Opioid Use Disorder- Pregnancy Principles and Myths. Brian Iriye MD and Farzad Kamyar MD High Risk Pregnancy Center

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1 Opioid Use Disorder- Pregnancy Principles and Myths Brian Iriye MD and Farzad Kamyar MD High Risk Pregnancy Center

2 History of NAS/NOWS Prior to 1875 infants not thought to be affected Congenital Morphinism Normal at birth Crying inconsolably day 3 of life Sometimes developed seizures Frequently fatal 1901 Result of withdrawal Give babies small quantities of morphine to ease the symptom Symptoms occur in 60-80% of neonates Neonatal Opioid Withdrawal Syndrome (NOWS)

3 Again, this is data up to 2012

4 Cost of NAS 2009 $732 million hospital cost 3.4/ 1000 births 2012 $1.5 billion 5.8 / 1000 births 81% of costs - Medicaid Patrick Am J Perinatol 2015

5 Increase in Opioid Rxs

6 Opioid Rx Map

7 Overdose Death Rates as a Sign of SUD

8 Maternal Mortality Rates- USA vs Developed Nations

9 Maternal Mortality Texas: Total Maternal Deaths 382 Deaths from Drug OD 64 (16.7%) Deaths from Opioid OD 37 Opioid 23 Heroin 18 Fentanyl 1

10 Pregnancy Associated Deaths and Drugs % of total deaths Texas Maryland Alaska Georgia Virginia % of total deaths

13 Methadone Vs Buprenorphine in Pregnancy Jones NEJM 2010

14 Methadone Vs Buprenorphine in Pregnancy Jones NEJM 2010

15 Pros of Buprenorphine vs Methadone Lower risk of overdose Fewer drug interactions Ability to be treated in a private office setting without the need for daily visits to a licensed treatment program Dosing of buprenorphine is similar to that in nonpregnant women Insurance in the United States may cover buprenorphine prescribed by a private physician in an office setting, while not covering methadone dispensed in a licensed opioid treatment program Fewer side effects Low risk of adverse cardiovascular side effects (in contrast, methadone is associated with small increase in risk of arrhythmia) For the newborn, in utero exposure to buprenorphine rather than methadone may result in a lower risk of preterm birth, higher birth weight, larger head circumference, and, potentially, a lower rate and severity of neonatal withdrawal

16 Cons of Buprenorphine Vs Methadone Only limited data are available on pregnancy outcomes after first trimester exposure Lack of long-term neurodevelopmental outcome data Clinically important patient dropout rate due to dissatisfaction with the drug More difficult induction protocol with the potential risk of precipitated withdrawal Increased risk of diversion -especially the buprenorphine monotherapy formulation Less stringent structure of some office-based treatment programs Reports of maternal hepatic dysfunction and elevated transaminases Effects of buprenorphine are only partially reversible by naloxone The maximum daily dose of buprenorphine is 32 mg, due to a ceiling effect, which may not be sufficient in all women (usually those requiring more than 140 mg per day of methadone) More expensive than methadone Treatment with methadone may result in greater reduction in illicit opioid use

17 Buprenorphine in Pregnancy Drug dosing similar to non-pregnancy women with standard induction protocols Initiation after objective observable signs of moderate opioid withdrawal Greater than 6 hours after short acting opioid hours after longer acting opioids Dose adjustments may be needed with increasing gestational age Blood volume increases from 5 to 8 L in pregnancy Maximum blood volume and cardiac output at 28 weeks Maintain dosing intrapartum and postpartum Women should be encouraged to breastfeed Less than 1% of maternal dose in breast milk

18 Buprenorphine Administration Very important to discuss and educate patient on sublingual administration Ingested buprenorphine gets extensively first pass metabolized with extremely poor bioavailability. What they swallow will not work. Conservative recommendation to place under tongue and Do not eat, drink, talk or smoke for 30 minutes Let completely dissolve

