Future Trends in the Treatment of

the Neonatal Abstinence Syndrome

Walter K. Kraft, MDWalter K. Kraft, MD

Associate ProfessorAssociate Professor

Director, Clinical Research Director, Clinical Research UnitUnit

Thomas Jefferson UniversityThomas Jefferson University

Philadelphia, PAPhiladelphia, PA

Disclosure (past 3 years)

Research Grants Research Grants

Merck, Schering

Bristol Myers Squibb

Data Safety Monitoring BoardData Safety Monitoring Board

Wyeth, RePros Therapeutics

Speakers Panel Speakers Panel

None

Consulting Consulting

Merck

Synageva

OutlineOutline

Limitations of Current TherapiesLimitations of Current Therapies Potential New DrugsPotential New Drugs

ClonidineClonidine BuprenorphineBuprenorphine

Ongoing ResearchOngoing Research Future NeedsFuture Needs

Opioid Neonatal Abstinence Opioid Neonatal Abstinence SyndromeSyndrome

Newborns of mothers with chronic useNewborns of mothers with chronic use Methadone, buprenorphine, morphine, heroinMethadone, buprenorphine, morphine, heroin 5% of 56,000 women in US who reported heroin 5% of 56,000 women in US who reported heroin

use in previous month were pregnantuse in previous month were pregnantSAMHSA. 2006 National Survey on Drug Use and Health: National Findings., SAMHSA. 2006 National Survey on Drug Use and Health: National Findings.,

NSDUH Series H-32, NSDUH Series H-32, DHHS Publication No. SMA 07-4293). Rockville, MD. 2007DHHS Publication No. SMA 07-4293). Rockville, MD. 2007

In Australia 40 cases per 10,000 live In Australia 40 cases per 10,000 live birthsbirths US extrapolation—16,000/yrUS extrapolation—16,000/yr

O'Donnell M. Pediatrics. 2009; 123(4):e614-21 O'Donnell M. Pediatrics. 2009; 123(4):e614-21

Signs and symptomsSigns and symptoms NeurologicNeurologic GIGI AutonomicAutonomic

Why do we treat NAS with Why do we treat NAS with medications?medications?

Weight gainWeight gain Ensure developmentEnsure development Prevent seizuresPrevent seizures Patient comfortPatient comfort

Pharmacologic Pharmacologic TreatmentTreatment

Opiates are preferred therapyOpiates are preferred therapy Improve weight gain and reduce need for Improve weight gain and reduce need for

supportive care, but at cost of longer supportive care, but at cost of longer hospital stayshospital stays

Osborn, DA; Opiate treatment for opiate withdrawal in newborn infants. The Cochrane Osborn, DA; Opiate treatment for opiate withdrawal in newborn infants. The Cochrane Library 2007Library 2007

Benzodiazapines helpful only in seizuresBenzodiazapines helpful only in seizures Phenobarbital useful as adjunct therapyPhenobarbital useful as adjunct therapy

Osborn, DA; Sedatives for opiate withdrawal in newborn infants. The Cochrane Osborn, DA; Sedatives for opiate withdrawal in newborn infants. The Cochrane Library 2007Library 2007

Common Drug Common Drug TreatmentsTreatments

MorphineMorphine PhenobarbitalPhenobarbital Tincture of opiumTincture of opium MethadoneMethadone Chloral hyrdateChloral hyrdate Paregoric Paregoric

What is the problem?What is the problem?

