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Estelle B. Gauda, M.D.Professor of Pediatrics

Johns Hopkins School of Medicine

To understand the neurobiology mediating the different types of withdrawal from illicit drugs: physical and psychological

To understand why clonidine may be an effective adjunct treatment choice for individuals with moderate to severe withdrawal from opiates

Opiates: methadone, buprenorphine, heroin,

Prescription drugs: ◦ Vicodin, OxyContin, Percocet

Benzodiazipenes

Stimulants: cocaine, methamphetamine

Cannabinoids

Tobacco

SSRI

Past Month Illicit Drug Use among Persons Aged 12 or Older: 2012

http://www.samhsa.gov/data/nsduh/2k11results/NSDUHresults2011.htm#Fig1-

9.2% of total population ≥ 12 yrsUsed drugs within the last month

Tennessee: 10-fold increase (12yrs) 0.7 per 1,000 live births 1999, 8.5 per 1,000 live births in 2011.

Kentucky : 11-fold increase (10yrs)1.2 cases per 1,000 live births in 200113.2 cases per 1,000 live births in 2011

Florida: 3-fold increase (6 yrs)2.31 per 1,000 live births in 20077.52 per 1,000 live births in 2011.

Vermont, 8-fold increase (8 yrs)3 per 1,000 deliveries in 200226 per 1,000 deliveries in 2010

Washington: 3-fold increase (8 yrs)1.2 per 1,000 live births in 2000 3.3 per 1,000 live births in 2008.

INCIDENCE OF NAS ACROSS THE COUNTRY

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Shift from abuse of classical opioids such as heroin, morphine and methadone to abuse of prescription opioids

such as hydrocodone, hydromorphone and oxycodone.

Prescription of opioids in the U.S. during the last ten years

2000 ---- 174 million2011 ---- 238 million

Prescription drug abuse:Women 15-17 years of age

23% of pregnant women

13% in non-pregnant women

National Survey on Drug Use and Health

2010 , 2012-2013

OPIOIDS: Vicodin

OxyContin Codeine

Fentanyl ...

Diminish perception of pain Addiction Euphoria

Dependence Drowsiness Constipation

Slow respiration Death

DEPRESSANTS: Valium Xanax

Ambien...

Calming Drowsiness Addiction

Dependence Uncoordinated

Slow respiration Decrease heart rate

Death

STIMULANTS: Adderall Ritalin...

Alertness Addiction

Dependence Irregular heartbeat High body temp.

High blood pressure

Heart failure Seizures Paranoia Death

IDAHO OFFICE OF DRUG POLICY PRESCRIPTION DRUG ABUSE WORKGROUP

• ONE in FIVE Idaho students report taking a prescription drug without a physicians prescription at least once during their lifetime (Idaho Youth Risk Behavior Survey, 2011)

• In 2010, an Idaho citizen died every 45 HOURS because of a drug induced death caused by illicit, prescription, or over the counter drug-use. 250% increase since 2000. (Idaho Vital Statistics, 2010) This rise is greatly attributed to the increase in prescription drug abuse.

• From 2005 to 2010, Idaho addiction treatment facilities experienced a SEVEN FOLD increase in percent of opioid admissions as the primary substance of abuse. (SAMHSA, Idaho Treatment Episode Data Set)

• In 2011, more Americans (6.1 MIL-LION) reported the nonmedical use of prescription drugs within the preceding month than had used cocaine, heroin, hallucinogens, and inhalants combined. (SAMHSA NSDUH 2011)

• 54% of prescription opioids being used for nonmedical purposes are obtained from a friend or relative for free, with these friends or relatives most often obtaining them from 1 physician (82%) (SAMHSA NSDUH 2011)

IDAHO OFFICE OF DRUG POLICY PRESCRIPTION DRUG ABUSE WORKGROUP

16.4

$53,400

EVERY HOUR, one baby in the US is born suffering from opiate withdrawal.

(National Institute of Drug Abuse, 2012)

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Kellogg. Narcotic use in pregnancy. Am J Obstet Gynecol 2011.

Oxycodone/morphine/codeine/hydromorphone

5 fold increase over ~12 years

Tobacco exposure---toxicity vs withdrawal---

Only tobacco-exposed infants – within 24 hrs of birth:

• excitable hypertonic, required more handling and

• More stress/abstinence signs

• specifically in the central nervous system (CNS), GI, and visual areas.

