Comprehensive Treatment of the Opioid-dependent Pregnant Patient

American Osteopathic Academy of Addiction Medicine San Diego, CA October 8, 2012 Comprehensive Treatment of the Opioid-dependent Pregnant Patient 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 3 medications, methadone, buprenorphine, and naltrexone, that are not currently approved for use in pregnant women. All 3 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 Outline Contexts of Opioid Use during Pregnancy Pharmacotherapy for the opioiddependent pregnant patient: Methadone Buprenorphine Naltrexone The need to address psychosocial issues in the treatment of the opioid-dependent pregnant patient Physical, sexual, and emotional abuse HIV-risk behaviors Concomitant drug use Co-occurring psychological issues

4 Historical Context of Opioid Use during Pregnancy Substance use during pregnancy in the USA has been a long-standing important health issue. In the 1800s: 66 75% of individuals with opium use disorders were women Women s most common opium source was medical prescriptions to treat pain Physicians recognized neonatal opioid withdrawal and the need to treat in utero opium exposure with morphine in order to prevent morbidity and mortality Following the1914 Harrison Narcotic Act, the treatment of substance use disorders was segregated from mainstream medical practice Kandall, Substance and shadow, 1996. Earle, Medical Standards, 1888.

5 Historical Context of Opioid Use during Pregnancy During the 1980s the War on Drugs was at its height and the media proclaimed a crack baby epidemic News stories cast these children as damaged and unable to learn Equally stigmatizing, the mothers of these children were portrayed as selfish and unloving Crack baby" reports fueled the most punitive strategy towards substance-using pregnant women to date: Legal actions against illicit drug using pregnant women under a variety of state laws such as delivery of a controlled substance to a minor, manslaughter, child abuse and neglect Kandall, Substance and shadow, 1996. Paltrow, Criminal Justice Ethics, 1990.

6 Current Context of Opioid Use during Pregnancy Self Reported Use (%) 100 80 60 40 20 0 National Survey on Drug Use and Health 2009/2010 Past Month Use Any Illicit Drug Marijuana Cocaine Opioids Alcohol Tobacco Pregnant Not Pregnant 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 SAMHSA Office of Applied Statistics, 2009-2010.

7 Current Context of Opioid Use during Pregnancy Neonatal abstinence syndrome (NAS) Treated baby Neurologic excitability hyperactivity, irritability, sleep disturbance Gastrointestinal dysfunction uncoordinated sucking, swallowing, vomiting Autonomic signs fever, sweating, nasal stuffiness Finnegan and Kaltenbach. In: R.A. Hoekelman, S.B. Friedman, N.M. Nelson and H.M. Seidel, Editors, 1992.

8 Current Context in the United States one infant every hour suffers from neonatal abstinence syndrome (NAS) Weighted National Estimates of the Rates of Maternal Opiate Use per 1000 Hospital Births per Year 6 5.63 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. Rate of Maternal Opiate Use per 1000 Hospital Births 5 4 3 2 1 0 1.2 1.25 2.2 2000 2003 2006 2009 Low Birthweight, Respiratory Diagnoses, and Medicaid Coverage in 2009 Weighted National Estimates of the Rates of NAS per 1000 Hospital Births per Year Percentage 100 80 60 40 20 0 78.1 45.5 30.9 19.1 7 0.7 Low 1 Respiratory 2 Medicaid 3 Birthweight Diagnoses Coverage Rate of NAS per 1000 Hospital Births 4 3 2 1 0 1.2 1.5 1.8 3.4 2000 2003 2006 2009 NAS neonates non-nas neonates

9 Current Context of Opioid Use during Pregnancy 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.

10 Current Context of Opioid Use during Pregnancy 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.

11 Current Context of Opioid Use during Pregnancy Why are more individuals, including pregnant women, using opioids? There has been an increase in the access to these medications Pain became the 5 th vital sign in the early 21 st 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.

12 Current Context of Opioid Use during Pregnancy Issues facing drug-using pregnant women and their children Exposure to violence and trauma Generational drug use Lack of formal education Lack of job acquisition and maintenance skills Gender inequality/malefocused society Legal involvement 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 These factors with or without drug use can influence mother and child outcomes

13 Current Context of Opioid Use during Pregnancy 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 13 Stable caregiver and environment Nutrition 13

14 Context of Opioid Use during Pregnancy Successful Treatment of Opioid Dependence in Pregnant Women Requires a Comprehensive Care Model Interdisciplinary approach Psychiatry Psychology Obstetrics Pediatrics Nursing Social Work Focus on determining the factors that maintain the continuing use of opioids 14

15 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 15

16 Pharmacotherapy for Opioid Dependence Prevention of erratic maternal opioid levels lessens fetal exposure to repeated withdrawal episodes Reduces fetal exposure to illicit drugs With drug abstinence, other behavior changes can follow which decrease risks to mother fetus of infection from HIV, hepatitis and sexually transmitted infections Reduces the incidence of obstetrical and fetal complications and improves outcomes Review in Kaltenbach et al., Obstet Gynecol Clin North Am, 1998.

17 Methadone Schedule II opioid Synthetically derived μopioid receptor agonist also uniquely a δopioid receptor agonist Antagonist at NMDA receptors Half-life estimated to fall in the range of 24-36 hours

18 Methadone 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% 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

19 Methadone: Induction and Dosing Patients typically begun on methadone when they are in mild withdrawal Patients are typically given a small test dose and observed for possible adverse effects Assuming no adverse effects, dose is titrated until it prevents withdrawal, cravings, and possible continued use of illicit opioids Optimal dose varies greatly between patients Blood concentrations of patients on an equivalent dose, adjusted for body weight, have been estimated to vary between 17- and 41-fold Dosing does not have to be more complicated for pregnant patients