At least 50% of infants require At least 50% of infants require pharmacologic treatmentpharmacologic treatment We just don’t know which onesWe just don’t know which ones

Hospital stays are too longHospital stays are too long Home treatment difficultHome treatment difficult No generally recognized standard of No generally recognized standard of

carecare Other drug-induced withdrawal Other drug-induced withdrawal

symptomssymptoms

Goals of treatment for Goals of treatment for NASNAS

shortened hospital stayshortened hospital stay shortened time of exposure to shortened time of exposure to

opiatesopiates lowered hospital costs lowered hospital costs improved parentingimproved parenting

maternal-infant bondingmaternal-infant bonding lessened maternal guilt lessened maternal guilt

Greif J. Subst Abuse Treat. 1993; 10(4):339-34Greif J. Subst Abuse Treat. 1993; 10(4):339-34

ClonidineClonidine

Alpha 2 adrenergic agonistAlpha 2 adrenergic agonist Decreases catecholamine release in Decreases catecholamine release in

the CNSthe CNS Common usesCommon uses

HypertensionHypertension Acute opioid withdrawalAcute opioid withdrawal

Low dose opioidsLow dose opioids Low dose methadoneLow dose methadone Rapid detoxificationRapid detoxification

ClonidineClonidine Cochrane Review: Adult opioid withdrawalCochrane Review: Adult opioid withdrawal

More effective than placeboMore effective than placebo More side effects compared to tapering More side effects compared to tapering

methadonemethadone

Gowing L, Farrell M, Ali R, White JM. Alpha2-adrenergic agonists for the Gowing L, Farrell M, Ali R, White JM. Alpha2-adrenergic agonists for the management of opioid withdrawal. Cochrane Database Syst Rev. 2009 Apr 15;management of opioid withdrawal. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD002024(2):CD002024

Side effectsSide effects HypotensionHypotension Rebound hypertensionRebound hypertension Dry mouthDry mouth SedationSedation

Clonidine in NASClonidine in NASYearYear nn Clonidine Clonidine

dose dose (mcg/kg)(mcg/kg)

Hoder, Hoder, 19841984

Case Case SeriesSeries

77 0.5–1.0 po 0.5–1.0 po Q 6 hrQ 6 hr

13 day LOS13 day LOS

Leikin, Leikin, 20092009

Case Case SeriesSeries

1414 0.5–1.0 po 0.5–1.0 po Q 6 hrQ 6 hr

7 day LOT7 day LOT

In utero In utero exposures = 3exposures = 3

Iatrogenic NAS = Iatrogenic NAS = 1111

EsmaeEsmaeili, ili, 20102010

Case Case SeriesSeries

2929 0.5–3.0 hr 0.5–3.0 hr IV IV

14 day LOT14 day LOT

32 day LOS32 day LOS

Chloryl hydrate Chloryl hydrate rescuerescue

Agthe, Agthe, 20092009

RCTRCT 4040 1.0 po Q 4 1.0 po Q 4 hr (+ hr (+ morphine)morphine)

11 day LOT vs. 15 11 day LOT vs. 15 for placebofor placebo

AgtheAgtheMorphine dose requirements

Square = clonidine Circle = placebo

Length of Treatment

Agthe: Secondary Agthe: Secondary EndpointsEndpoints

Treatment failures: 5 vs. 0 with clonidineTreatment failures: 5 vs. 0 with clonidine Seizures: 3 vs. 0 with clonidineSeizures: 3 vs. 0 with clonidine Deaths: 0 vs. 3 with clonidine (all post Deaths: 0 vs. 3 with clonidine (all post

discharge)discharge) MyocarditisMyocarditis SIDSSIDS Homicide (methadone overdose)Homicide (methadone overdose)

DSMB ruled these not clonidine relatedDSMB ruled these not clonidine related SVT noted 3 days following cessation of SVT noted 3 days following cessation of

clonidineclonidine Heart rate and blood pressure changes noted, Heart rate and blood pressure changes noted,

but none outside of normal rangesbut none outside of normal ranges

ClonidineClonidine Optimal useOptimal use

Adjunct to opioidAdjunct to opioid Fixed doseFixed dose 1.5 mcg/kg q 4 starting week 2?1.5 mcg/kg q 4 starting week 2?

