Transcript Clonidine

Future Trends in the
Treatment of the
Neonatal Abstinence
Syndrome
Walter K. Kraft, MD
Associate Professor
Director, Clinical Research Unit
Thomas Jefferson University
Philadelphia, PA
Disclosure (past 3 years)
Consulting
Merck
Synageva
Speakers Panel
None
Research Grants
Merck, Schering
Bristol Myers Squibb
Data Safety Monitoring Board
Wyeth, RePros Therapeutics
Outline


Limitations of Current Therapies
Potential New Drugs
Clonidine
 Buprenorphine
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Ongoing Research
Future Needs
Opioid Neonatal Abstinence
Syndrome
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Newborns of mothers with chronic use

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Methadone, buprenorphine, morphine, heroin
5% of 56,000 women in US who reported heroin use in
previous month were pregnant
SAMHSA. 2006 National Survey on Drug Use and Health: National Findings., NSDUH Series H-32,
DHHS Publication No. SMA 07-4293). Rockville, MD. 2007

In Australia 40 cases per 10,000 live births
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US extrapolation—16,000/yr
O'Donnell M. Pediatrics. 2009; 123(4):e614-21
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Signs and symptoms
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Neurologic
GI
Autonomic
Why do we treat NAS with
medications?
Weight gain
 Ensure development
 Prevent seizures
 Patient comfort
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Pharmacologic Treatment

Opiates are preferred therapy
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Improve weight gain and reduce need for supportive
care, but at cost of longer hospital stays
Osborn, DA; Opiate treatment for opiate withdrawal in newborn infants. The Cochrane Library 2007
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Benzodiazapines helpful only in seizures
Phenobarbital useful as adjunct therapy
Osborn, DA; Sedatives for opiate withdrawal in newborn infants. The Cochrane Library 2007
Common Drug Treatments
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Morphine
Phenobarbital
Tincture of opium
Methadone
Chloral hyrdate
Paregoric
What is the problem?

At least 50% of infants require pharmacologic
treatment
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We just don’t know which ones
Hospital stays are too long
Home treatment difficult
No generally recognized standard of care
Other drug-induced withdrawal symptoms
Goals of treatment for NAS
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shortened hospital stay
shortened time of exposure to opiates
lowered hospital costs
improved parenting
maternal-infant bonding
 lessened maternal guilt

Greif J. Subst Abuse Treat. 1993; 10(4):339-34
Clonidine
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Alpha 2 adrenergic agonist
Decreases catecholamine release in the CNS
Common uses
Hypertension
 Acute opioid withdrawal

Low dose opioids
 Low dose methadone
 Rapid detoxification
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Clonidine
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Cochrane Review: Adult opioid withdrawal
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More effective than placebo
More side effects compared to tapering methadone
Gowing L, Farrell M, Ali R, White JM. Alpha2-adrenergic agonists for the management of opioid
withdrawal. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD002024
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Side effects
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Hypotension
Rebound hypertension
Dry mouth
Sedation
Clonidine in NAS
Year
n
Hoder,
1984
Case
Series
7
Leikin,
2009
Case
Series
14
Esmaeili, Case
2010
Series
29
Agthe,
2009
40
RCT
Clonidine dose
(mcg/kg)
0.5–1.0 po Q 6 13 day LOS
hr
0.5–1.0 po Q 6 7 day LOT
hr
In utero exposures = 3
Iatrogenic NAS = 11
0.5–3.0 hr IV
14 day LOT
32 day LOS
Chloryl hydrate rescue
1.0 po Q 4 hr 11 day LOT vs. 15 for
(+ morphine) placebo
Agthe
Morphine dose requirements
Square = clonidine Circle = placebo
Length of
Treatment
Agthe: Secondary Endpoints
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Treatment failures: 5 vs. 0 with clonidine
Seizures: 3 vs. 0 with clonidine
Deaths: 0 vs. 3 with clonidine (all post discharge)
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Myocarditis
SIDS
Homicide (methadone overdose)
DSMB ruled these not clonidine related
SVT noted 3 days following cessation of clonidine
Heart rate and blood pressure changes noted, but none
outside of normal ranges
Clonidine

Optimal use
Adjunct to opioid
 Fixed dose
 1.5 mcg/kg q 4 starting week 2?