19 Buprenorphine Induction Setting can vary [Inpatient Office Home] Patient should be abstinent From short acting opioid for > 6 hours (have them stop the day before) From long acting opioids from 1-3 days (ie. Methadone) Key here is to monitor for signs and symptoms of mild to moderate withdrawal, not just time since last use Score signs and symptoms using the Clinical Opiate Withdrawal Scale (aka COWS). Looking for COWS score of ~10-12 This will lessen the likelihood of precipitated withdrawal

20 Buprenorphine Induction Cont. Day 1 Administer test dose to patient of 2-4 mg sublingually Monitor for ~2 hours If still experiencing withdrawal symptoms can administer another 2-4 mg dose This can be repeated later in the day when the patient is at home depending on previous dosing Max on day one 8 mg

21 Buprenorphine Induction Cont. Day 2 Administer total dose from day 1 sublingually Monitor for ~2 hours If still experiencing withdrawal symptoms can administer another 2-4 mg dose This can be repeated later in the day when the patient is at home depending on previous dosing Max on day two 12 mg

22 Buprenorphine Induction Cont. Day 3 Administer total dose from day 2 sublingually Monitor for ~2 hours If still experiencing withdrawal symptoms can administer another 2-4 mg dose This can be repeated later in the day when the patient is at home depending on previous dosing Max on day three 16 mg This will likely be the stabilization dose Continue this dose for next several days to let it reach steady state

23 Buprenorphine Stabilization and Maintenance Early on recommend more frequent visits (ie. Weekly) and can advance as patient becomes more stable with their sobriety (ie. Monthly) Perform Urine Drug Screen testing make sure to test for buprenorphine If patient experiences cravings, withdrawal symptoms, return to substance use, etcetera. Assess needs, reasons, social situation, other stressors Consider increasing frequency of visits Consider increased intensity of treatment (including behavioral interventions) Consider increasing dose or split dosing Most will stabilize and maintain on 8-16 mg daily. Consider capping maximum dose at 24 mg daily (per guideline recommendations)

24 Subutex vs Suboxone No reason for preferential starting of one over the other in pregnancy Past concerns of naloxone in suboxone probably unwarranted Do to risks of diversion, suboxone use will probably expand No need to preferentially switch a patient already on either medication

25 Methadone Risks--Reprotox Neonatal effects that were related to the gestational use of this agent included prematurity, low birth weight, microcephaly, jaundice, thrombocytosis, arrhythmias, abnormal flash visual evoked potentials, the neonatal abstinence syndrome, lower language and cognition scores, and poorer neurological development, particularly with respect to executive function, up to 57 months of age Quick Take: Experimental animal studies show congenital anomalies to be increased in the offspring of some species after pregnancy exposure to high dose levels of methadone. The main concern in humans has been neonatal withdrawal after antepartum exposure to methadone.

26 Subutex Risks (buprenorphine) Placental transfer of buprenorphine might be limited in comparison with other opioids including methadone, thereby limiting fetal exposure and the development of dependency. However, there are reports of neonatal abstinence syndrome of variable intensity that might occur less often or subside sooner than in methadone-exposed infants. Studies indicated better outcome as evaluated by Apgar score, birth length, respiratory distress, or preterm labor with buprenorphine compared with methadone. Quick take: Based on experimental animal studies, buprenorphine exposure during pregnancy is not expected to increase the risk of adverse outcomes at birth but might produce later behavioral changes. As with other opioids, a neonatal abstinence syndrome can occur.