20 Methadone v. Tapering Days Retained in Treatment 140 120 100 80 60 40 20 0 100 3 meth taper (n=67) 80 60 40 20 14 53 104 33 30 57 95 15 122 Urine-positive Drug Screen Percentage at Delivery 23 3 meth taper+mm (n=8) 7 meth taper (n=28) 7 meth taper+mm (n=20) MM (n=52) MM = Methadone Maintenance Guidance regarding tapering v. maintenance was based largely on good clinical judgment Methadone taper followed by drug-free treatment is frequently unsuccessful Methadone maintenance facilitates retention of patients and reduces drug use Biggest concern with methadone during pregnancy is the potential for occurrence of neonatal abstinence syndrome (NAS) 0 Jones et al., Am J Addict, 2008. 20

21 Methadone: Dosing during Pregnancy In the 1970s, a positive relationship between maternal methadone dose and NAS severity was reported Recommendations to maintain pregnant women on methadone doses between 20 to 40 mg 3 decades of research shows an inconsistent relationship between maternal methadone dose and NAS severity The latest systematic review and meta-analysis concluded that the Severity of the neonatal abstinence syndrome does not appear to differ according to whether mothers are on high- or low-dose methadone maintenance therapy. Review in Cleary et al., Addiction, 2010.

22 Methadone: Dosing during Pregnancy Often methadone dose needs adjustment upwards Greater plasma volume Increased renal blood flow Induction of CYP3A Possible contribution of CYP3A7 from fetus Pond et al., 1985; Swift et al., 1989; Jarvis et al., 1999; Wolff et al., 2004. 22

23 Methadone: Fetal Outcomes Trough mean Peak 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., Am J Obstet Gynecol, 2005. 23

24 Methadone: Fetal Outcomes Split dosing (N=40) Single Dosing Split Dosing Trough Peak Trough Peak mean mean mean mean Heart Rate (bpm) 138.3 130.4 139.5 133.4 HR Variability 5.9 4.1 6.2 4.6 # Accelerations 3.6 1.1 4.1 1.3 Motor Activity 5.7 4.6 6.1 5.6 Fetal heart rate, fetal heart rate variability, the number of fetal heart rate accelerations declined from trough to peak for both forms of dosing. Significant changes between peak and trough were observed in both the split and single dosing conditions. each fetal neurobehaviour value was significantly higher at peak during the split condition as compared with peak levels during single dosing Jansson et al., Am J Obstet Gynecol, 2009. 24

25 Methadone: NAS Methadone-associated NAS NAS signs 55-90% Requiring medication NAS appears NAS peaks ~ 60% 45 to 72 hrs 40 to 120 hrs Most common medication for treatment is morphine 25 Most common assessment tool is a modified Finnegan scale No current standard uniform protocol for treatment 25

26 Methadone: NAS Other 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

27 Smoking and Neonatal Abstinence Syndrome (NAS) Mean Time to Peak NAS Score Mean Peak NAS Score 10 8 6 4 2 0 120 100 80 60 40 20 0 4.8 Light Smoking (< 10/day) Peak NAS Score p <.05 9.8 Light Smoking Heaving Smoking (< 10/day) (> 20/day) n = 16 n = 13 Heavy Smoking (> 20/day) Time to Peak NAS Score 37.8 Light Smoking (< 10/day) p <.05 113 Light Smoking Heaving Smoking (< 10/day) (> 20/day) n = 16 n = 13 Heavy Smoking (> 20/day) Heavier cigarette smoking has been found to be related to: peak NAS score and time to peak NAS score in neonates of 29 methadone-maintained women lower neonatal birth weight, smaller birth length, and greater NAS severity in neonates of 139 opioidmaintained pregnant women NAS symptoms and duration of hospitalization in 65 neonates of methadone-maintained women NAS symptoms and unrelated to any NAS treatment in 64 neonates of methadone-maintained women duration of NAS treatment in 26 neonates of methadonemaintained pregnant women but not in 12 neonates of buprenorphine-maintained pregnant women 27 Choo et al., Drug Alcohol Depend. 2004;75(3):253-60. Winklbaur et al., Eur Addict Res 2009;15(3):153-6. Bakstad et al., Eur Addict Res 2009;15(3):128-134. Miles et al., J Reprod Med 2006;51(7):567-572. Jansson et al., Drug Alcohol Depend. 2010;109(1-3):198-204.

28 MOTHER Study: Cigarette Smoking RESULTS Average number of cigarettes smoked in the past 30 days was significantly positively related to: Mean Amount of Morphine (mg) 6 5 4 3 2 1 0 1.5 Non- Smoking Total Amount of Morphine Needed to Treat NAS 2 Below Average Smoking 3.2 Average Smoking 5 Aboveaverage Smoking Total amount of morphine needed to treat NAS Number of days neonate was medicated for NAS Mean Number of Days 10 8 6 4 2 0 3.7 Non- Smoking Number of Days Medicated for NAS 4.6 Below Average Neonatal Length Smoking of Hospital Stay 6.3 Average Smoking 8.4 Aboveaverage Smoking Neonatal length of hospital stay Mean Number of Days 18 15 12 9 6 8.9 10.5 13 16.2 3 0 Non-Smoking Below Average Smoking Average Smoking Above-average Smoking OLS and Poisson regression analyses were used to test average number of cigarettes smoked in the past 30 days at α=.05, adjusting for both Medication Condition and Site. Below-average cigarette smoking was defined as 6 cigarettes/day (-1 SD), average cigarette smoking as 14 cigarettes/day (Mean), and above-average cigarette smoking as 21 cigarettes/day (+1 SD). Jones et al., under review

29 MOTHER Study: Cigarette Smoking RESULTS Average number of cigarettes smoked in the past 30 days was significantly negatively related to: Mean Birth Weight (gm) 3200 3100 3000 2900 2800 3149 Non- Smoking Neonatal Weight at Birth 3075 Below Average Smoking 2978 Average Smoking 2881 Aboveaverage Smoking Neonatal weight at birth Apgar score at 1 minute Apgar score at 5 minutes Maternal weight gain, study entry to delivery Mean Apgar Score 10 8 6 4 2 0 Apgar Score at 1 Minute 8.6 8.4 8 7.7 Non- Smoking Below Average Smoking Average Smoking Apgar Score at 5 Minutes Aboveaverage Smoking Mean Apgar Score 10 8 6 4 2 0 9.5 9.3 9 8.7 Non- Smoking Below Average Smoking Average Smoking Aboveaverage Smoking OLS and Poisson regression analyses were used to test average number of cigarettes smoked in the past 30 days at α=.05, adjusting for both Medication Condition and Site. Below-average cigarette smoking was defined as 6 cigarettes/day (-1 SD), average cigarette smoking as 14 cigarettes/day (Mean), and above-average cigarette smoking as 21 cigarettes/day (+1 SD). Jones et al., under review

