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    T h e n e w e ngl a nd j o u r na l o f m e dic i n e

    n engl j med 363;24 december 9, 20102320

    Neonatal Abstinence Syndrome after Methadone or Buprenorphine Exposure Hendrée E. Jones, Ph.D., Karol Kaltenbach, Ph.D., Sarah H. Heil, Ph.D.,

    Susan M. Stine, M.D., Ph.D., Mara G. Coyle, M.D., Amelia M. Arria, Ph.D., Kevin E. O’Grady, Ph.D., Peter Selby, M.B., B.S., Peter R. Martin, M.D.,

    and Gabriele Fischer, M.D.

    From the Departments of Psychiatry and Behavioral Sciences and Obstetrics and Gynecology, Johns Hopkins University School of Medicine, Baltimore (H.E.J.); the Departments of Pediatrics, Psychiatry, and Human Behavior, Jefferson Medical Col- lege, Thomas Jefferson University, Phila- delphia (K.K.); the Departments of Psy- chiatry and Psychology, University of Vermont, Burlington (S.H.H.); the De- partment of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit (S.M.S.); the Department of Pediatrics, Warren Alpert Medical School of Brown University, Prov- idence, RI (M.G.C.); the Center for Young Adult Health and Development (A.M.A.) and Department of Psychology (K.E.O.), University of Maryland, College Park; the Departments of Family and Community Medicine and Psychiatry, University of Toronto, Toronto (P.S.); the Departments of Psychiatry and Pharmacology and Ad- diction Center, Vanderbilt University School of Medicine, Nashville (P.R.M.); and the Department of Psychiatry and Psycho- therapy, Addiction Clinic, Medical Univer- sity Vienna, Vienna (G.F.). Address reprint requests to Dr. Jones at the Center for Addiction and Pregnancy, D-3 E., Johns Hopkins Bayview Medical Center, 4940 Eastern Ave., Baltimore, MD 21224, or at

    N Engl J Med 2010;363:2320-31. Copyright © 2010 Massachusetts Medical Society.

    A BS TR AC T


    Methadone, a full mu-opioid agonist, is the recommended treatment for opioid dependence during pregnancy. However, prenatal exposure to methadone is associ- ated with a neonatal abstinence syndrome (NAS) characterized by central nervous system hyperirritability and autonomic nervous system dysfunction, which often re- quires medication and extended hospitalization. Buprenorphine, a partial mu-opioid agonist, is an alternative treatment for opioid dependence but has not been exten- sively studied in pregnancy.


    We conducted a double-blind, double-dummy, flexible-dosing, randomized, controlled study in which buprenorphine and methadone were compared for use in the com- prehensive care of 175 pregnant women with opioid dependency at eight interna- tional sites. Primary outcomes were the number of neonates requiring treatment for NAS, the peak NAS score, the total amount of morphine needed to treat NAS, the length of the hospital stay for neonates, and neonatal head circumference.


    Treatment was discontinued by 16 of the 89 women in the methadone group (18%) and 28 of the 86 women in the buprenorphine group (33%). A comparison of the 131 neonates whose mothers were followed to the end of pregnancy according to treatment group (with 58 exposed to buprenorphine and 73 exposed to methadone) showed that the former group required significantly less morphine (mean dose, 1.1 mg vs. 10.4 mg; P

  • Methadone, Buprenorphine, and Neonatal Abstinence Syndrome

    n engl j med 363;24 december 9, 2010 2321

    Opioid dependence during pregnan-cy is compounded by multiple risk factors contributing to adverse maternal, neo- natal, and long-term developmental consequenc- es.1-6 Improved treatment options should reduce the public health and medical costs associated with the treatment of neonates exposed to opioids, which in 2009 was estimated at $70.6 million to $112.6 million in the United States alone.7 Just as the use of methadone in nonpregnant patients with opioid dependence improves patient out- comes,8 its use as part of a comprehensive ap- proach to the care of pregnant women improves maternal and neonatal outcomes, as compared with no treatment and with medication-assisted withdrawal.4,9,10 However, exposure to methadone in utero can result in a neonatal abstinence syn- drome (NAS) characterized by hyperirritability of the central nervous system and dysfunction in the autonomic nervous system, gastrointestinal tract, and respiratory system.11 When left untreated, NAS can result in serious illness (e.g., diarrhea, feeding difficulties, weight loss, and seizures) and death.11 Methadone-associated NAS often re- quires prolonged hospitalization, pharmacologic intervention, and monitoring.