• Resolved with in 24-48 hrsLaw et al, Lester: PEDIATRICS Vol. 111 No. 6 June 2003

Increase Severity

◦ Polymorphisms in µ-opioid receptor OPRM1, variant A11AG and catecholo-methyltransferase (COMT)

◦ Higher maternal dose methadone during last trimester (5.5mg increased LOS by 1 day)

◦ GA >36 wks

◦ Lower maternal weight at delivery

◦ High infant BW

◦ Benzodiazepines

◦ SSRI exposure

◦ Cigarettes smoke 24 hrs prior to delivery

Reviewed in CLINICAL OBSTETRICS AND GYNECOLOGY ; 56,, 186–192 Addiction. 2012 Nov;107

Past Month and Past Year Heroin Use among Persons Aged 12 or Older: 2002-2012

In utero exposure

Opiate Exposure

Heroin,Methadoneoxycodone

bupernorphine

Presentation24-72 hoursAfter birth

4-5 days for buprenorphine

Incidence

Heroin >90%Methadone – 50-90%Oxycodone – 5.6%

Buprenorphine- 20-70%

Tolerance-Loss of effect following repeated treatments such that

a higher dose is required for equivalent effect

Dependence –Superactivation of cAMP

Physical signs:– withdrawal (autonomic and somatic signs associated with drug absence)

Psychological –(addiction) –loss of control over drug use (impulsivity and

compulsivity) –

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Neurocircuitry: Reward PathwayDopamine

(Ventral TegmentalArea)

DOPAMINE

benzodiazepine

Chocolate/Excercise

WI THDRAWAL

Wakefulness

Irritability

Tremors, Temperature Instability, Tachypnea

Hyperactive, High Pitch Cry, Hypertonia, Hyper-reflexia

Diarrhea, Dysfunctional Suck and Swallow

Rub Marks, Respiratory Distress, Rhinorrhea, Reflux

Apnea, Alkalosis (respiratory), Acidosis (metabolic)

Weight Loss

Autonomic Dysfunction (sneeze, yawn, sweating)

Lacrimation

Clinical Signs

http://scientopia.org/blogs/scicurious/2008/12/08/historical-science-cocaine-and-dopamine/

Norepinephrine neurocircutry in the brain mediates the physical signs of withdrawal leading to

Elevated Sympathetic Output

Cerebellum

Locus Ceruleus

hypothalamus

Limbic

Frontal Cortex

PrefrontalFrontal Cortex

HPAxis –CRF- ACTH – ADRENALS-CORTISOL-EPI and NE

Opiate receptors

Increased vigilanceAlertnessInsomniaStressAnxiety

Locus ceruleus

Norepinephrine

µ-op

-

Adenylyl cyclase

cAMP

PKA

Gi/o-

NE

NENE

Summation of cellular events:

Acute responses to opiate exposure in a neuron in the LC

PresynapticNeuron

LC-neuron

NE

NE PostsynapticNeuron

NENE

NE

µ-op

+

Adenylyl cyclase

cAMP

PKA

Gi/o-

NE

NE

NE

NE

NE

NENE

NE

NENE

α1- receptors, β1 - receptorsVasoconstriction smooth muscle, Diaphoresis, Tachycardia, Hypertension, GI irritability

LC neurons cellular adaptation after chronic exposure

Myenteric plexus of gut- constipation◦ Tolerance to opiate-induced reduction in

intestinal motility and increase in motility during withdrawal

Dorsal horn of Spinal Cord – hyperalagesia◦ Tolerance to opiate- induced analgesia

Multiple Brain regions – dysphoria, ◦ involved in psychological addiction

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NALTREXONE PRECIPITATED OPIATE WITHDRAWAL IN METHADONE ADDICTED

HUMAN SUBJECTS: EVIDENCE FOR NORADRENERGIC HYPERACTIVITY

Life Sciences 1984 Vol 35 pp 1263-1272

Dennis S. Charney; D. Eugene Redmond, Jr.; Matthew P. Galloway;Herbert D. Kleber; George R. Heninger; Michelle Murberg; Robert H. Roth

craving, anxiety,piloerection, hot and cold flashes, aching bones, anorexia, restlessness

nausea, vomiting, diarrhea, spontaneous orgasm, yawning, perspiration,

lacrimation, rhinorrhea, and tremors) on a

five point rating scale (l=not at all, 2=mild, 3=moderate, 4=severe, 5=extremely severe)