30 MOTHER Study: Cigarette Smoking A Practical Viewpoint on the Results Relative to a pregnant woman in opioid agonist treatment who didn t smoke during her pregnancy, a pregnant woman in opioid agonist treatment who smokes a pack of cigarettes a day on average during her pregnancy would likely face: More than triple the total amount of morphine needed to treat her neonate s NAS More than double the number of days required to treat her neonate s NAS Almost double the length of hospital stay for her neonate A more than 8% decrease in her neonate s birth weight A decrease of almost 1 point in her neonate s Apgar scores at 1 minute A more than ½ point decrease in her neonate s Apgar scores at 5 minutes A more than 3 kg (more than 7 lbs) decrease in her own weight gain during pregnancy Jones et al., under review

31 Reducing Cigarette Smoking in Methadone Treated Pregnant Patients Providing monetary rewards for meeting smoking reduction targets over 12 weeks Took baseline and then measured CO 3 times a week. Rewards given for reducing by: 25% for 3 wks 50% for 3 wks 75% for 3 wks smoking abstinence for 3 wks % of participants meeting CO reduction from baseline Tuten et al., Addiction, 2012

32 Methadone: Pain Management Savage and Schofferman noted that patients who use opioids may have a syndrome of pain facilitation Their pain is worsened by their experience of their addiction, including: - subtle withdrawal signs and symptoms - intoxication - withdrawal-related sympathetic nervous system arousal - sleep disturbances - affective changes Patients who are dependent on opioids are known to be less tolerant of pain than formerly opioid-dependent individuals Long-term exposure to opioids produces both tolerance and hyperalgesia, reducing the analgesic effectiveness of opioids themselves Treatment 32 of post-partum acute pain likely best attempted with PCA and/or acetaminophen and/or NSAIDS in addition to methadone dosage Savage & Schofferman, In: N Miller & M Gold, Editors, 1995. 32

33 Methadone: Pain Management No randomized controlled trials have been published examining pain management for opioid-dependent pregnant women during labor and delivery and postpartum One study found that women stabilized on methadone experienced adequate pain control post-partum with the use of other full mu opioids in combination with acetaminophen and an NSAID Second study found that methadone maintained pregnant women had similar analgesic requirements and response during labor but required more opioid analgesic after cesarean delivery when compared to women not on methadone maintenance These results suggest that routine pain management protocols are effective in reducing pain in methadone maintained patients following either a vaginal or cesarean delivery Pregnant women in methadone maintenance treatment should not receive opioid 33 agonist/antagonist pain medications (such as pentazocine or butorphanol) for acute pain because these medications may cause an acute opioid withdrawal syndrome Jones et al., Am J Drug Al Abuse, 2009; Meyer et al., Obstet Gynecol, 2007. 33

34 Historical Context Breastfeeding in Methadone-Stabilized Mothers Methadone detected in breast milk in very low levels Methadone concentrations in breast milk are unrelated to maternal methadone dose The amount of methadone ingested by the infant is low (i.e., an average 0.2 mg/day by 30 days post-delivery) The amount of methadone ingested by the infant remains low even 6 months later Several studies show relationships between breastfeeding and reduced NAS severity and duration Hepatitis C is not a contraindication for breastfeeding Contraindications: HIV+, unstable recovery McQueen KA, et al., 2011; Jansson et al., 2007; Jansson et al., 2010.

35 Methadone: Child Development Research focusing on the effects of prenatal exposure to methadone has been inconsistent Although some research has shown that methadone-exposed school-age children to be less interactive, more aggressive, and showing poorer achievement than children not so exposed, other research has failed to show any differences in either cognitive or social development The issue is confounded by the fact that children exposed to methadone in utero may experience a nutritional, family, and parenting history quite different than children not so exposed. Farid et al., Curr Neuropharm, 2008. 35

36 Methadone: Summary 40 years of documented benefits of methadone during pregnancy Induction is relatively simple Adequate doses are needed to prevent withdrawal and other opioid use Indicators of fetal well-being are less compromised with spilt-dosing NAS is worse with heavier smoking Breastfeeding is compatible with methadone Review in Kaltenbach et al., Obstet Gynecol Clin North Am, 1998.

37 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 2-5 hours Reviews in Jones et al., Drugs, 2012, and Addiction, in press.

38 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, in press.

39 Buprenorphine: Induction and Dosing Patient must already be in withdrawal or buprenorphine may precipitate withdrawal Patients dependent on short-acting opioids (e.g. heroin, most prescription narcotics) will not take as long to enter withdrawal as patients dependent on long-acting opioids (e.g., methadone) Induction typically then takes places over a 3-day period, beginning with either 2 mg or 4 mg, with a maximum dose of: - 8 mg 12 mg on Day 1-12 mg 16 mg on Day 2-16 mg up to 32 mg on Day 3

40 Buprenorphine: Induction and Dosing The best induction protocol for opioid-dependent pregnant women is not known Meyer has developed an outpatient protocol: Similar to established protocols for non-pregnant patients Ask patient to abstain from opioid use 1-2 days prior Expect a CINA score in 10-12 range to initiate treatment Adjust dose every 1-3 days Titrate to symptom control as for non-pregnant patients Takes place in the context of considerable program staff support As with methadone, there is the need to increase dosage during the course of pregnancy

41 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 to 32 mg 88% reported concomitant drug use Reviews in Jones et al., Drugs, 2012, and Addiction, in press.

42 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, in press.

