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Hendrée E. Jones, PhD Senior Research Psychologist, RTI International

Bethesda, MD November 1 , 2012 Association for Medical Education and Research in Substance Abuse Betty Ford Award Plenary Address

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Hendrée E. Jones, PhD Senior Research Psychologist, RTI International

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  1. Bethesda, MD November 1, 2012 Association for Medical Education and Research in Substance Abuse Betty Ford Award Plenary Address Treating Opioid-dependent Women during Pregnancy: How Research Findings Can Inform Clinical Practice Hendrée E. Jones, PhD Senior Research Psychologist, RTI International Adjunct Professor, Department of Psychiatry and Behavioral Sciences and Department of Obstetrics and Gynecology Johns Hopkins University School of Medicine

  2. Disclosures • Discussing 2 medications, methadone and buprenorphine. Neither medication is approved for use in pregnant women. Both medications are currently labeled by the US Food and Drug Administration (FDA) as Category C for use in pregnancy for the treatment of maternal opioid dependence: “Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.” • Reckitt-Benckiser Pharmaceuticals Inc. for active and placebo Subutex tablets and time and travel reimbursement

  3. Acknowledgements • Study patients and infants • Staff at the Center for Addiction and Pregnancy, Behavioral Pharmacology Research Pharmacy and Nursing staff • Johns Hopkins University Co-Investigators: • Drs. Donald Jasinski, Lauren Jansson, Robert Dudas, Lorraine Milio, Martha Velez, Vickie Walters, Eric Strain, George Bigelow • National Institute on Drug Abuse • R01 DAs: 015764, 015738, 017513, 015778, 018410, 018417, 015741, 15832 • Maternal Opioid Treatment: Human Experimental Research (MOTHER) Site PIs and investigative teams • Reckitt-Benckiser Pharmaceuticals Inc. for active and placebo Subutex tablets

  4. Outline • Historical and current context of opioid use and opioid agonist treatment during pregnancy • Comparison of methadone v. buprenorphine: maternal and neonatal outcomes • Primary and secondary outcome findings • Latest key secondary analysis study results • Impact of behavioral intervention for smoking cessation • Clinical implications and unanswered questions

  5. Historical Context • Concern over pregnant women using substances in the United States has been an important health issue in the United States for more than a century: • In the 1800s, 66–75% of individuals with opium use disorders were women • The most common substance source of opium for women was medical prescriptions to treat pain • During the late 1800s physicians recognized the neonatal opioid withdrawal syndrome, and the need to treat the newborns of mothers who had taken opium during pregnancy with morphine in order to prevent morbidity and mortality Kandall, Substance and shadow, 1996. Earle, Medical Standards, 1888.

  6. Historical Context • By the 1900s physicians becoming better educated about the drawbacks of prescribing narcotics, and legitimate supplies of narcotics then shrank • Women unable to stop using substances were forced to seek them from illegitimate sources • Passage of the Harrison Narcotic Act of 1914 greatly changed narcotic prescribing and dispensing practices, requiring that addictive substances needed to be prescribed by a licensed health professional • Some enlightened physicians treated opioid addiction with morphine • In 1919, this practice was prohibited by the Supreme Court • Result: Segregation of the treatment of substance use disorders from general medical practice Kandall, Substance and shadow, 1996.

  7. Historical Context: Methadone Schedule II opioid Synthetically derived μ opioid receptor agonist Antagonist at NMDA receptors Half-life estimated to fall in the range of 24-36 hours

  8. Historical Context: Methadone • In the 1960s, Dole and Nyswander found that heroin-dependent patients could be safely maintained on methadone • Effective dosing leads to tolerance and a reduction or elimination of craving for heroin Developed and first used as an analgesic in Germany prior to World War II First utilized in the United States in the 1940s for medication-assisted withdrawal for heroin addicted individuals, using decreasing doses over a 7-10 day period Follow-up research found relapse rates exceeding 90%

  9. Historical Context Treated baby Neonatal abstinence syndrome (NAS) • Neurologic excitabilityhyperactivity, irritability, sleep disturbance • Gastrointestinal dysfunctionuncoordinated sucking, swallowing, vomiting • Autonomic signsfever, sweating, nasal stuffiness Finnegan and Kaltenbach. Neonatal abstinence syndrome. In: R.A. Hoekelman, S.B. Friedman, N.M. Nelson and H.M. Seidel, Editors, Primary Pediatric Care (2nd ed.), Mosby Year Book, St. Louis, MO 1992):1367–1378.