Xie HG. J Clin Pharmacol. 2010 May 19. [Epub ahead of print]Xie HG. J Clin Pharmacol. 2010 May 19. [Epub ahead of print]

FormulationFormulation Liquid oral vs. transdermalLiquid oral vs. transdermal

BuprenorphineBuprenorphine Cochrane Review: Management of Cochrane Review: Management of

withdrawal in adultswithdrawal in adults More effective than clonidineMore effective than clonidine Probably quicker in resolution of withdrawal Probably quicker in resolution of withdrawal

symptomssymptoms Longer duration of treatment but higher rates Longer duration of treatment but higher rates

of completionof completion

Gowing L, Ali R, White JM. Buprenorphine for the management of opioid Gowing L, Ali R, White JM. Buprenorphine for the management of opioid withdrawal. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD002025.withdrawal. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD002025.

Safety margin Safety margin Increasing use in adultsIncreasing use in adults

Pregnant femalesPregnant females

Buprenorphine is a partial Buprenorphine is a partial mu receptor agonistmu receptor agonist

Potential Advantage in Potential Advantage in NASNAS

SafetySafety Ceiling effect on respiratory depressionCeiling effect on respiratory depression Fatalities in adults primarily seen with Fatalities in adults primarily seen with

concomitant benzodiazapine abuse concomitant benzodiazapine abuse Less abuse potentialLess abuse potential Long half lifeLong half life

Improved control of abstinence?Improved control of abstinence? Ability to wean out of the hospital?Ability to wean out of the hospital?

Challenges to use in Challenges to use in NeonatesNeonates

No pediatric indicationNo pediatric indication One study in preterm critically ill infants One study in preterm critically ill infants

using IV formulationusing IV formulation Case reports of maternal use of Case reports of maternal use of

buprenorphinebuprenorphine No good PK dataNo good PK data Sublingual administrationSublingual administration Metabolic ontogenyMetabolic ontogeny Unknown potency of norbuprenorphineUnknown potency of norbuprenorphine

Clinical Trial Study GoalClinical Trial Study Goal

PrimaryPrimary

Demonstrate sublingual buprenorphine for Demonstrate sublingual buprenorphine for NAS is safe, tolerable, and feasibleNAS is safe, tolerable, and feasible

SecondarySecondary

1) Investigate comparative efficacy for 1) Investigate comparative efficacy for endpoints of length of treatment and endpoints of length of treatment and length of staylength of stay

2) Explore buprenorphine 2) Explore buprenorphine pharmacokinetics pharmacokinetics

Buprenorphine ProtocolBuprenorphine Protocol

4.4 4.4 gm/kg q8 buprenorphine sublingual gm/kg q8 buprenorphine sublingual (Buprenex in 30% alcohol/sucrose)(Buprenex in 30% alcohol/sucrose)

Dose up-titration by 20%Dose up-titration by 20% ~one PK sample/day~one PK sample/day Weaning by 10%/dose after stable 48 hoursWeaning by 10%/dose after stable 48 hours Cessation at or near initial doseCessation at or near initial dose Provision for rescue dose followed by up-Provision for rescue dose followed by up-

titrationtitration At maximum 39 At maximum 39 gm/kg/day, rescue with gm/kg/day, rescue with

phenobarbitalphenobarbital Observation for 48 hr after cessation of Observation for 48 hr after cessation of

therapytherapy

Buprenorphine NOS

Need for Phenobarbital Rescue 3 1

Dose adjustmentDose adjustment

ObservationObservation Lower than expected bup concentrationLower than expected bup concentration Rapid up-titrationRapid up-titration Relatively frequent need for phenobarbital rescueRelatively frequent need for phenobarbital rescue

Adjusted doseAdjusted dose 1) Increase initial daily dose from 13.2 mcg/kg to 15.9 1) Increase initial daily dose from 13.2 mcg/kg to 15.9

mcg/kgmcg/kg 2) Increase the up-titration from 20% increase to 25% 2) Increase the up-titration from 20% increase to 25%

increaseincrease 3) Increase maximum daily dose from 39 mcg/kg to 60 3) Increase maximum daily dose from 39 mcg/kg to 60

mcg/kgmcg/kg

UpdateUpdate

24 patients randomized to new dose schema24 patients randomized to new dose schema