43 Buprenorphine: Fetal Outcomes As with methadone, there is very limited on the fetal effects of in utero exposure to buprenorphine All such studies are based on relatively small sample sizes No fetal data regarding any possible adverse effects of withdrawal following transfer from heroin or methadone Reviews in Jones et al., Drugs, 2012, and Addiction, in press.

44 MOTHER Study: Secondary Outcomes p <.01 EGA 32 week 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 p =.095 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 Salisbury et al., Addiction, accepted for publication, 2012

45 MOTHER Study: Secondary Outcomes Fetal Cardiac and Movement Parameters at 36 weeks (N=11) Primary Outcomes Methadone n=6 Mean (SD) Buprenorphine n=5 FHR, bpm 133.42 (7.89) 134.58 (7.12) -0.18 FHR variability 4.43 (0.78) 5.30 (2.16) -0.37 Accelerations 1.17 (1.17) 2.80 (3.83) 0.0 Motor activity 3.58 (1.18) 5.92 (2.95) -2.01* FM duration 8.74 (2.71) 21.53 (13.22) -2.01* FHR-FM coupling, % 27.42 (13.97) 18.88 (6.90) -1.10 Z *p <.05 Compared with methadoneexposed fetuses, buprenorphine-exposed fetuses have better indications of fetal wellbeing, 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 Jansson et al Neurotoxicol Teratol. 2011.

46 Buprenorphine: Neonatal Outcomes Most research has compared buprenorphine to methadone rather than to untreated or placebocontrolled groups, so neonatal outcomes must be seen against this background Conclusions regarding the prenatal exposure to buprenorphine are limited by statistical power and methodological challenges (e.g., varied dose ranges, lengths of exposure, treatment settings, etc.) Total number of neonates exposed in utero to buprenorphine on which reports are available in the literature are less than 1,000, restricting the ability to detect low-incidence birth anomalies and small effects NAS experienced by neonates exposed in utero to buprenorphine likely less severe than with in utero methadone exposure Reviews in Jones et al., Drugs, 2012, and Addiction, in press.

47 Buprenorphine: NAS Incidence rate for NAS is estimated to be 50% about the same as for methadone NAS onset approximately 48 hours Peaking within approximately 72-96 hours Exceptions to this onset history have been the few neonates with NAS onset of 8-10 days postnatal age - such a protracted withdrawal syndrome may to be due to withdrawal from concomitant drug exposure (e.g., benzodiazepines) rather than a direct effect of buprenorphine withdrawal Correlation between buprenorphine dose and NAS severity has been inconsistent Reviews in Jones et al., Drugs, 2012, and Addiction, in press.

48 Buprenorphine: Pain Management No randomized controlled trials have been published with a primary focus on examining pain management for opioid-dependent pregnant women during labor and delivery and postpartum Findings are similar to those for methadone The previously discussed studies found similar results for buprenorphine An additional retrospective study found buprenorphine-maintained women had increased pain during vaginal delivery and increased postpartum pain and opioid utilization following cesarean delivery, requiring 47% more opioid analgesic than control women Like methadone, tailored pain medication regimens for buprenorphine treated women are needed (e.g., pain medications + prescribed opioid agonist during labor, delivery and the immediate postpartum period) Reviews in Jones et al., Drugs, 2012, and Addiction, in press.

49 Buprenorphine and Breastfeeding Studies of Breastfeeding Buprenorphine is found in breast milk 2 hours post-maternal dosing Concentration of buprenorphine in breast milk is low Amount of buprenorphine or norbuprenorphine the infant receives via breast milk is only 1% Most recent guidelines: the amounts of buprenorphine in human milk are small and unlikely to have negative effects on the developing Infant The advantages of breast feeding prevail despite the risks of an infant opiate intoxication caused by methadone or buprenorphine. Atkinson et al., 1990; Marquet et al., 1997; Johnson, et al., 2001; Grimm et al., 2005; Lindemalm et al., 2009; Jansson et al., 2009; Müller et al., 2011.

50 Buprenorphine: Child Development Research on the neonatal consequences of prenatal exposure to buprenorphine is quite limited Not enough births have been followed for a sufficient period of time to collect convincing data regarding factors such as cognitive and social development Same issue of confounding parental and family factors in teasing apart developmental effect Reviews in Jones et al., Drugs, 2012, and Addiction, in press.

51 Buprenorphine v. Methadone 100 75 50 25 20 15 10 5 0 0 Treated for NAS [Yes] Days of infant hospital stay p =.00012 25 20 15 10 5 0 NAS peak score Methadone Buprenorphine Total amount of morphine for NAS (mg) 15 10 5 0 50 40 30 20 10 0 Head circumference (cm) p =.00000012 Compared with methadoneexposed 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 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. Jones et al., N Engl J Med. 2010. 51

52 Buprenorphine v. Methadone 100 75 50 25 0 Normal presentation [Yes] 100 75 50 25 0 Medication dose at delivery, mg 50 40 30 20 10 0 Premature discontinuance [Yes] Methadone 50 40 30 20 10 0 Cesarean section [Yes] 25 20 15 10 5 0 Maternal weight gain, kg 10 8 6 4 2 0 Drug screen at delivery [Positive] Buprenorphine Number of prenatal obstetrical visits 10 8 6 4 2 0 100 80 60 40 20 0 Medical complications at delivery [Yes] Amount of voucher money earned for drug-negative tests, US$ 2000 1500 1000 500 0 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 Note: Bonferroni s principle was used to set familywise α =.003125 (nominal α =.05/16) for the secondary outcome measures. Jones et al., N Engl J Med. 2010. 52

53 Buprenorphine v. Methadone Obstetrical and neonatal complications: Few obstetrical and neonatal complications for both the buprenorphine and methadone. Liver enzymes: No effect of either medication on ALT or GGT. However, methadone-maintained participants have shown higher GGT levels than buprenorphine-maintained patients over the course of pregnancy. Predicting NAS: Higher infant birth weight and greater maternal nicotine use at delivery predicted receipt of NAS treatment for infants. Maternal SSRIs use, higher nicotine use, and fewer days of study medication received also predicted total dose of medication required to treat NAS symptoms. Neonatal neurobehavioral effects: Relative to methadone, buprenorphine results in superior neurobehavioral scores up to one month. Reviews in Jones et al., Drugs, 2012, and Addiction, in press.