Direct correlation between the abstinence Scores and plasma MHPG levels

(a biomarker for centrally released NE)In adult humans during opiate withdrawal

Life Sciences 1984 Vol 35 pp 1263-1272

µ-op

+

Adenylyl cyclase

cAMP

PKA

Gi/o-

NE

NE

NE

NE

Methadone, Morphine,

Burpernorphine

NE

NENE

NE

NENE

α1- receptors, β1 - receptorsVasoconstriction smooth muscle, Diaphoresis, Tachycardia, Hypertension, GI irritability

µ-op

Gi/o

-

-

Adenylyl cyclase

cAMP

PKA

LC neurons cellular adaptation after chronic exposure

Morphine Methadone Buprenorphine

Mechansism of Action

Mu-receptor agonist

Mu-receptor NMDA antagonist

partial μ-opioid agonist; high affinity for and slow dissociation“ceiling effect”

Ethanol content 0% 8% 30%

Bioavailability Variable, <40% 36–100% NA

Half-life (t½, h) Preterm: 10–20, neonates: 7.6(4.5–13.3)

Children: 19h (4–62)

Premature neonates20±8hBr J clin Pharmac 1993; 36: 215-219

Protein binding (%)

<20 85–90Highly lipid soluble

96

Metabolic pathway (metabolites)

glucuronidation(morphine-6-glucuronide(active) and morphine-3-glucuronide (inactive))

Hepatic N-demethylation via CYP3A4(2-ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidene(inactive)

Hepatic N-dealkylationprimarily via CYP3A4 (norbuprenorphine(active)) and glucuronidationof active metabolite

Opioids used to treat NAS in infants Methadone: CON

• Half life ~26 h in neonates compared with 8 h with morphine,

– Drug accumulation – prolongs hospitalization

• Metabolism rates vary by factor of 100

• No single ratio for equianalgesic dosing can be found between morphine and methadone -

Difficult to convert to morphine

.

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Methadone: PRO

• Effective in treating opiate induced hyperalgesia, thus methadone may be useful in infants with iatrogenic NAS who also might have pain

-In 80% of cancer patients with uncontrolled pain or significant side effects, switching from morphine to methadone – better pain control and reduced side effects

J Clin Oncol. 2001;19:2898–2904.

Prenatal Buprenorphine Versus Methadone Exposure and Neonatal Outcomes: Systematic Review and Meta-Analysis

12 studies infants born 1996-2012

• Design: random-effects meta-analysis model – --evaluated for confounding, publication bias, and heterogeneity

• Subjects: 515 neonates mothers on BupMT855 neonates mothers on MethMT

• OUTCOMES: The unadjusted NAS Bup vs Meth – treatment risk was lower – (risk ratio = 0.90, 95% (CI: 0.81, 0.98) – mean length of hospital stay shorter – (-7.23 days, 95% CI: -10.64, -3.83).– NAS treatment duration was shorter– (-8.46 days, 95% CI: -14.48, -2.44)– morphine dose lower – (-3.60 mg, 95% CI: -7.26, 0.07)– Higher mean GA, BW, and Head Circ

Brogly SB, . Am J Epidemiol. 2014

CONFOUNDER

Fewer women treated with BMT used illicit opioids near delivery

risk ratio = 0.44, (95% CI: 0.28, 0.70).

Bupernorphine for treatment of NAS in methadone exposed infants

On going RCT – Jefferson medical College, Thomas Jefferson

Given sublingual – dissolved in ETOH – Randomized – Not blinded13-39 mcg/kg/dayKraft et al 2008Pediatrics

BupernorphineN=12

MorphineN=12

Length of treatmentdays

12 (11-47)Mean (range)

32 (14-60)

LOS 27 (17-51) 38 (19-66)

Phenob, adjunct 3 1

16-60mcg/kg/dayKraft – 2011Addiction

BupernorphineN=12

MorphineN=12

Length of treatment 23±12 38±14

LOS 32 ± 24 42 ±13

Phenob, adjunct 3 1

Exclusion Criteria

Infants exposed to benzodiazepines

Infants who have severe NASMay need 2nd agent to control symptoms

What about Phenobarbital as adjunct treatment for NAS

µ-op

NE

NE

MOR

NE

NENE

Adenylyl cyclase

cAMP

PKA

Gi/o

-

Phenobarb and benzo prolongs and potentiates the action of GABA on GABAA receptors

Cl-Cl

-Cl

-

GABA

GABA-

Cl-

Cl-Cl

-

Hyperpolarization

Cl-

Cl-Cl

-

LC neuron

Cl-

Cl-

Cl-

• DESIGN: Partially randomized, controlled trial: infants exposed to methadone and/or heroin in utero. Finnegan scoring system used. Treatment groups:

• DTO and placebo (n = 10) vs

• DTO and phenobarbital (n = 10)

DOSE: DTO 0.02 mg/kg (morphine equivalents) dose Q 3-4 hrs;

Phenobarbital LD: 30 mg/kg divided in three oral 10 mg/kg given q 12 hrs.

