1. 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

2. Disclosure (past 3 years) Research Grants Merck, Schering Bristol Myers Squibb Data Safety Monitoring Board Wyeth, RePros Therapeutics Speakers Panel NoneConsulting Merck Synageva

3. Outline Limitations of Current Therapies Limitations of Current Therapies Potential New Drugs Potential New Drugs Clonidine Clonidine Buprenorphine Buprenorphine Ongoing Research Ongoing Research Future Needs Future Needs

4. Opioid Neonatal Abstinence Syndrome Newborns of mothers with chronic use Newborns of mothers with chronic use Methadone, buprenorphine, morphine, heroin Methadone, buprenorphine, morphine, heroin 5% of 56,000 women in US who reported heroin use in previous month were pregnant 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 In Australia 40 cases per 10,000 live births US extrapolation—16,000/yr US extrapolation—16,000/yr O'Donnell M. Pediatrics. 2009; 123(4):e614-21 Signs and symptoms Signs and symptoms Neurologic Neurologic GI GI Autonomic Autonomic

5. Why do we treat NAS with medications? Weight gain Weight gain Ensure development Ensure development Prevent seizures Prevent seizures Patient comfort Patient comfort

6. Pharmacologic Treatment Opiates are preferred therapy Opiates are preferred therapy Improve weight gain and reduce need for supportive care, but at cost of longer hospital stays 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 Benzodiazapines helpful only in seizures Benzodiazapines helpful only in seizures Phenobarbital useful as adjunct therapy Phenobarbital useful as adjunct therapy Osborn, DA; Sedatives for opiate withdrawal in newborn infants. The Cochrane Library 2007

7. Common Drug Treatments Morphine Morphine Phenobarbital Phenobarbital Tincture of opium Tincture of opium Methadone Methadone Chloral hyrdate Chloral hyrdate Paregoric Paregoric

8. What is the problem? At least 50% of infants require pharmacologic treatment At least 50% of infants require pharmacologic treatment We just don’t know which ones We just don’t know which ones Hospital stays are too long Hospital stays are too long Home treatment difficult Home treatment difficult No generally recognized standard of care No generally recognized standard of care Other drug-induced withdrawal symptoms Other drug-induced withdrawal symptoms

9. Goals of treatment for NAS shortened hospital stay shortened hospital stay shortened time of exposure to opiates shortened time of exposure to opiates lowered hospital costs lowered hospital costs improved parenting improved parenting maternal-infant bonding maternal-infant bonding lessened maternal guilt lessened maternal guilt Greif J. Subst Abuse Treat. 1993; 10(4):339-34

10. Clonidine Alpha 2 adrenergic agonist Alpha 2 adrenergic agonist Decreases catecholamine release in the CNS Decreases catecholamine release in the CNS Common uses Common uses Hypertension Hypertension Acute opioid withdrawal Acute opioid withdrawal Low dose opioids Low dose opioids Low dose methadone Low dose methadone Rapid detoxification Rapid detoxification

11. Clonidine Cochrane Review: Adult opioid withdrawal Cochrane Review: Adult opioid withdrawal More effective than placebo More effective than placebo More side effects compared to tapering methadone 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 Side effects Side effects Hypotension Hypotension Rebound hypertension Rebound hypertension Dry mouth Dry mouth Sedation Sedation

12. Clonidine in NAS Yearn Clonidine dose (mcg/kg) Hoder, 1984 Case Series 7 0.5–1.0 po Q 6 hr 13 day LOS Leikin, 2009 Case Series 14 0.5–1.0 po Q 6 hr 7 day LOT In utero exposures = 3 Iatrogenic NAS = 11 Esmaeili, 2010 Case Series 29 0.5–3.0 hr IV 14 day LOT 32 day LOS Chloryl hydrate rescue Agthe, 2009 RCT40 1.0 po Q 4 hr (+ morphine) 11 day LOT vs. 15 for placebo

13. Agthe Morphine dose requirements Square = clonidine Circle = placebo Length of Treatment

14. Agthe: Secondary Endpoints Treatment failures: 5 vs. 0 with clonidine Treatment failures: 5 vs. 0 with clonidine Seizures: 3 vs. 0 with clonidine Seizures: 3 vs. 0 with clonidine Deaths: 0 vs. 3 with clonidine (all post discharge) Deaths: 0 vs. 3 with clonidine (all post discharge) Myocarditis Myocarditis SIDS SIDS Homicide (methadone overdose) Homicide (methadone overdose) DSMB ruled these not clonidine related DSMB ruled these not clonidine related SVT noted 3 days following cessation of clonidine SVT noted 3 days following cessation of clonidine Heart rate and blood pressure changes noted, but none outside of normal ranges Heart rate and blood pressure changes noted, but none outside of normal ranges