54 Outcomes with Buprenoprhine + Naloxone (N=10) Maternal f (%) M (SD) Maternal weight gain (kg) 7.8 (3.9) Cesarean section [yes] 1 (10%) Analgesia during delivery [yes] 6 (67%) Urine drug screening at delivery [positive] 0 (0%) Days of maternal hospital stay 4.1 (4.5) Began breastfeeding after delivery [yes] 3 (30%) Neonatal Gestational age at delivery (in weeks) 37.5 (3.5) Preterm (< 37 weeks) 2 (20%) Apgar score at 1 min / 5 min 8.0 (2.5) / 8.6 (1.3) Head circumference (cm) 32.8 (1.2) Birthweight (gm) 2816.1 (368.3) Infant length (cm) 46.3 (2.2) Treated for neonatal abstinence syndrome [yes] 4 (40%) Total amount of morphine for NAS (mg) 3.5 (2.6) Days treated for neonatal abstinence syndrome 6.9 (10.1) Days of infant hospital stay 10.1 (9.8) Debelak et al., Am J Addict, in press.

55 Naltrexone Naltrexone is a thebaine-derivative Schedule III opioid Pure antagonist at the μopioid receptor with no intrinsic agonist effects A single oral dose reaches peak plasma concentration in 1-2 hours with an apparent half life of about 14 hours Ability to effectively antagonize heroin use has been clearly established, but the exact level required is still in question 55

56 Naltrexone: Pregnant Patient Interest Are Pregnant Women Seeking Treatment for Opioid Dependence Willing to Take Naltrexone? Initial survey regarding the potential interest in naltrexone treatment by pregnant women enrolled in comprehensive treatment for substance use disorders, of whom 58 were in methadone maintenance treatment Acceptance of Naltrexone by 58 Pregnant Women Enrolled in Methadone Maintenance Treatment Mean Rating 4 3 2 1 0 3.6 3.4 3.3 3.1 3.1 3 Learning more about Naltrexone Oral Naltrexone No Neonatal Withdrawal Doesn't Feel Like on Methadone Injection Once a Month Stop Use, Feel Clearheaded Rating scale: 1 = not at all 2 = a little 3 = somewhat 4 = a lot or extremely 56

57 Naltrexone: Maternal Outcomes Data are quite limited in regard to exposure of opioiddependent pregnant women to naltrexone At present, there are no findings to suggest that the incidence of adverse events would be any different than for nonpregnant women Adverse event profile is modest, and quite similar to placebo Sustained released formulations do present issue with injection site reactions 57

58 Naltrexone: Fetal Outcomes Animal Research Continuous naltrexone exposure at doses up to 50 times human therapeutic doses throughout pregnancy have not altered pregnancy s course or adversely impacted maternal rat health measures Naltrexone, at up to 200 times the human therapeutic dose, has not increased congenital malformations in the offspring of treated pregnant rats or rabbits At similar does, naltrexone has not been shown to impair implantation or viability of early mouse embryos At doses far exceeding human therapeutic doses, oral naltrexone has shown early fetal loss in rats and rabbits Human Research The only known fetal findings are clinical impressions that naltrexone induction was undertaken without apparent fetal distress 58

59 Naltrexone: Neonatal Outcomes 25 published cases of prenatal exposure to implanted naltrexone All showed normal birth outcomes Outcomes for 17 neonates showed mean gestational ages (38 weeks for both groups) and mean birth weights (3037 v. 2888 gm) similar to a historical sample of 90 methadone-treated pregnant patients. Significantly fewer naltrexone- than methadone-exposed neonates were born before 37 weeks (6% v. 24%, respectively), or at less than 2500 g (12% v. 23%, respectively) naltrexone-exposed infants had higher mean 1-minute APGAR scores (9 v. 8, respectively) Review in Jones et al., Addiction, 2012. 59

60 Naltrexone: NAS As an opioid antagonist rather than an opioid agonist such as methadone and burprenrophine, naltrexone does not produce NAS 60

61 Naltrexone: Pain Management Naltrexone precludes use of opioids for pain relief Opioids are the most common analgesics used for pain control during labor and delivery The endogenous opioid system appears to modify the perception of pain Pre-clinical naltrexone administration can prevent pregnancy-induced hypoalgesia Human maternal exposure to naltrexone during pregnancy may decrease the pain threshold and require responsive and tailored pain management practices Pain management efforts might include using non-opioid medications such as high-dose non-steroidal anti-inflammatory medications and/or local anesthesia (e.g., nerve blocks, epidurals) Review in Jones et al., Addiction, 2012.

62 Naltrexone: Breastfeeding N=1 lactating woman who was 1½ months postpartum, taking 50 mg of oral naltrexone daily during pregnancy and lactation Breastmilk sampled several times between 3.7 and 23 hours after dosing Naltrexone milk levels were undetectable (<2 mcg/l) by 8 hours after dosing 6-beta-naltrexol milk levels remained detectable and averaged 46 mcg/l Half-life of elimination from milk was 2.5 and 7.7 hours for naltrexone and 6-beta-naltrexol, respectively Undetectable (<2 mcg/l) infant plasma levels of both naltrexone and 6-betanaltrexol were found 9½ hrs post maternal dose and 30 minutes following feeding Data suggest that an exclusive breastfed infant would receive about 7 mcg/kg of naltrexone daily, less than 1% of the maternal weight-adjusted dosage Chan et al., J Hum Lact, 2004. 62

63 Naltrexone: Breastfeeding The extent to which naltrexone might alter breastmilk production is currently unknown The amount of naltrexone and its metabolites that might be transferred to the infant through breastmilk are currently unknown The effects on the nursing infant are unknown Review in Jones et al., Addiction, 2012. 63