Main: 2.5 mg/kg Q 12 hr - target plasma level 20 to 30 mcg/ml

• OUTCOMES:

LOS: (hospital)

DTO with phenobarbital group -- 38 days

DTO alone - 79 days ( DTO+phen vs DTO alone) P<0.001).

TOTAL DURATION OF TREATMENT:

On average the infants in the Phenobarbital group continued phenobarbital therapy 3.5 months (range 2—9 months), after the DTO was discontinued

Coyle MG, et al J Pediatr 2002; 140(5): 561–564.

Phenobarbital as adjunct treatment for NAS based study with an N of 10 infants!!

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Pediatric Neurologist avoid exposing neonates to phenobarbital longer than for treatment of the acute seizure 

episode

Because data from human and animal studies implicating cognitive delays and apoptosis, respectively

Phenobarbital in therapeutic dosagescauses apoptosis in developing neurons in newborn

rats

PETRA BITTIGAU, Ann. N.Y. Acad. Sci. 993: 103–114 (2003).

• FARWELL, J.R., Y.J. LEE, et al. 1990. Phenobarbital for febrile seizures—effects on intelligence and on seizure recurrence. N. Engl. J. Med. 322: 364–369.

• REINISCH, J.M., S.A. SANDERS, et al. 1995. In utero exposure to phenobarbital and intelligence deficits in adult men. JAMA 274: 1518–1525.

• SULZBACHER, S., J.R. FARWELL, et al. 1999. Late cognitive effects of early treatment with phenobarbital. Clin. Pediatr. Philad. 38: 387–394.

• THORP, J.A., M. O’CONNOR, et al. 1999. Does perinatal phenobarbital exposure affect developmental outcome at age 2? Am. J. Perinatol. 16: 51–60.

• DESSENS, A.B., P.T. COHEN-KETTENIS, et al. 2000. Association of prenatal phenobarbital and phenytoin exposure with small head size at birth and with learning problems. Acta Paediatr. 89: 533–541

Review of the literature  Adverse effects of phenobarbital on outcome in humans‐

For these reasons, at Johns Hopkins,we do not use

Phenobarbital as adjunct therapy for treatment of NAS

But we do use CLONIDINE

to directly targetLC neuronal hyperactivity

µ-op

+

Adenylyl cyclase

cAMP

PKA

Gi/o-

NE

NE

NE

NE

Summation of cellular events:

Role of 2-noradrenergic stimulation during superactivation of cAMPsystems induced by chronic opioid exposure

NE

NENE

NE

NENE

α1- receptors, β1 – receptors on postsynaptic neuronsVasoconstriction smooth muscle, Diaphoresis, Tachycardia, Hypertension, GI irritability

2

Adenylyl cyclase

cAMP

PKA

Gi/o

-

-

2

Clonidine

Clonidine

Representative recording of a patient addicted to opioids undergoing detoxification demonstrating the effects of -opioid receptor blockade by naloxone during propofol anesthesia, and the effects of clonidine on efferent sympathetic activity to muscle and on arterial blood pressure.

Clonidine decrease sympathetic overactivity in response to withdrawal

in adults

Plasma epi levels

Plasma NE levels

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Clonidine as an Adjunct Therapy to Opioids for Neonatal Abstinence

Syndrome: A Randomized, Controlled Trial

Investigators: Alex G. Agthe, M.D, George Kim, M.D.,

Kay Mathias, NNP, Raul Chavez-Valdez, M.D.Tamorah Lewis, Lauren Jansson, M.D., Craig W.

Hendrix, M.D., Ph.D., and Myron Yaster, M.D, Estelle B. Gauda, M.D

Funding: NIDA

Pediatrics 123(5):e849-e856, 2009.