23

35

30

40

4 2

Length of treatment Length of Stay PhenobarbitalAdjunct

Buprenorphine (12)

Morphine (25)

0

10

20

30

40

50

60

70

Morphine Buprenophine

Length of Treatment: All treated patients in

trial (N=50)

Safety: Serious EventsSafety: Serious Events Status epilepticus, Status epilepticus,

treated with treated with lorazepam and lorazepam and phenobarbitalphenobarbital

Full-term female, Full-term female, scores of 4-6 after 3 scores of 4-6 after 3 days of treatmentdays of treatment

Neurological work Neurological work up negativeup negative

Level = 0.35 ng/mL Level = 0.35 ng/mL Normal Normal development at 12 development at 12 months of agemonths of age

Elevated liver Elevated liver enzymes enzymes associated with associated with cytomegalovirus cytomegalovirus infectioninfection

Poor feeding, Poor feeding, aminoaciduriaaminoaciduria

Abnormalities Abnormalities persisted weeks persisted weeks after dechallengeafter dechallenge

BuprenorphineBuprenorphineSummarySummary

Appears as safe as, and more Appears as safe as, and more efficacious than morphineefficacious than morphine

Efficacy needs to be tested in Efficacy needs to be tested in blinded clinical trialblinded clinical trial

Use may facilitate expansion into Use may facilitate expansion into outpatient treatmentoutpatient treatment

3138

47

0

10

20

30

40

50

Duration of

Therapy (days)

Non-benzodiazepineexposedPoly-substanceexposed

Benzodiazepineexposed

Polysubstance abusePolysubstance abuseThomas Jefferson University Hospital 2000-06Thomas Jefferson University Hospital 2000-06

Seligman NS,. Am J Obstet Gynecol. 2008; 199(4):396.e1-396.e7

Polysubstance abusePolysubstance abuse

CommonCommon Up to 50% of babies at risk for NAS Up to 50% of babies at risk for NAS

have exposure to benzodiazepineshave exposure to benzodiazepines Worse outcomesWorse outcomes

Cause or marker of treatment Cause or marker of treatment resistance?resistance?

Even less clarity of optimal Even less clarity of optimal treatmenttreatment

Effects of concomitant Effects of concomitant psychiatric medicationspsychiatric medications

10.3% of drug-using pregnant women 10.3% of drug-using pregnant women had other psychiatric disorders had other psychiatric disorders compared to 1.4% of controlscompared to 1.4% of controls

Kennare R. Aust N Z J Obstet Gynaecol 2005;45:220–225Kennare R. Aust N Z J Obstet Gynaecol 2005;45:220–225. .

56% of participants in MOTHER study 56% of participants in MOTHER study had prescription for psychiatric had prescription for psychiatric medication during pregnancymedication during pregnancy Mostly anxiolytics and SSRIsMostly anxiolytics and SSRIs Benzodiazepines were exclusion criteriaBenzodiazepines were exclusion criteria

Martin PR. Am J Addict. 2009 ; 18(2): 148–156Martin PR. Am J Addict. 2009 ; 18(2): 148–156

Neonatal responses Neonatal responses to to in uteroin utero exposure exposure

AntidepressantAntidepressant Mild CNS and respiratory systemsMild CNS and respiratory systems 3-5 day duration, self limited3-5 day duration, self limited

Koren G. CMAJ. 2005; 172(11):1457-1459 Koren G. CMAJ. 2005; 172(11):1457-1459 Ferreira E. Pediatrics. 2007; 119(1):52Ferreira E. Pediatrics. 2007; 119(1):52

AntipsychoticsAntipsychotics Adults have mild withdrawal symptoms of Adults have mild withdrawal symptoms of

agitation and insomnia agitation and insomnia Anecdotal reports of hypertonicity and early Anecdotal reports of hypertonicity and early

onset NASonset NAS Paucity of published reports of neonatal Paucity of published reports of neonatal

withdrawalwithdrawalEinarson A. Use and safety of antipsychotic drugs during pregnancy. J Einarson A. Use and safety of antipsychotic drugs during pregnancy. J

Psychiatr Pract. 2009 Psychiatr Pract. 2009 May;15(3):183-92.May;15(3):183-92.