27 Suboxone Risks- Buprenorphine/naloxone Same as buprenorphine For Naloxone Component: Quick take: Based on experimental animal studies, use of naloxone during pregnancy is not expected to increase the risk of congenital anomalies. It is not known whether naloxone administration to pregnant women might increase the risk of preterm labor by blocking the endogenous opioid suppression of oxytocin release from the posterior pituitary, a phenomenon observed in rats- BUT THIS IS NOT SEEN IN LIMITED STUDIES WITH SUBUXONE IN PREGNANCY IN HUMANS There is a decrease in prolactin after naloxone administration (not oral dose)- Old Category C Oral bioavailability of naloxone is %

28 NAS and Newborn HC Visconti, Towers 2015 AJP

29 These pregnancies require special ultrasound follow up during pregnancyusually only available in MFM centers

31 Drug Withdrawal During Pregnancy- Old School Not recommended from the 1970s until recently due to risk Fetal Demise Fetal Distress 1973 Rementeria AJOG Case report of stillbirth in a patient with withdrawal sxs shortly before 39 wks Reviewed literature from preceding 10 years on stillbirth and meconium stained fluid in opioid addicted women Conclusion- methadone maintenance----don t withdrawal during pregnancy

32 Drug Withdrawal During Pregnancy- Old School Zuspan 1975 AJOG Serial amnios to assess epi and norepi levels over 9-10 weeks in pregnancy being detoxed from methadone Epinephrine levels increased suggesting fetal stress so the process was discontinued Delivered at 39 weeks on methadone maintenance Conclusion- Detox causes stress----don t do it!!

33 Drug Withdrawal During Pregnancy Mass 1990 (J Perinatal Med) Dashe 1998 (Obstet Gynecol) 57 mothers over 7 years in methadone detox program 30% (n=17) successful- 2 cases of NAS (12%) 70% (n=40) unsuccessful- 30 cases of NAS (75%) NO FETAL DEATHS OR ADVERSE OUTCOMES REPORTED 34 mothers over 10 years with inpatient day methadone detox 20 (59%) successful- 3 cases of NAS (15%) NO FETAL DEATHS OR FETAL DISTRESS Luty 2003 (J Sub Abuse Treat) 101 mothers over 12 years with inpt methadone detox (21 days) 1 SAB in the 5 pts detoxed in the first trimester No fetal deaths in 2 nd or 3 rd tri detox No data on relapse or NAS

34 Drug Withdrawal During Pregnancy Jones 2008 (A J Addict) 175 pts over 7 years in a comprehensive care center 95 with methadone withdrawal over 3-7 days 51/95 relapsed (54%)- NAS rate of 28% 80 maintained on methadone- NAS rate of 24% No fetal loss or PTD in detox group More prenatal visits in Methadone maintenance (MM) group Conclusion Methadone maintenance is better due to relapse rates Stewart 2013 (AJOG) 95 pts over 6 years with day methadone detox program 53/95 successful- NAS rate 10% 42/95- unsuccessful- NAS rate of 80% No fetal deaths or distress during detox

35 Conclusions of Withdrawal Studies 5 papers spanning 24 years 382 patients who went thru detox NO FETAL DEATHS 1 SAB with first trimester detox- not significantly different from baseline miscarriage rate but limited data

36 Possibilities of Opioid Withdrawal Haabrekke 2014 (J Addictive Dis) 21 pts in residential living detox program over 5 years compared to 78 pregnancies of opioid addicted pregnant women 22% NAS vs 77% NAS No fetal deaths or preterm deliveries in the detox group 26% preterm deliveries in the opiate group

37 Detox in Pregnancy- Bell &Towers AJOG 2016 Evaluate the safety of opiate detoxification in pregnancy Secondary outcome- to assess the manner of detox and the rate of NAS Prospective observational data collection during ongoing prenatal care of opiate addicted pregnant women during a 5 ½ year period from 2010 to 2015 with the complete data assessed retrospectively at the end

38 Detox in Pregnancy- Bell &Towers AJOG 2016 Four Groups of patients were studied Group 1 acute detox of incarcerated patients Group 2 inpatient detox with intense outpatient behavioral health follow-up Group 3 inpatient detox without intense outpatient behavioral health follow-up Group 4 slow outpatient buprenorphine detox with ongoing behavioral health