  10. Historical Context 40 years of documented benefits of methadone during pregnancy • Prevention of erratic maternal opioid levels lessens fetal exposure to repeated withdrawal episodes • Reduces fetal exposure to illicit drugs • Decreases risks to fetus of infection from HIV, hepatitis and sexually transmitted infections • Reduces the incidence of obstetrical and fetal complications • Improves newborn outcomes Review by Kaltenbach et al., Obstet Gynecol Clin North Am 1998.

  11. Historical Context Methadone (mg) • In the 1970s, a positive relationship between maternal methadone dose and NAS severity was reported • Thus, early recommendations were to maintain pregnant women on methadone doses between 20 to 40 mg per day • Subsequently, 3 decades of research have shown an inconsistent relationship between maternal methadone dose and NAS severity • Only in the last 10 years have pregnant women been appropriately medicated using the same principles as those used for non-pregnant patients Review by Cleary et al., Addiction. 2010.

  12. Historical Context • Methadone Dosing • during Pregnancy • Often methadone dose needs adjustment upwards as gestational age increases • Greater plasma volume • Increased renal blood flow • Induction of CYP3A • Possible contribution of CYP3A7 from fetus 40 50 60 65 70 80 Methadone (mg) 12 Pond et al., 1985; Swift et al., 1989; Jarvis et al., 1999; Wolff et al., 2004

  13. Historical Context Fetal Physiologic Effects of Maternal Methadone Administration • Trough Peak • mean mean • Heart Rate 136.5 128.3* • HR Variability 5.9 3.7* • # Accelerations 3.6 0.5* • Movement Bouts 66.8 63.6 • Movement Duration 26.9 13.7* • Motor Activity Total 1627.8 880.1* * p < .05 Jansson et al., 2005 13

  14. Historical Context Days Retained in CAP Treatment Methadone Tapering v. Maintenance • Guidance regarding tapering v. maintenance was based largely on sound clinical judgment • Methadone maintenance facilitates retention of patients and reduces drug use • Biggest concern with methadone during pregnancy is the potential for occurrence of a neonatal abstinence syndrome % Mothers with Positive Urine Drug Screen at Delivery MM = Methadone Maintenance Jones et al., 2008. 14

  15. Historical Context:Summary • For over 4 decades methadone has been the recommended standard of care for treating opioid-dependent pregnant patients • Methadone maintenance is superior to tapering for pregnant patients • Maternal methadone dosing may need to be increased as gestational age advances • Fetal heart rate and variability as well as fetal movements are reduced following single daily dosing of methadone • NAS is an expected yet treatable complication in methadone-exposed infants 15

  16. Current Context • The two most common drugs used by non-pregnant women have been alcohol and tobacco • This same statement is true for pregnant women • Among pregnant women in the United States, approximately 16.3% smoke cigarettes, 10.8% drink alcohol, and 4.4% used illicit drugs in the past month National Survey on Drug Use and Health 2008/9Past Month Use  SAMHSA Office of Applied Statistics, 2009-2010; Patrick et al., JAMA, 2012.

  17. Current Context • A retrospective, serial, cross-sectional analysis of a nationally representative sample of newborns with NAS. • Clinical conditions were identified using ICD-9-CM diagnosis codes. • NAS and maternal opiate use were described as an annual frequency per 1000 hospital births. 2000 2003 2006 2009 in the United States—one infant every hour—suffers from neonatal abstinence syndrome (NAS) Low Respiratory Medicaid Birthweight Diagnoses Coverage 2000 2003 2006 2009

  18. Current Context Policy and Opinion Setting Bodies have given attention to this issue Neonatal Drug Withdrawal. Mark L. Hudak, Rosemarie C. Tan, THE COMMITTEE ON DRUGS and THE COMMITTEE ON FETUS AND NEWBORN. Pediatrics; originally published online January 30, 2012. ACOG Committee Opinion No. 524: Opioid abuse, dependence, and addiction in pregnancy. ACOG Committee on Health Care for Underserved Women; American Society of Addiction Medicine. Obstet Gynecol. 2012 May;119(5):1070-6.

  19. MEDIA AND POLITICAL ATTENTION July, 2012. New York Senator Charles Schumer called on the FDA to provide clear labels so women and health care professionals know the potential dangers of the medication they are taking. He said that SAMHSA must educate physicians to better identify symptoms of prescription drug abuse, and NIH and CDC need to conduct more research that will help mothers avoid addiction. Current Context

  20. Current Context • Why are more individuals, including pregnant women, using opioids? • There has been an increase in the access to these medications • Pain became the 5th vital sign in the early 21st century • Federal prosecutors allege in documents filed in U.S. District Court that Chris and Jeff George from Florida dramatically increased the numbers of pain clinics in Florida and routed opioid pain medications to Kentucky, Ohio and South Carolina.