15. Clonidine Optimal use Optimal use Adjunct to opioid Adjunct to opioid Fixed dose Fixed 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] Formulation Formulation Liquid oral vs. transdermal Liquid oral vs. transdermal

16. Buprenorphine Cochrane Review: Management of withdrawal in adults Cochrane Review: Management of withdrawal in adults More effective than clonidine More effective than clonidine Probably quicker in resolution of withdrawal symptoms Probably quicker in resolution of withdrawal symptoms Longer duration of treatment but higher rates of completion 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. Safety margin Safety margin Increasing use in adults Increasing use in adults Pregnant females Pregnant females

17. Buprenorphine is a partial mu receptor agonist

18. Potential Advantage in NAS Safety Safety Ceiling effect on respiratory depression Ceiling effect on respiratory depression Fatalities in adults primarily seen with concomitant benzodiazapine abuse Fatalities in adults primarily seen with concomitant benzodiazapine abuse Less abuse potential Less abuse potential Long half life Long half life Improved control of abstinence? Improved control of abstinence? Ability to wean out of the hospital? Ability to wean out of the hospital?

19. Challenges to use in Neonates No pediatric indication No pediatric indication One study in preterm critically ill infants using IV formulation One study in preterm critically ill infants using IV formulation Case reports of maternal use of buprenorphine Case reports of maternal use of buprenorphine No good PK data No good PK data Sublingual administration Sublingual administration Metabolic ontogeny Metabolic ontogeny Unknown potency of norbuprenorphine Unknown potency of norbuprenorphine

21. 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

23. Buprenorphine Protocol 4.4  gm/kg q8 buprenorphine sublingual (Buprenex in 30% alcohol/sucrose) 4.4  gm/kg q8 buprenorphine sublingual (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 hours Weaning by 10%/dose after stable 48 hours Cessation at or near initial dose Cessation at or near initial dose Provision for rescue dose followed by up-titration Provision for rescue dose followed by up-titration At maximum 39  gm/kg/day, rescue with phenobarbital At maximum 39  gm/kg/day, rescue with phenobarbital Observation for 48 hr after cessation of therapy Observation for 48 hr after cessation of therapy

24. Buprenorphine NOS Need for Phenobarbital Rescue 3 1

25. Dose adjustment Observation Observation Lower than expected bup concentration Lower than expected bup concentration Rapid up-titration Rapid up-titration Relatively frequent need for phenobarbital rescue Relatively frequent need for phenobarbital rescue Adjusted dose Adjusted dose 1) Increase initial daily dose from 13.2 mcg/kg to 15.9 mcg/kg 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 2) Increase the up-titration from 20% increase to 25% increase 3) Increase maximum daily dose from 39 mcg/kg to 60 mcg/kg 3) Increase maximum daily dose from 39 mcg/kg to 60 mcg/kg

26. Update 24 patients randomized to new dose schema

27. Length of Treatment: All treated patients in trial (N=50)

28. Safety: Serious Events Status epilepticus, treated with lorazepam and phenobarbital Status epilepticus, treated with lorazepam and phenobarbital Full-term female, scores of 4-6 after 3 days of treatment Full-term female, scores of 4-6 after 3 days of treatment Neurological work up negative Neurological work up negative Level = 0.35 ng/mL Normal development at 12 months of age Level = 0.35 ng/mL Normal development at 12 months of age Elevated liver enzymes associated with cytomegalovirus infection Elevated liver enzymes associated with cytomegalovirus infection Poor feeding, aminoaciduria Poor feeding, aminoaciduria Abnormalities persisted weeks after dechallenge Abnormalities persisted weeks after dechallenge

29. BuprenorphineSummary Appears as safe as, and more efficacious than morphine Appears as safe as, and more efficacious than morphine Efficacy needs to be tested in blinded clinical trial Efficacy needs to be tested in blinded clinical trial Use may facilitate expansion into outpatient treatment Use may facilitate expansion into outpatient treatment

30. Polysubstance abuse Thomas Jefferson University Hospital 2000-06 Seligman NS,. Am J Obstet Gynecol. 2008; 199(4):396.e1-396.e7

