated with a shorter hospital stay. [55]


Antiepileptic agents

Class Summary

These drugs have a long half-life and can be orally administered, allowing for the neonate to be discharged and treated as an outpatient.

Disadvantages include lack of effect on GI symptoms and ineffectiveness in treating seizures secondary to withdrawal. In addition, antiepileptics contain 14-25% alcohol, and larger doses are required to achieve the desired effect.

Phenobarbital (Luminal)

Interferes with transmission of impulses from thalamus to cortex of brain. Used as a sedative. Irritability and insomnia are controlled. Available in PO and IV preparations.



Class Summary

These agents are the mainstay of treatment for opiate withdrawal, either alone or in combination with other medications. These agents are CNS depressants with advantages that include oral administration, mild sedation that improves the effectiveness of sucking, and effectiveness in treating seizures secondary to opiate withdrawal.

Morphine sulfate (Roxanol, Astramorph PF)

PO solutions are available in concentrations of 2 mg/mL, 4 mg/mL, and alcohol-free 20 mg/mL. Administered to neonates as diluted PO solution containing 0.4 mg/mL.

Bioavailability is 20-40% when administered orally. Elimination half-life is approximately 9 h. Recommended that Neonatal Abstinence Scoring System be used to guide treatment management of NAS.


Long-acting narcotic analgesic. PO bioavailability is 50%, with peak plasma levels obtained in 2-4 hours. Serum half-life ranges from 16-25 hours in neonates and is prolonged in patients with renal failure. Available as PO solutions in 1-mg/mL and 2-mg/mL concentrations containing 8% alcohol and 10-mg/mL alcohol-free solution.


Alpha2 Agonists, Central-Acting

Clonidine (Catapres, Catapres-TTS, Duraclon)

Alpha2-receptor agonists cause a decrease in sympathetic outflow (drop in vasomotor tone). These agents can be used as adjunct for infant with NAS (second- or third-line agent), and they are helpful for infants with acquired dependency, particularly if they are on a dexmedetomidine drip.