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