39 Detox in Pregnancy- Bell &Towers AJOG total patients in the study 28 patients (9%) detoxed in the first trimester (5-13 weeks gestation) 2 IUFD s First was fully detoxed at 10 weeks but had an IUFD at 18 weeks from a placental abruption (she was still incarcerated and her drug screen was negative) Second was fully detoxed at 12 weeks but had an IUFD at 34 weeks fetus was hydropic autopsy declined all testing was negative on the fetus and her drug screen was negative

40 Detox in Pregnancy- Bell &Towers AJOG patients (49%) detoxed in the second trimester (14 to 26 weeks) no fetal losses 125 patients (42%) detoxed in the third trimester (27 weeks and greater) no fetal losses No cases of preterm labor/delivery or PPROM during the process of detox

41 incarcerated IP detox +BH OP detox - BH Slow OP detox + BH Detoxification with appropriate behavioral health follow up should be considered an appropriate option for well selected patients

42 Detox in Pregnancy- Bell &Towers AJOG 2016 Excluding Group 1 patients that were acutely detoxed after being incarcerated Combining Groups 2 & 4 (those fully detoxed and maintained in intense long-term behavioral health follow-up) The rate of NAS was 20 in 116 patients (17.2%) Compared with Group 3 (not maintained in FU) The rate of NAS was 54 in 77 patients (70.1%) Highly significant difference p <.0001 YOU NEED TO HAVE BEHAVIORAL THERAPY F/U for DETOXED MOMS

43 Detox Fears Appear Overstated With this study data and a review of the current literature, there are more than 700 cases of reported opiate detoxification during pregnancy without a fetal demise related to the process Risk of stillbirth in the low risk population of pregnant women in U.S. is 3-4 per 1000

44 What to Do Now With This Data Offer patients continued treatment vs detox No coercion just options Put patients into MAT program to stabilize and then wean down or enter an inpatient detox program. Do this only in motivated patients with access to behavioral health and adequate follow up

45 Detoxing in Pregnancy--Method For outpatient slow detoxification, each patient is different, but overall, the dose is decreased systematically in a stair step pattern per week Methadone 10 mg increments Buprenorphine 2 mg increments When fully discontinued, use ancillary treatments of symptoms Clonidine / antiemetics / antidiarrheals / others Naltrexone Antenatal testing in 3 rd trimester Need behavioral health thru delivery and 6 months PP Relapse Rate in Towers Group in 13% up to 6 months PP

46 Prenatal Care Issues Discuss the role of DCS involvement How participation will help Birth control 80% of patients are multiparous LARC/BTL Antenatal testing at 32 weeks Growth sonography monthly after 28 weeks Routine 39 week delivery unless o/w indicated

47 Post Partum Issues Vaginal Delivery 95% of time does not need opiates Cesarean delivery Bupivicane injection incisionally- recent data not great NSAIDs/ acetaminophen Naltrexone if completely off opioids Maintain patient s current total daily dose of buprenorphine Can spilt into TID dosing for better pain control regimen, supplement as above. If above not providing adequate coverage for breakthrough consider fentanyl or dilaudid

48 Post partum Pregnancy only coverage stops 60 days after delivery + remaining month Increased stressors after delivery with new baby, increased housing and financial needs OD deaths peak 7-12 months after delivery New paperwork and new doctors after delivery

Anesthetics, Local a / or Anesthesia, Epidural a / or Anesthesia, Obstetrical a / or Pain, Postoperative a / or Postpartum Period a

Anesthetics, Local a / or Anesthesia, Epidural a / or Anesthesia, Obstetrical a / or Pain, Postoperative a / or Postpartum Period a Appendix 1. Literature Search Databases Years Search Terms Pubmed 01/1966 1. Analgesics, Opioid a / or Opioid-related Disorders a / PsycINFO EMBASE Cochrane 09/2016 or Heroin a / or Heroin Dependence a