    Buprenorphine, a partial mu-opioid agonist and kappa-opioid antagonist, effectively treats opioid dependence.12 Its low intrinsic receptor efficacy results in a less-than-maximal opioid effect13 and a diminished risk of overdose, as com- pared with methadone. In nonpregnant adults, the effects of abrupt withdrawal of buprenor- phine are minimal relative to the effects of withdrawal of full mu-opioid agonists.14,15 Bu- prenorphine’s pharmacologic advantages led to prospective open-label and controlled studies of its use in prenatal treatment,16-19 and the results of some of these studies suggested that neonates exposed to buprenorphine might be less likely to require treatment for NAS than those exposed to methadone.20 Recent studies of methadone and buprenorphine have had inconsistent results with respect to NAS outcomes.21-26 Given the calls to increase representation of pregnant women in medication research,27 we conducted the Maternal Opioid Treatment: Human Experimental Research (MOTHER) project, a multicenter, randomized, controlled trial comparing buprenorphine with methadone for the treatment of opioid-depen- dent pregnant patients.28

    Me thods

    Study Sites and Participants

    Between May 4, 2005, and October 31, 2008, opioid-dependent women between the ages of 18 and 41 years with a singleton pregnancy between 6 and 30 weeks of gestation (calculated on the basis of the last menstrual period and confirmed by ultrasonographic results) were screened and recruited at eight international sites — six in the United States and one each in Austria and Cana- da. Seven sites contributed randomized data; one site screened participants but did not complete randomization.

    Women were eligible for participation in the study if they had no medical or other conditions contraindicating participation, were not subject to pending legal action that might prevent their participation, had no disorders related to the use of benzodiazepines or alcohol, and did not plan to give birth outside the hospital at the study site (Fig. 1). Study referral sources included commu- nity providers, self-referral, and the site’s treat- ment program.28-30

    Screening for eligibility consisted of a compre- hensive battery of tests (see Fig. 1 in the Supple- mentary Appendix, available with the full text of this article at The screening tests were performed either at the time of treatment initiation (in the case of patients who were new to treatment) or after a patient’s request for a change in her established treatment (e.g., in the case of patients who were already being treated with a mu-opioid agonist and who agreed to randomization). Patients who were not eligible for participation in the study were so informed and transferred to standard care available at the site’s clinic or at a local community clinic.

    Each site’s local institutional review board ap- proved the study. All participants provided writ- ten informed consent at the time of screening. Buprenorphine tablets and the associated pla- cebo were supplied by Reckitt Benckiser Health- care, Hull, United Kingdom. These tablets were distributed to U.S. study investigators by the Na- tional Institute on Drug Abuse. Schering-Plough distributed buprenorphine tablets and placebo to Austrian investigators. Neither Reckitt Benckiser Healthcare nor Schering-Plough had involvement in the study design; data collection, analysis, or interpretation; or manuscript preparation.

    The New England Journal of Medicine Downloaded from on February 22, 2013. For personal use only. No other uses without permission.

    Copyright © 2010 Massachusetts Medical Society. All rights reserved.

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    n engl j med 363;24 december 9, 20102322

    Study Medications and Patient Care

    Before randomization, all participants received rapid-release morphine sulfate as inpatients to achieve medical stabilization and to ease the tran- sition to the double-blind medication.26,29,31 Qual- ifying participants underwent randomization and started the assigned study medication as inpa- tients.

    A blinded, individualized dosing schedule was used for the study medications, and a double-

    blind method was used to implement dose-unit increases or decreases (with dose adjustments of 2 mg for buprenorphine and 5 or 10 mg for methadone). Dose adjustments entailed clinical decisions based on medication adherence, the participant’s request, urine toxicologic results, and self-reported symptoms of withdrawal or craving.26 Tablets of buprenorphine (Subutex, Reckitt Benckiser) were used to avoid prenatal exposure to naloxone. (Neither buprenorphine

    175 Underwent randomization

    1074 Patients were screened for eligibility

    243 Did not provide consent 656 Were excluded

    557 Failed to meet inclusion criteria 149 Had estimated gestational age outside

    range 124 Were taking a benzodiazepine 105 Had medical reason 57 Were usin