64 Naltrexone: Child Development Animal Models Animal models examining the impact of naltrexone on development have produced conflicting results Some studies suggest stimulatory effects on growth Other studies suggest inhibitory effects on growth Other studies still report no effects Discrepancies may be due to the dosage of naltrexone No experimental studies of sustained-release naltrexone Human Research Limited to an extremely small number of cases followed after maternal treatment with oral or sustained-release naltrexone of varying lengths Neonatal outcomes were unremarkable Results were only for those patients who maintained contact with the clinic Farid et al., Curr Neuropharm, 2008. 64

65 Buprenorphine v. Methadone v. Naltrexone Benefits and Risks of Pharmacotherapy Methadone Buprenorphine Naltrexone Longer treatment retention than detoxification? Reduced HIV drug risk behaviors? Greater birthweight than no treatment? Recommended for pregnancy?? Independent replication of results Fetal behavior? NAS 65

66 Pharmacotherapy for Opioid Dependence: Unresolved Issues Neither of the 3 medications is FDA approved for use in pregnancy Treatment programs are expected to use evidence-based practices Cost/reimbursement within the public sector is uncertain How best to induct pregnant women onto buprenorphine is not known How best to transition pregnant women onto naltrexone is unknown Practitioners have little experience inducting pregnant women onto buprenorphine Practitioners may be reluctant to continue prescribing buprenorphine during pregnancy No data are available to inform selection of patients who should be maintained on which medication Insufficient data are available regarding the longer-term outcomes (growth, learning, development, behavior) for either of the 3 medications 66

67 Pharmacotherapy for Opioid Dependence: Case Example 33-year-old woman 16 weeks EGA Unmarried Unemployed None of her 3 children are living with her 10-year history of i.v. heroin dependence Currently on methadone maintenance Questions for discussion 1. What would you tell this patient about risks and benefits of opioid medication? 2. How would you approach her care?

68 Pharmacotherapy for Opioid Dependence: Case Example 28-year-old pregnant woman 20 weeks EGA Unmarried 1 child in her custody 5-year history of oral oxycontin dependence Using benzodiazepines to reduce anxiety Smokes packs of cigarettes a day Past methadone and buprenorphine treatment Presenting to treatment due to court order Questions for discussion 1. What would you tell this patient about risks and benefits of opioid medication? 2. How would you approach her care?

69 Pharmacotherapy for Opioid Dependence: Case Example 23-year-old pregnant woman 4 weeks EGA Married Employed Supportive husband No children 2-year history of Vicodin dependence No history of opioid-agonist pharmacotherapy Questions for discussion 1. How would you approach her care?

70 Outline Contexts of Opioid Use during Pregnancy Pharmacotherapy for the opioiddependent pregnant patient: Methadone Buprenorphine Naltrexone The need to address psychosocial issues in the treatment of the opioid-dependent pregnant patient Physical, sexual, and emotional abuse HIV-risk behaviors Concomitant drug use Co-occurring psychological issues

71 Interpersonal Violence Prevalence and identifying pregnant women experiencing interpersonal violence Assessing the impact of interpersonal violence on the pregnant patient s health and wellbeing Intervention with pregnant women who experience interpersonal violence and substance abuse

72 Interpersonal Violence: Definition A systematic pattern of intentional intimidation through the use of threats and violence for the purpose of gaining power and control over one s partner in an intimate relationship

73 Interpersonal Violence: Types Physical: Assault on the woman s person (hit, kick, slap, etc.) Sexual: Forced or unwanted sexual acts Psychological: Woman s psychological well-being deteriorates or remains at an unhealthy level (threats, destruction of property, etc.)

74 Interpersonal Violence: Myths and Realities True or False: Interpersonal violence affects only a small percentage of the population Interpersonal violence occurs only in low-income, uneducated, and minority populations Drug and alcohol use cause interpersonal violence Pregnancy is a protective factor against interpersonal violence

75 Interpersonal Violence: Myths and Realities Interpersonal violence affects only a small percentage of the population FALSE One in four women has experienced interpersonal violence in her lifetime (women = 85% of the victims men = 15%) Approximately 960,000 incidents of violence against a current or former spouse, boyfriend, or girlfriend Another estimate indicates that 3 million women per year are physically abused by their husband or boyfriend. U.S. Department of Justice, Violence by Intimates: Analysis of Data on Crimes by Current or Former Spouses, Boyfriends, and Girlfriends, March 1998. The Commonwealth Fund, Health Concerns Across a Woman s Lifespan: 1998 Survey of Women s Health, 1999

76 Interpersonal Violence: Interpersonal violence occurs only in low-income, uneducated, and minority populations FALSE Myths and Realities Women of all races are about equally vulnerable to interpersonal violence Interpersonal violence affects people regardless of income. However, individuals earning below $25,000/year are at a three-times higher risk of intimate partner violence than people earning over $50,000/year Urban areas experienced highest level of nonfatal interpersonal violence. Suburban and rural areas have interpersonal violence rates 20% less than those in urban areas Bureau of Justice Statistics Interpersonal Violence Statistics 1993-2004, 2006; Violence Against Women: Estimates from the Redesigned Survey, 1995.

77 Interpersonal Violence: Myths and Realities Drug and alcohol use cause interpersonal violence FALSE While there is a correlation between drug and alcohol use and perpetration of interpersonal violence, perpetrators tend to use substance use as an excuse for loss of control and for violence itself

78 Interpersonal Violence: Pregnancy is a protective factor against interpersonal violence FALSE Myths and Realities Review of the literature reported 1-20% prevalence of interpersonal violence during pregnancy Among 104 Appalachian women during pregnancy, 81% of participants reported some type of IPV during the current pregnancy, with 28% reporting physical IPV, and 20% reporting sexual violence. Among 715 urban drug-dependent pregnant women attending a drug addiction treatment program, lifetime abuse ranged from 73% for physical to 71% for emotional to 45% for sexual. During pregnancy abuse rates remained high: 41% for emotional, 20% for physical and 7% for sexual. Gazmararian et al., 1996; Bailey et al., 2007; Velez et al., 2004

79 Interpersonal Violence: Myths and Realities Interpersonal violence is... the leading cause of injury among women of reproductive age the single most common trigger for female suicide and up to 60% of women who are murdered die as a result of a domestic dispute Homicide was the leading cause of pregnancy-associated death, responsible for 20.2% of all pregnancy-associated deaths in a sample of 247 pregnancy-associated deaths identified through vital statistics records Webster, Irish Medical Journal, 1995; Horan & Cheng, JAMA, 2001; Frye, JAMA, 2001.