  21. Current Context Issues facing pregnant drug users and their children • Multiple drug exposures • Limited parenting skills and resources • History of child abuse and neglect • Multiple psychiatric issues • Unstable housing • Lack of positive and supportive relationships • Food insecurity and lack of nutrition • Exposure to violence and trauma • Generational drug use • Lack of formal education • Lack of job acquisition and maintenance skills • Gender inequality/male-focused society • Legal involvement These factors with or without drug use can influence mother and child outcomes

  22. Current Context Factors Influencing Mother and Child Outcomes • Exposure to violence/trauma • Multiple drug exposures (e.g., alcohol and tobacco) • Poor maternal/child attachment • Child abuse • Psychiatric status of caregiver • Stable caregiver and environment • Nutrition 22 22

  23. Current Context Comprehensive Care • Interdisciplinary approach • Psychiatry • Psychology • Obstetrics • Pediatrics • Nursing • Social Work • Multiple modalities • Medically-assisted withdrawal and aftercare • Methadone with behavioral treatment 23

  24. Summary • While occurring less frequently than alcohol and tobacco use, opioid misuse during pregnancy is nonetheless a serious and growing public health problem • This increase in use of opioids by pregnant women appears to be fueling an increase in the incidence of neonatal opioid withdrawal • Opioid use by pregnant women is often complicated by polydrug use, and often occurs intertwined with complex personal, interpersonal, family, social, and environmental factors that can contribute to adverse consequences • Multi-faceted interventions are needed to help prevent and treat opioid-dependence among women during pregnancy and their infants 24

  25. Buprenorphine • A derivative of the opioid alkaloid thebaine • Schedule III opioid • μ opioid receptor partial agonist • primarily antagonistic actions on κ opioid and δopioid receptors • Half-life estimated to fall in the range of 24-60 hours Reviews in Jones et al., Drugs, 2012, and Addiction, 107 (Suppl. 1), 5–27.

  26. Buprenorphine: Formulations • Buprenorphine mono product (e.g., Subutex) • Buprenorphine + naloxone (e.g., Suboxone) • 4:1 ratio to prevent misuse by injection • 2 mg and 8 mg sublingual tablets • 2 mg/0.5 mg and 8 mg/2 mg sublingual film strips Reviews in Jones et al., Drugs, 2012, and Addiction, 107 (Suppl. 1), 5–27.

  27. Buprenorphine and Pregnancy • Since 1995, over 40 published reports of prenatal exposure to buprenorphine maintenance • Approximately 750 babies prenatally exposed to buprenorphine (number of cases per report ranged from 1 to 159; Median=14) • Dose range 0.4 to32 mg • 88% reported concomitant drug use Reviews in Jones et al., Drugs, 2012, and Addiction, 107 (Suppl. 1), 5–27.

  28. Buprenorphine: Maternal Outcomes Research with buprenorphine not as extensive as with methadone Well-tolerated and generally safe In contrast to the research with methadone, little research has compared buprenorphine to a non-treated control group Rather, buprenorphine has been compared in both retrospective and prospective studies to methadone Majority of research would suggest that maternal outcomes are not in any way different than for methadone Reviews in Jones et al., Drugs, 2012, and Addiction, 107 (Suppl. 1), 5–27.

  29. p = .021 PROMISE Study * P=.021. • Methadone (n=11) • Buprenorphine (n=10, 1 twin set) • PROMISE study combined with double-blind RCT in Vienna (Fischer et al., 2006) provided preliminary data • The advancement of treatment research for opioid-dependent pregnant women may be best served through a multisite international network able to conduct randomized controlled trials Jones et al., Drug Alcohol Depend, 2005. 29

  30. Location of MOTHER Study Sites Lead Site Johns Hopkins U PI: H Jones Brown U PI: B Lester Thomas Jefferson U PI: K Kaltenbach U Vermont PI: S Heil U Vienna PI: G Fischer U Toronto PI: P Selby Vanderbilt U PI: P Martin Wayne State U PI: S Stine Coordinating Center PI: A Arria * * * * * * * *

  31. MOTHER Study: Participants Eligibility • 18 to 40 years of age • Gestational age 6 to 30 weeks • Opioid-dependent (DSM-IV, SCID I) • Opioid-positive urine • Single-fetus pregnancy • Plan to deliver at site hospital • No medical or other conditions contraindicating participation • No pending legal action potentially preventing participation • Without benzodiazepine or alcohol disorders Jones et al., N Engl J Med, 2010.