PharmacogeneticsPharmacogenetics P glycoproteinP glycoprotein

ABB1 haplotypes have been associated with ABB1 haplotypes have been associated with decreased methadone requirementsdecreased methadone requirements

Coller JK. Cln Pharmacol Ther. 2006,80:682-90

Mu opioid receptor Mu opioid receptor Polymorphism A118G has reduced response to Polymorphism A118G has reduced response to

ligands and has been associated with ligands and has been associated with differential pain response, but not methadone differential pain response, but not methadone dosagedosage

A118G may represent propensity for heroin A118G may represent propensity for heroin abuseabuse

Weaker candidatesWeaker candidates dopamine receptor type 1, preproenkephalin dopamine receptor type 1, preproenkephalin

and preprodynorphinand preprodynorphin

Drakenberg K,. Proc Natl Acad Sci U S A. 2006; 103(20):7883-7888Somogyi AA, Clin Pharmacol Ther. 2007;81(3):429

Skorpen F, Palliat Med. 2008; 22(4):310-327

Will a genetic test tell us Will a genetic test tell us who we can send home who we can send home

early?early?Not any time soon!Not any time soon!

Association of genes with addiction Association of genes with addiction in adults not establishedin adults not established

Relevance of adult polymorphisms to Relevance of adult polymorphisms to neonates unclearneonates unclear

Responses are polygenic and not Responses are polygenic and not monogenicmonogenic Example of sickle cell anemiaExample of sickle cell anemia

PK/PD modelingPK/PD modeling

Powerful mathematical techniques to Powerful mathematical techniques to evaluate dataevaluate data Drug levels with sparse samplingDrug levels with sparse sampling NAS scoresNAS scores Age, weight, developmentAge, weight, development

Assess sources of variabilityAssess sources of variability Understand the biology of Understand the biology of

developmentdevelopment Predict best dosePredict best dose

PK/PD model of PK/PD model of buprenorphine in neonatesbuprenorphine in neonates

Time (hr)

Con

c (n

g/m

L)

0 100 200 300

0.0

0.1

0.2

0.3

0.4

0.5

ID = 12

ObservedPredicted Individual

PK/PD models in NASPK/PD models in NAS

ClonidineClonidineXie HG. J Clin Pharmacol. 2010 May 19. [Epub ahead of print]Xie HG. J Clin Pharmacol. 2010 May 19. [Epub ahead of print]

BuprenorphineBuprenorphine MorphineMorphine

IV models availableIV models available NO ORAL DATA!NO ORAL DATA!

Long term developmental Long term developmental effects of NAS treatmenteffects of NAS treatment

Very difficult data to obtainVery difficult data to obtain NAS treatment vs. NASNAS treatment vs. NAS Post discharge effects likely dwarf Post discharge effects likely dwarf

treatmenttreatment Even if there were developmental Even if there were developmental

effects, how would these risks effects, how would these risks compare to non-treatment of NAS?compare to non-treatment of NAS?

Actively Recruiting Actively Recruiting Clinical TrialsClinical Trials

Maternal acupuncture Maternal acupuncture P. Janssen, Univ. British ColumbiaP. Janssen, Univ. British Columbia LOT primary outcomeLOT primary outcome RCTRCT

Fetal neurobehavior and autonomic Fetal neurobehavior and autonomic tonetone L. Jansson, Johns HopkinsL. Jansson, Johns Hopkins Two observational cohortsTwo observational cohorts

Summary of Future Summary of Future TrendsTrends

Increased research in clonidine and Increased research in clonidine and buprenorphinebuprenorphine

PharmacogeneticsPharmacogenetics Polysubstance abuse treatmentPolysubstance abuse treatment Dose optimizationDose optimization Clear need for more researchClear need for more research

Black Walnut, Blenerhasset Island, WV