80 Interpersonal Violence: Sexual Abuse Medical Consequences of Sexual Abuse in Women Unintended Pregnancy Abortion Anal and/or vaginal tearing Painful intercourse Sexual dysfunction STIs HIV/AIDS Urinary tract infection Chronic pelvic pain Homicide

81 Interpersonal Violence: Perinatal Effects Perinatal Effects Related to Interpersonal Violence Psychological Anxiety Depression/Suicide PTSD Poor self-esteem Blame and guilt Uncontrollable emotions Social Isolation/Withdrawn Few social interactions Rigid sex-role expectations Physical/Stress Related Injury Sleep problems Nutritional/ Low weight gain Substance abuse/ Smoking Chronic pain Hypertension Inadequate prenatal care Miscarriage Pre-term labor Fetal fracture/ Fetal death Placental abruption Uterine rupture

82 Interpersonal Violence: Effects on Children 15 times more likely to be abused than children from non-violent homes Parents usually think children do not know what is happening Children witness between 60-80% of assaults When children live with interpersonal violence they may witness some of the physical violence Physical injuries - Hurt while trying to intervene Abuse and Neglect Sleeping disorders - Difficulty falling asleep - Wake frequently - Refuse to sleep in their own bed - Night mares Anxiety - Worry about parents - Worry about self PTSD

83 Interpersonal Violence: Intergenerational Cycle of Violence A child s exposure to the father abusing the mother is the strongest risk factor for transmitting violent behavior from one generation to the next. (American Psychological Association Presidential Task Force on Violence and the Family, 1996) Partner Maltreatment Siblings Peers Maltreatment Violence Child Abuse and Neglect

84 Interpersonal Violence: Danger Assessment Signs of Increasing Danger Abuse happens more frequently Abuse gets rougher Abuser tries to choke her Abuser threatens to kill her There is a gun in house/car Abuser forces sex Abuser uses drugs Abuser hits woman during pregnancy Abuser is extremely jealous, possessive, controlling Abuser has been reported for child abuse J. C. Campbell, Assessing Dangerousness, 1995.

85 Interpersonal Violence: Case Example 30-week pregnant patient 30 years old Uncontrolled hypertension Only attended 2 prenatal care appointments Children ages 10 and 3 Woman s separated partner has repeatedly threatened her, police reports on file Family dog run over last year by partner 6 years ago started taking pain medication for back pain - currently takes more than prescribed Questions for discussion 1. How would you approach her care? 2. What can you do to help the patient increase her personal safety?

86 Interpersonal Violence: Action Plan Patient Contact Acknowledge Safety Containment Support/Affirm Focus on coping Referral Documentation in patient s medical record Patient s own words of injury or abuse Diagram of the injuries (body map) Photographs of injuries (consent needed) Police phone calls Safety plan discussed Medical follow-up care advised Community resources recommended

87 Interpersonal Violence: Empowerment Respect Confidentiality Promote Access to Community Services Help Her Plan for Future Safety ADVOCACY Respect Her Autonomy Believe Her and Validate Her Experiences Acknowledge the Injustice Domestic Violence Project

88 Depression Twice as common in women as it is in men Peak incidence is during 25-45 years of age The link between reproductive status and depressive illness is seen with high frequency during the premenstrual phase perimenopausal period immediate postpartum period Depression is not identified in 50% of pregnant women experiencing it

89 Anxiety Literature focuses on symptoms not disorders Like depression, anxiety disorders are more prevalent in women than men Anxiety has been shown to be a predictor of postpartum depression Life stressors are frequently antecedents of the development of mood or anxiety disorders

90 Depression and Anxiety: Prevalence Depression Lifetime prevalence of major depression in women ranges from 9% to 26%. Depression risk is greatest during the childbearing years In general pregnant population, 18% have depressive symptoms and 13% have an episode of major depression Rates of depression among pregnant women with a substance use disorder are higher than among pregnant women without a co-morbid substance use disorder. 56 73% of substance-dependent pregnant women are estimated to have depressive symptoms Anxiety Approximately 6% of women have an anxiety disorder during pregnancy 36% of methadone-maintained women were observed to have an anxiety disorder during pregnancy In Contrast: Hypertension occurs in 18% of pregnancies Diabetes occurs in 3-8% of pregnancies

91 Depression and Anxiety during Pregnancy: Maternal Outcomes Poor nutrition Impaired self-care Failure to follow medical guidelines Failure to follow prenatal guidelines Worsening of co-morbid medical illness Increased exposure to tobacco, alcohol, and drugs Postpartum psychiatric complications Impact on family members Fishell, J Popul Ther Clin Pharmacol, 2010.

92 Depression and Anxiety during Pregnancy: Fetal Outcomes Increased risk for: Spontaneous early labor Fetal distress Fetal growth Spontaneous abortion Pre-eclampsia Operative/instrumental deliveries Pre-term delivery Lower birth weight Fishell, J Popul Ther Clin Pharmacol, 2010.

93 Depression and Anxiety during Pregnancy: Neonatal Outcomes Increased risk for: Lower Apgar scores Smaller head circumference Poor neonatal adaptation Admission to NICU Growth retardation Slowed mental development Excessive crying, irritability, hostility, erratic sleep Fishell, J Popul Ther Clin Pharmacol, 2010.

94 Depression and Anxiety during Pregnancy: Child Development Negative effect on maternal-fetal and maternal-infant bonding Difficulties with affect regulation (for example, tantrums) Cognitive delays, behavioral and emotional difficulties, maladaptive social interactions Displays more fear and anxiety and have more insecure and disorganized attachment styles Higher rates of ADHD Higher impulsivity and lower IQ at age 14-15 Fishell, J Popul Ther Clin Pharmacol, 2010.