  32. MOTHER Study:Design MOTHER Experimental Design Cocaine + Cocaine - • Randomized clinical trial • 8 sites • Double-blind • Double-dummy • Stratified • Parallel group • Flexible dosing: • 20 to 140 mg methadone • 2 to 32 mg buprenorphine Buprenorphine Early EGA Initial consent Screening Medical clearance Late EGA Methadone Early EGA Late EGA • Pre-delivery • Induction • Daily dosing • Weekly assessments 28 days Post-delivery Jones et al., N Engl J Med, 2010.

  33. MOTHER Study:Screening Screened (N=1,074) at 8 sites Refused participation (n=243) Excluded (n=656) • 27% outside EGA range (n=149) • 22% benzodiazepine use (n=124) • 19% medical reason (n=105) • 10% alcohol use (n=57) Failed to meet inclusion criteria (n=557) Randomized (n=175) at 7 sites Jones et al., N Engl J Med, 2010.

  34. MOTHER Study:Randomization Randomized (n=175) at 7 sites Buprenorphine (n=86) Methadone (n=89) Completed (n=73) Completed (n=58) Dissatisfied with medication Premature discontinuance (n=28) Premature discontinuance (n=16) 20 2 Jones et al., N Engl J Med, 2010.

  35. MOTHER Study:Baseline Comparisons • Randomized participants compared by study conditionhad no statistically significant differences in baseline characteristics • Completers compared by study condition had similar results Notes: Site was a blocking factor in all analyses; Bonferroni’s principle was used to set family wise α = .0045. Jones et al., N Engl J Med, 2010.

  36. MOTHER Study: Primary Outcomes p = .00000012 • Buprenorphine p = .00012 • Methadone Notes: Significant results are encircled. Site was a blocking factor in all analyses. The O’Brien-Fleming α spending function resulted in α = .0091 for the inferential tests of the Medication Condition effect for the 5 primary outcome measures at the conclusion of the trial. • Compared with methadone-exposed neonates, buprenorphine-exposed neonates • Required 89% less morphine to treat NAS • Spent 43% less time in the hospital • Spent 58% less time in the hospital being medicated for NAS • Both medications in the context of comprehensive care produced similar maternal treatment and delivery outcomes 36 Jones et al., N Engl J Med. 2010.

  37. MOTHER Study: Secondary Outcomes • Methadone • Buprenorphine Note: Bonferroni’s principle was used to set familywise α = .003125 (nominal α = .05/16) for the secondary outcome measures. • Clinically meaningful attrition rate in buprenorphine condition • Low rates of illicit drug use during pregnancy and at delivery • Maternal outcomes similar in the 2 study conditions Jones et al., N Engl J Med, 2010. 37

  38. MOTHER Study: Secondary Analysis Studies One of the goals of the MOTHER Study was to collect comprehensive data on maternal, fetal, and neonatal behavior that could be shared with the broader research community This broad availability of the MOTHER data has allowed MOTHER Principal Investigators and other researchers to ask a variety of questions about maternal, fetal, and neonatal issues related to maternal buprenorphine and/or methadone treatment. An Addiction Supplement issue will be published shortly reporting on these studies. The following slides present findings from a number of these secondary outcome studies, including: • The extent to which 32-week fetal movement and cardiac measures differ between methadone and buprenorphine before and after dosing • Differences between buprenorphine- and methadone-maintained pregnant women in obstetrical and neonatal complications • Liver enzymes and their relationship to buprenorphine and methadone treatment, as well as HCV status • Differences in NAS signs between medications • Predicting treatment for neonatal abstinence syndrome • Neonatal neurobehavioral effects following buprenorphine v. methadone exposure MOTHER User’s Guide and Databases can be found at: http://www.jefferson.edu/jmc/pediatrics/mother/

  39. MOTHER Study: Secondary Analysis Studies • Compared withmethadone-exposed fetuses, buprenorphine-exposed fetuses have better indications of fetal well-being, including: • greater FHR variability • more accelerations • better FM-FHR coupling early in the second half of gestation • In contrast, FM was most consistently suppressed in methadone-exposed fetuses at the later gestational age period *p < .05 Jansson et al.,Neurotoxicol Teratol. 2011.