Xie HG. J Clin Pharmacol. 2010 May 19. [Epub ahead of print]
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Formulation
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Liquid oral vs. transdermal
Buprenorphine
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Cochrane Review: Management of withdrawal in adults
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More effective than clonidine
Probably quicker in resolution of withdrawal symptoms
Longer duration of treatment but higher rates of completion
Gowing L, Ali R, White JM. Buprenorphine for the management of opioid withdrawal. Cochrane
Database Syst Rev. 2009 Jul 8;(3):CD002025.
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Safety margin
Increasing use in adults
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Pregnant females
Buprenorphine is a partial mu
receptor agonist
Potential Advantage in NAS
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Safety
Ceiling effect on respiratory depression
 Fatalities in adults primarily seen with concomitant
benzodiazapine abuse
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Less abuse potential
Long half life
Improved control of abstinence?
 Ability to wean out of the hospital?
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Challenges to use in Neonates
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No pediatric indication
One study in preterm critically ill infants using IV
formulation
 Case reports of maternal use of buprenorphine
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No good PK data
Sublingual administration
Metabolic ontogeny
Unknown potency of norbuprenorphine
Clinical Trial Study Goal
Primary
Demonstrate sublingual buprenorphine for NAS is
safe, tolerable, and feasible
Secondary
1) Investigate comparative efficacy for endpoints
of length of treatment and length of stay
2) Explore buprenorphine pharmacokinetics
Buprenorphine Protocol
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4.4 gm/kg q8 buprenorphine sublingual (Buprenex in
30% alcohol/sucrose)
Dose up-titration by 20%
~one PK sample/day
Weaning by 10%/dose after stable 48 hours
Cessation at or near initial dose
Provision for rescue dose followed by up-titration
At maximum 39 gm/kg/day, rescue with
phenobarbital
Observation for 48 hr after cessation of therapy
Buprenorphine
Need for Phenobarbital Rescue
3
NOS
1
Dose adjustment
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Observation
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Lower than expected bup concentration
Rapid up-titration
Relatively frequent need for phenobarbital rescue
Adjusted dose
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1) Increase initial daily dose from 13.2 mcg/kg to 15.9 mcg/kg
2) Increase the up-titration from 20% increase to 25% increase
3) Increase maximum daily dose from 39 mcg/kg to 60 mcg/kg
Update
24 patients randomized to new dose schema
40
35
30
23
Buprenorphine (12)
Morphine (25)
4
Length of treatment
Length of Stay
2
Phenobarbital
Adjunct
Length of Treatment: All
treated patients in trial (N=50)
70
60
50
40
30
20
10
0
Morphine
Buprenophine
Safety: Serious Events
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Status epilepticus,
treated with lorazepam
and phenobarbital
Full-term female, scores
of 4-6 after 3 days of
treatment
Neurological work up
negative
Level = 0.35 ng/mL
Normal development at
12 months of age
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Elevated liver enzymes
associated with
cytomegalovirus
infection
Poor feeding,
aminoaciduria
Abnormalities persisted
weeks after dechallenge
BuprenorphineSummary
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Appears as safe as, and more efficacious than
morphine
Efficacy needs to be tested in blinded clinical
trial
Use may facilitate expansion into outpatient
treatment
Polysubstance abuse
Thomas Jefferson University Hospital 2000-06
47
50
40
Duration
30
of
Therapy 20
(days)
38
31
Nonbenzodiazepine
exposed
Poly-substance
exposed
Benzodiazepine
exposed
10
0
Seligman NS,. Am J Obstet Gynecol. 2008; 199(4):396.e1-396.e7
Polysubstance abuse
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Common
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Worse outcomes
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Up to 50% of babies at risk for NAS have exposure
to benzodiazepines
Cause or marker of treatment resistance?
Even less clarity of optimal treatment
Effects of concomitant psychiatric
medications
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10.3% of drug-using pregnant women had other
psychiatric disorders compared to 1.4% of
controls
Kennare R. Aust N Z J Obstet Gynaecol 2005;45:220–225.
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56% of participants in MOTHER study had
prescription for psychiatric medication during
pregnancy
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Mostly anxiolytics and SSRIs
Benzodiazepines were exclusion criteria
Martin PR. Am J Addict. 2009 ; 18(2): 148–156
Neonatal responses to in
utero exposure
 Antidepressant
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Mild CNS and respiratory systems
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3-5 day duration, self limited
Koren G. CMAJ. 2005; 172(11):1457-1459
Ferreira E. Pediatrics. 2007; 119(1):52
 Antipsychotics
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Adults have mild withdrawal symptoms of agitation and
insomnia
Anecdotal reports of hypertonicity and early onset NAS
Paucity of published reports of neonatal withdrawal
Einarson A. Use and safety of antipsychotic drugs during pregnancy. J Psychiatr Pract. 2009
May;15(3):183-92.
Pharmacogenetics
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P glycoprotein
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ABB1 haplotypes have been associated with decreased
methadone requirements
Coller JK. Cln Pharmacol Ther. 2006,80:682-90
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Mu opioid receptor
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Polymorphism A118G has reduced response to ligands and
has been associated with differential pain response, but not
methadone dosage
A118G may represent propensity for heroin abuse
Drakenberg K,. Proc Natl Acad Sci U S A. 2006; 103(20):7883-7888
Somogyi AA, Clin Pharmacol Ther. 2007;81(3):429
Weaker candidates
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dopamine receptor type 1, preproenkephalin and
preprodynorphin
Skorpen F, Palliat Med. 2008; 22(4):310-327
Will a genetic test tell us who we can
send home early?
Not any time soon!
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Association of genes with addiction in adults
not established
Relevance of adult polymorphisms to neonates
unclear
Responses are polygenic and not monogenic
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Example of sickle cell anemia
PK/PD modeling
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Powerful mathematical techniques to evaluate
data
Drug levels with sparse sampling
 NAS scores
 Age, weight, development
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Assess sources of variability
Understand the biology of development
Predict best dose
PK/PD model of buprenorphine in
neonates
0.5
ID = 12
0.0
0.1
Conc (ng/mL)
0.2
0.3
0.4
Observ ed
Predicted Indiv idual
0
100
200
Time (hr)
300
PK/PD models in NAS
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Clonidine
Xie HG. J Clin Pharmacol. 2010 May 19. [Epub ahead of print]

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Buprenorphine
Morphine
IV models available
 NO ORAL DATA!
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Long term developmental effects of
NAS treatment
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Very difficult data to obtain
NAS treatment vs. NAS
Post discharge effects likely dwarf treatment
Even if there were developmental effects, how
would these risks compare to non-treatment of
NAS?
Actively Recruiting Clinical Trials
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Maternal acupuncture
P. Janssen, Univ. British Columbia
 LOT primary outcome
 RCT
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Fetal neurobehavior and autonomic tone
L. Jansson, Johns Hopkins
 Two observational cohorts
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Summary of Future Trends
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Increased research in clonidine and
buprenorphine
Pharmacogenetics
Polysubstance abuse treatment
Dose optimization
Clear need for more research
Black Walnut, Blenerhasset Island, WV