31. Polysubstance abuse Common Common Up to 50% of babies at risk for NAS have exposure to benzodiazepines Up to 50% of babies at risk for NAS have exposure to benzodiazepines Worse outcomes Worse outcomes Cause or marker of treatment resistance? Cause or marker of treatment resistance? Even less clarity of optimal treatment Even less clarity of optimal treatment

32. Effects of concomitant psychiatric medications 10.3% of drug-using pregnant women had other psychiatric disorders compared to 1.4% of controls 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. 56% of participants in MOTHER study had prescription for psychiatric medication during pregnancy 56% of participants in MOTHER study had prescription for psychiatric medication during pregnancy Mostly anxiolytics and SSRIs Mostly anxiolytics and SSRIs Benzodiazepines were exclusion criteria Benzodiazepines were exclusion criteria Martin PR. Am J Addict. 2009 ; 18(2): 148–156 Martin PR. Am J Addict. 2009 ; 18(2): 148–156

33. Neonatal responses to in utero exposure Antidepressant Antidepressant Mild CNS and respiratory systems Mild CNS and respiratory systems 3-5 day duration, self limited 3-5 day duration, self limited Koren G. CMAJ. 2005; 172(11):1457-1459 Ferreira E. Pediatrics. 2007; 119(1):52 Antipsychotics Antipsychotics Adults have mild withdrawal symptoms of agitation and insomnia Adults have mild withdrawal symptoms of agitation and insomnia Anecdotal reports of hypertonicity and early onset NAS Anecdotal reports of hypertonicity and early onset NAS Paucity of published reports of neonatal withdrawal 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.

34. Pharmacogenetics P glycoprotein P glycoprotein ABB1 haplotypes have been associated with decreased methadone requirements ABB1 haplotypes have been associated with decreased methadone requirements Coller JK. Cln Pharmacol Ther. 2006,80:682-90 Mu opioid receptor Mu opioid receptor Polymorphism A118G has reduced response to ligands and has been associated with differential pain response, but not methadone dosage 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 A118G may represent propensity for heroin abuse Weaker candidates Weaker candidates dopamine receptor type 1, preproenkephalin and preprodynorphin dopamine receptor type 1, preproenkephalin and preprodynorphin Drakenberg K,. Proc Natl Acad Sci U S A. 2006; 103(20):7883-7888 Somogyi AA, Clin Pharmacol Ther. 2007;81(3):429 Skorpen F, Palliat Med. 2008; 22(4):310-327

35. Will a genetic test tell us who we can send home early? Not any time soon! Association of genes with addiction in adults not established Association of genes with addiction in adults not established Relevance of adult polymorphisms to neonates unclear Relevance of adult polymorphisms to neonates unclear Responses are polygenic and not monogenic Responses are polygenic and not monogenic Example of sickle cell anemia Example of sickle cell anemia

36. PK/PD modeling Powerful mathematical techniques to evaluate data Powerful mathematical techniques to evaluate data Drug levels with sparse sampling Drug levels with sparse sampling NAS scores NAS scores Age, weight, development Age, weight, development Assess sources of variability Assess sources of variability Understand the biology of development Understand the biology of development Predict best dose Predict best dose

37. PK/PD model of buprenorphine in neonates

38. PK/PD models in NAS Clonidine Clonidine Xie HG. J Clin Pharmacol. 2010 May 19. [Epub ahead of print] Buprenorphine Buprenorphine Morphine Morphine IV models available IV models available NO ORAL DATA! NO ORAL DATA!

39. Long term developmental effects of NAS treatment Very difficult data to obtain Very difficult data to obtain NAS treatment vs. NAS NAS treatment vs. NAS Post discharge effects likely dwarf treatment Post discharge effects likely dwarf treatment Even if there were developmental effects, how would these risks compare to non-treatment of NAS? Even if there were developmental effects, how would these risks compare to non-treatment of NAS?

40. Actively Recruiting Clinical Trials Maternal acupuncture Maternal acupuncture P. Janssen, Univ. British Columbia P. Janssen, Univ. British Columbia LOT primary outcome LOT primary outcome RCT RCT Fetal neurobehavior and autonomic tone Fetal neurobehavior and autonomic tone L. Jansson, Johns Hopkins L. Jansson, Johns Hopkins Two observational cohorts Two observational cohorts

41. Summary of Future Trends Increased research in clonidine and buprenorphine Increased research in clonidine and buprenorphine Pharmacogenetics Pharmacogenetics Polysubstance abuse treatment Polysubstance abuse treatment Dose optimization Dose optimization Clear need for more research Clear need for more research

42. Black Walnut, Blenerhasset Island, WV