  40. MOTHER Study: Secondary Analysis Studies • Fetuses exposed to buprenorphine were more likely to have a reactive non-stress test with more fetal heart rate (FHR) accelerations than fetuses exposed to methadone treatment • Medications did not differ on these measures immediately prior to dosing • Buprenorphine dosing has less of a suppressive effect than does methadone on mean FHR, FHR variability, and the ability of the autonomic system to respond to integrate response to movement p < .01 p = .095 Salisbury et al., Addiction, 107 (Suppl. 1), 36–44

  41. MOTHER Study: Secondary Analysis Studies Obstetrical and Neonatal Complications • Several studies have compared obstetrical outcomes for opioid-dependent pregnant women in maintenance treatment with buprenorphine or methadone • Results have suggested that obstetrical outcomes are comparable between the two medications • However, only two of these studies were randomized controlled trials, both with small sample sizes • This study compared obstetrical and neonatal measures between buprenorphine and methadone for outcomes that were not presented in the MOTHER primary outcomes paper Holbrook et al., Addiction, 107 (Suppl. 1), 83–90.

  42. MOTHER Study: Secondary Analysis Studies • There were few obstetrical and neonatal complications in the total sample, as well as in both the buprenorphine and methadone conditions Holbrook et al., Addiction, 107 (Suppl. 1), 83–90.

  43. MOTHER Study: Secondary Analysis Studies • Maternal methadone versus buprenorphine maintenance treatment was associated with: • a higher incidence of preterm labor • a higher percentage of respiratory distress signs in neonates p < .05 • Methadone • Buprenorphine p < .05 Holbrook et al., Addiction, 107 (Suppl. 1), 83–90.

  44. MOTHER Study: Secondary Analysis Studies Liver enzymes, buprenorphine, methadone, and HCV Status • Possible relationship between buprenorphine treatment and hepatic injury or dysfunction in opioid-dependent individuals • Liver enzymes do not show much variation from normal in healthy pregnant women • However, rates of HCV infection in pregnant opioid-dependent women have been reported as high as 93% • Thus, the extent to which agonist medication, HCV exposure, or both have an effect on liver enzymes in pregnant opioid-dependent women is unknown • Liver enzymes assayed: • aspartate aminotransferase (AST) • alanine aminotranferase (ALT) • gamma-glutamyl transferase (GGT) McNicholas et al., Addiction, 107 (Suppl. 1), 91–97.

  45. MOTHER Study: Secondary Analysis Studies • AST, ALT, and GGT decline during the course of pregnancy, and then return to baseline during the postpartum period • Participants with HCV had higher liver function levels at all time points • There was no effect of medication on ALT or GGT. However, methadone-maintained participants had higher GGT levels than did buprenorphine-maintained patients over the course of the study • HCV status did not moderate the effects of the medication in either group AST, ALT, and GGT Levels by Trimester AST ALT • Trimester • First • Second • Third • Postpartum GGT Liver function test results are in IU/L All ps < .05 McNicholas et al., Addiction, 107 (Suppl. 1), 91–97.

  46. 53% of the total sample required treatment for NAS Receipt of NAS treatment for infants was predicted by: infant birthweight greater maternal nicotine use Total medication dose needed to treat NAS was predicted by: Maternal use of SSRIs higher nicotine use fewer days of study medication received also predicted. No variables predicted length of treatment for NAS MOTHER Study: Secondary Analysis Studies Kaltenbach et al., Addiction, 107 (Suppl. 1), 45–52.

  47. MOTHER Study: Secondary Analysis Studies Incidence of NAS signs • Three signs were observed significantly more often in the buprenorphine than in the methadone condition: sneezing, loose stools, and nasal stuffiness • Two signs were observed significantly more often in the methadone than in the buprenorphine condition: undisturbed tremors and hyperactive Moro reflex • Methadone-exposed neonates had higher mean NAS total scores than buprenorphine-exposed neonates Gaalema et al., Addiction, 107 (Suppl. 1), 53–62.

  48. MOTHER Study: Secondary Analysis Studies • Methadone-exposed neonates had higher mean scores for: disturbed tremors, undisturbed tremors, hyperactive Moro reflex, excessive irritability and failure to thrive • Buprenorphine-exposed neonates had higher mean scores Gaalema et al., Addiction, 107 (Suppl. 1), 53–62. All ps ≤ 0.04

  49. There was a significant difference between medication conditions in mean time to initiation of morphine treatment for those neonates treated for NAS, with the methadone condition requiring morphine treatment earlier than the buprenorphine condition MOTHER Study: Secondary Analysis Studies p = .01 Methadone (n = 41) Buprenorphine (n = 27) Gaalema et al., Addiction, 107 (Suppl. 1), 53–62.

  50. Methadone: NASOther Factors Contributing to Severity • Structural • The NAS assessment and medication initiation and weaning protocols • Non-modifiable • Genetics • Other Substances • Benzodiazepines • SSRIs • Cigarette smoking Jansson and Velez,Curr. Opin Pediatrics, 2012

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