Primary Endpoints:

• Length of treatment, defined as the need for any pharmacological treatment for NAS

• Amount of DTO (Diluted tincture of opium) needed to treat NAS DTO: 0.4mg/ml of morphine

Inclusion Criteria:

• All newborns age 0 to 14 days who were prenatally exposed to opioids (methadone and/or heroin)

• NAS (moderate to severe) defined by two consecutive NAS-scores of 9 on the adapted Finnegan Scale,

INFANT CHARACTERISTICS

CLONIDINE-DTO GROUP(N=40)

PLACEBO-DTOGROUP(N=40)

Birth weight – g † 2863 ± 365 3045 ± 415

Gestational age – wk 38.5 ± 1.7 39.1 ± 2.0

Prenatal exposure – no. (%)

Methadone 35 (87.5%) 35 (87.5%)

Morphine 26 (65) 29 (72.5)

Cocaine with opioids 25 (62.5) 24 (60)

0 10 20 30 40 50 60 70 80 90 1000

25

50

75

100

ClonidinePlacebo

Days on DTO

Perc

ent of in

fan

ts o

n D

TO

Median length of treatment CLONIDINE+DTO = 11 daysPLACEBO + DTO = 15 days27% shorter with clonidine

P=0.02 log rank

Clonidine decreased the median length of pharmacotherapy by 4 days

Clonidine PlaceboDTO (ml) 19.4 (20.1) 47.9 (89.2)

Morphine Equivalents (mg)

7.7 (8.0) 19.2 (3.3)

Day of treatment

2 4 6 8 10 12 14 16 18 20 22 24 26 28

PLACEBO

No. of infants40 40 36 27 25 22 22 21 17 15 12 12 11 10

CLONDINE

No. of infants40 40 40 31 26 24 19 15 12 11 8 7 7 2

0 2 4 6 8 10 12 14 16 18 20 22 24 26 280.00.10.20.30.40.50.60.70.80.91.01.11.21.3

Day of treatment

Mea

n D

TO

(m

l/kg

/day

)

Infants in the clonidne group required less opiate after first 3 days of therapy

clonidne

Summary of Study • Clonidine combined with DTO (oral morphine) is

effective in treating infants with NAS.

• Clonidine combined with DTO at dosage of 1mcg/kg every 4 hours was not associated with adverse cardiovascular outcomes in this newborn population

• Infants with the worst signs of NAS benefited most from the addition of clonidine.

• More treatment failures were observed in the placebo+DTO group (5 vs 0) and seizures (3 vs 0).

• 3 Deaths in the overall cohort: Myocarditis, Homicide, SIDS ---all after discharge to home. One infant developed SVT resolved

88

8.3 10.116.2

42.7

94

0

10

20

30

40

50

60

70

80

90

100

Tobacco Alcohol SSRIs BZD Marijuana Opioids

Concurrent drug exposures in women on Methadone Maintenance Therapy

n=136

PER

CEN

T

Retrospective;  Eastern Maine Medical Center, Bangor Maine  (2005‐2007)Pritham et al: JOGNN 41, 180‐190 2012 

FACTORS THAT INCREASED LOSMaternal  BZD UseAnd Bottle feeding

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Ativan (lorazepam)Valium (diazepam)

Klonopin (clonazepam)Tranxene-SD (clorazepate)

Xanax (alprazolam)Restoril (temazepam)Dalmane (flurazepam)

µ-op

NE

NE

MOR

NE

NENE

2

Adenylyl cyclase

cAMP

PKA

Gi/o

-

Clonidine

Phenobarb and benzo prolongs and potentiates the action of GABA on GABAA receptors

GABA Cl-Cl

-Cl

-

GABA

-

Cl-

Cl-Cl

-

Hyperpolarization

Cl-

Cl-Cl

-

HYPERPOLARIZATION

Withdrawal associated with BZD exposure –later onset and protracted

• Neonates exposed to benzodiazepines > LOT than those unexposed  ~14 days– Am J Obstet Gynecol 2008;199:396.e1‐396.e7.

• Neonates exposed to BZD have a later presentation of NAS that is bimodal

Case report:  (2 infants) Clin Pediatr (Phila) 1990;29:108‐11. • Diazepam use by pregnant women can be associated with a later presentation of withdrawal symptoms in the neonate than that induced by the use of other drugs. Intensification of symptoms after 7‐14 days of therapy

• BZD exposures effects on infant: ‐‐ floppy infant syndrome, or marked neonatal withdrawal symptoms  ‐‐ mild sedation, hypotonia, and reluctance to suck, apnoeic spells, cyanosis, and impaired metabolic responses to cold stress, movement disorders

Why

• Highly  lipophilic• High intake in animal fat tissue • Easy penetration into brain white matter• Long retention in neural tissue• High concentrations brain, the lungs, heart • Fetal‐maternal ratio of 1.2 to 2• T1/2 in the neonate about 31 hours

• Tissues act as depot for BZD (diazepam‐worst)

Daily or Almost Daily Marijuana Use in the Past Year and Past Month among Persons Aged 12 or Older:

2002-2012

Marijuana smoke contains higher levels of certain toxins than

tobacco smoke

Acute effects of THC exposureadults

• problems with memory and learning– neurons in the information processing system of the hippocampus and the

activity of the nerve fibers are suppressed by THC

• distorted perception

• difficulty in thinking and problem-solving

• loss of coordination

• increased heart rate

• anxiety

• panic attacks

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Anxiety, irritability, physical tension, depression, and loss of appetite.