95 Depression and Anxiety: Relationships to Substance Use Disorders For patients in treatment for substance use, less is known about mood and anxiety disorders in pregnant than non-pregnant patients Other psychiatric disorders can impede substance use treatment Co-morbid depression and anxiety may exacerbate the negative consequences of prenatal exposure to nicotine, alcohol, and illicit drugs Pregnant patients in treatment for substance use who have other psychiatric diagnosis may be at higher risk for low birth weight and pre-term deliveries than pregnant women without these disorders

96 Depression: Maternal Treatment Outcomes of Methadone Maintained Pregnant Patients Percent of Psychiatric Referrals Percent Percent Percent 75% 50% 25% 0% 75% 50% 25% 0% 75% 50% 25% 0% 37% 61% 63% No Co- Co-occurring Occurring Anxiety Disorder Percent in Psychiatric Disorder Treatment at Day 30 8% 23% No Co- Co-occurring Occurring Anxiety DisorderPercent Reporting Suicidal Disorder Thoughts 0% No Co- Occurring Disorder 9% Co-occurring Anxiety Disorder Co-occuring Mood Disorder 49% Co-occuring Mood Disorder 22% Co-occuring Mood Disorder No significant difference between the three groups in percent referred for psychiatric treatment Co-occurring Mood Disorder group was significantly more likely to be in psychiatric treatment thirty days postpartum than was the No Cooccurring Disorder group Fitzsimons et al., J Subst Abuse Treat, 2007.

97 Depression: Maternal Treatment Outcomes Estimated Gestational Age at Delivery Percent Percent Mean EGA in weeks 40 39 38 37 36 35 75% 50% 25% 0% 75% 50% 25% 0% 38 No Co- Co-occurring Occurring Percent Delivering by Anxiety Cesarean Section Disorder Disorder 11% No Co- Occurring Disorder 37 15% Co-occurring Anxiety Disorder Maternal Percent Urine Positive for Illicit Drugs at Delivery 27% No Co- Occurring Disorder 24% Co-occurring Anxiety Disorder 36 Co-occuring Mood Disorder 21% Co-occuring Mood Disorder 39% Co-occuring Mood Disorder Co-occurring Mood Disorder group had a significantly smaller EGA at delivery than the No Co-occurring Disorder group Co-occurring Mood Disorder group was more likely to deliver by cesarean section than was the No Co-occurring Disorder group Co-occurring Mood Disorder group was more likely to test positive for illicit drugs at delivery than were either the Co-occurring Anxiety group or the No Co-occurring Disorder groups Fitzsimons et al., J Subst Abuse Treat, 2007.

98 Depression and Anxiety: Summary Methadone-stabilized patients with anxiety disorders had better maternal treatment outcomes than mood or nondisorders patients Patients with mood disorders had poorer maternal and neonatal outcomes compared to other groups More proactive efforts are needed to treat patients with current mood disorders

99 Depression and Anxiety: Treatment Options Pharmacotherapy 13% of women have taken an antidepressant at some time during their pregnancy No randomized clinical trials examining antidepressant efficacy in the treatment of perinatal depression The FDA classifies SSRIs as Schedule C medications

100 Depression and Anxiety: Treatment Options Pharmacotherapy Risk:benefit domains to discuss Fetal demise Physical malformation Growth defects Neonatal complications Neurobehavioral teratogenicity Antidepressants during pregnancy Changes in body weight, body fat, renal function May require higher doses to maintain therapeutic levels

101 Depression and Anxiety: Treatment Options Non-Pharmacotherapy Interpersonal psychotherapy 12-16 weeks of individual therapy Focus on 4 topics: interpersonal role disputes, role transitions, interpersonal deficits and grief RCT supported efficacy compared to wait-list control Cognitive Behavioral Therapy 6 sessions shown to be equally efficacious to Prozac for PPMD symptoms ACOG/APA 2009 Joint Report recommends psychotherapy cognitive-behavioral therapy or interpersonal psychotherapy for treatment of mild-to-moderate depression during pregnancy

102 Treatment for Depression: Case Example 33-year-old woman 22 weeks EGA Unmarried Unemployed No children living with her 5-year history of heroin dependence Fifth admission to methadone maintenance treatment Reports history of depressive episodes since adolescence What are the treatment options available?

103 Treatment for Depression: Case Example 26-year-old woman 14 weeks EGA Married Homemaker 1 child living with her and her husband 8-year history of heroin dependence First admission to methadone maintenance treatment No prior history of depression until pregnancy What are the treatment options available?

104 Treatment for Anxiety: Case Example 28-year-old woman 24 weeks EGA Unmarried Employed part-time 2 children living with her 10-year history of heroin dependence Reports history of treatment for anxiety since early adulthood What are the treatment options available?

105 Treatment for Anxiety: Case Example 27-year-old woman 20 weeks EGA Married Employed full-time No children living with her 7-year history of heroin dependence Second admission to methadone maintenance treatment Currently receiving SSRI for moderate depression What are the treatment options available?

106 Treatment for Depression and Anxiety: Mother-Fetus-Neonate Triad Mother/Fetus/Neonate Exposure to Illness Exposure to Treatment Effects Of Illness Effects Of Treatment HPA Axis Genetics Environment Amniotic Fluid Placenta Breast milk Wellbeing of Mother, Fetus, Infant, Family

107 Summary Pregnant opioid dependent women have medications options to use as a part of a complete treatment process Effective treatments exist to reduce mood and anxiety symptoms Trauma is a common and critical issue to address to help improve the patient s health and well-being The treatment of the whole pregnant patient is complex and can be greatly rewarding

108 Acknowledgements Patients and infants Staff at the Center for Addiction and Pregnancy: 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 MOTHER Site PIs and investigative teams Reckitt-Benckiser Pharmaceuticals Inc. NIDA R01 12403

109 For More Information T H E E N D Hendrée E. Jones, PhD email: hjones@rti.org voice: 1-919-485-2664 The list of references used in preparing this slide set are available upon request. 109