Long T1/2 30 hrs

Worse during the first 10 days of abstinence

Prospective longitudinal assessments can increase the risk for ill behaviors (Goldschmidt et al, 2004; Day et al, 2011),

Cognitive deficit (Huizink & Mulder, 2006),

Drug seeking (Day et al, 2006)

Attention deficit (Leech et al, 1999)

Anxiety and depression (Leech et al,2006)

Growth retardation (El Marroun et al, 2009),

Cannabis use during pregnancypsychosocial effects on children

Review: Morris et al, Eur J Neurosci. 2011 November ; 34(10): 1574–1583

While essentially all drugs of abuse share similar signs and symptoms of

psychological dependence (NAc-Dopamine) this is not the case for

physical dependence (LC-NE)

Psychological dependencevs

Physical Dependence Increase Severity◦ Polymorphisms in µ-opioid

receptor OPRM1, variant A11AG and catecholo-methyltransferase(COMT)

◦ Higher maternal dose methadone during last trimester (5.5mg increase- LOS by 1 day)

◦ GA >36 wks◦ Lower maternal weight at delivery◦ High infant BW◦ Benzodiazepines ◦ SSRI exposure◦ Cigarettes smoke 24 hrs prior to

delivery

Decrease Severity

◦ Breastfeeding/Rooming In

◦ Quiet environments

◦ Buprenorphine

◦ COCAINE

Reviewed in CLINICAL OBSTETRICS AND GYNECOLOGY ; 56,, 186–192 Addiction. 2012 Nov;107

NAS from opiates is mediated by over activation of the sympathetic

nervous system with a large contribution from excessive release

of NE from LC neurons.

LC neurons contain opioid receptors and alpha 2 adrenergic

receptors both of which cause reduction in NE output from LC

neurons, making both receptors therapeutic targets for the treatment of NAS

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Alpha 2 adrenergic receptors have a restricted distribution in the brain

Clonidine binds to these receptors-reducing the release of NE

GABA-receptors are widely distributed throughout the brain

BZD and phenobarbital bind to these receptors throughout the brain

• Phenobarbital similar to BZD, enhance the binding of GABA to the GABA A receptor

• Depresses neuronal activity throughout the entire brain accounting during period of development

• Overall neuronal depression throughout the brain may be contributing to adverse effects on the developing nervous system

What I hope your remember

Using this information to help guide targeted pharmacological therapies for the treatment NAS -

Advocate for properly conducted clinical trials in vulnerable populations to provide evidence -

When evidence is lacking -- use biology and physiology as a guide.

What I hope you will considerPharmacological treatment of NAS:1) Opiate replacement alone (morphine) followed by clonidine

when adjunct therapy is required. ◦ Clonidine is added when infant is requiring ≥ 0.2 mg (flat

dose) of morphine every 4 hours ( 0.06mg/kg q 4)

◦ Clonidine dose 6-12mcg/kg/day divided q 3-6 hrs(may take 1-2 days to see full effect of clonidine)

2) Phenobarbital as adjunct therapy for the treatment of NAS should be avoided unless symptoms can not be controlled

with opiate/clonidine because of concurrent benzodiazepine withdrawal.

3) When phenobarbital is used for treatment of benzodiazepine withdrawal in neonates, it should be used at the lowest effective dose for the shortest period of time.

Thank you for your Attention

SUMMARY

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Positive urine toxicology screens in mothers and infants n= 114

4 wks prior to delivery

36.4

48.1

3.7

52.5

27.9

9.8

0

10

20

30

40

50

60

Other Opiate BZD Cocaine

Maternal

Infant

N=107 samples for mothersN=61 samples for infantsP

ercent

Prospective cohort study:   114 mother/infant dyads;   2009‐2010Cleary et al: Addiction 2012 107:1482‐1492

Drug use last 30 days: BZD 38%; cocaine 3.4%; marijuana 35%