Advancing the Care of Pregnant and Parenting Women with Opioid Use Disorder and their Infants: A Foundation for Clinical Guidance

Transcription

1 Advancing the Care of Pregnant and Parenting Women with Opioid Use Disorder and their Infants: A Foundation for Clinical Guidance Karol Kaltenbach, PhD Emeritus Professor of Pediatrics Sidney Kimmel Medical College at Thomas Jefferson University

2 Existing Guidelines Global World Health Organization 2014 Country Canada, Norway, Australia State Vermont, South Carolina

3 Existing Guidelines US does not have comprehensive national guidance for the optimal management of pregnant and parenting women with opioid use disorder and their infants CDC (2016) Prescriber Guidelines for pain management ASAM (2015) Practice Guidelines for treatment of opioid use disorders has a chapter on pregnant women SAMHSA TIP 43 (2005) has a chapter on pregnant women

4 Advancing the Care of Pregnant and Parenting Women with Opioid Use Disorder and Their Infants: A Foundation for Clinical Guidance Goal: SAMHSA set out to provide concrete recommendations for clinicians for providing care to pregnant and parenting women with opioid use disorder and their children, including recommendations for how to treat prenatal opioid use and neonatal abstinence syndrome (NAS). RAND/UCLA Appropriateness Method (RAM) Implementation RAM Report & Public Comment Period Clinical Guide 4

5 RAM Approach Differs from meta-analysis Meta-analysis combines the results of different studies to allow for the use of inferential statistical methods Strict inclusion criteria RAM literature review is to produce a synthesis of all available evidence, including the collective judgment of experts

6 RAM Process Review and synthesize the literature Develop a list of indications Convene an Expert Panel Rate Indications (1-3 inappropriate treatment, 4-6 uncertain, 7-9 appropriate) Classify appropriateness Process and analyze the data

7 Expert Panel Family Medicine 1 Neonatology 1 Nursing 1 Obstetrics/gynecology 3 Pediatrics 1 Psychiatry 1 Psychology 1 (Also 3 Scientific advisors with knowledge specific to the indications under discussion - did not rate the indication)

8 Example of Indication Rating Indication A pregnant woman with opioid use disorder should be advised that detoxification is associated with high rates of relapse and is not the recommended course of treatment Panel 2 7

9 Foundation for Clinical Guidance Currently available online (Summer of 2016) Describes detailed RAM process and results Not exceptionally user friendly Actual document is 37 pages of 274 pages Consists primarily of Appendices of all 285 Indications and how they were rated Notice in Federal Register last fall for Public comment SAMHSA now in process of developing a Clinical Guide that will be subject to scientific review and federal clearing process

10 Maternal Opioid Use Disorder and Medication for Addiction Treatment SAMHSA s goal is to produce a patient focused clinical guide that considers the maternal-fetal and maternal-infant dyad as a unit

11 Summary of RAM Literature Review Treating Women Who Are Pregnant and Parenting for Opioid Use Disorder and the Concurrent Care of Their Infants and Children: Literature Review to Support National Guidance Klaman SL., et al., Journal of Addiction Medicine, 2017 Titles that are used in the paper as well as literature citations are denoted with an * Conclusions included in the paper are also noted

12 Acronyms MAT For over the past 15 years has stood for Medication Assisted Treatment Definition has been the use of FDA approved medications in combination with evidence based behavioral therapies to provide-whole patient approach to treating a substance use disorder

13 Acronyms MAT Recently the use of the word assisted has been challenged because it implies medications are a corollary to treatment Recommended wording is now Medication for Addiction Treatment Implies medication has a central role

14 Acronyms SUD Substance Use Disorder OUD Opioid Use Disorder NAS Neonatal Abstinence Syndrome OTP Opioid Treatment Program

15 Medication Assisted Withdrawal* Medication assisted withdrawal/detoxification used to provide transition from illicit opioids to drug free state Taper is a gradual transition from maintenance to a drug free state

16 Medication Assisted Withdrawal Conclusion: Very high rate of relapse in opioid dependent women (Jones et al., 2008b*) Subjects woman and fetus to all the risks associated with substance misuse (Kaltenbach et al., 1998*, Mattick et al., 2009*)

17 Medication for Addiction Treatment (MAT) Conclusion: The accepted treatment for OUD during pregnancy is long acting opioid agonist MAT that includes methadone or buprenorphine provided within the context of a comprehensive program of obstetrical care and behavioral intervention Klaman et al., 2017

18 Why MAT during Pregnancy Prevents erratic maternal opioid levels and protects the fetus from repeated episodes of withdrawal Associated with improved obstetrical care, increased growth, and reduced fetal and neonatal morbidity and mortality Supports and sustains recovery

19 MAT Medications used to treat opioid use disorders Methadone Buprenorphine (mono and combination products) Naltrexone (not recommended for use during pregnancy)

20 Historical Context The recognition of methadone as the standard of care can be traced historically in the USA through multiple federal publications: Drug Dependence in Pregnancy: Clinical Management of Mother and Child, Services Research Monograph Series, NIDA, 1979 State Methadone Treatment Guidelines, CSAT, US DHHS, 1993 Effective Medical Treatment of Opiate Addiction, National Institutes of Health Consensus Development Panel, 1998

21 Historical Context Buprenorphine has been used in Europe since the 1990 s. It was approved for use in the United States in 2002 and it is widely used in the US Joint Committee Opinion: American College of Obstetricians and Gynecologists and the American Society of Addiction Medicine recommend the use of methadone or buprenorphine for pregnant opioid dependent women

22 Methadone and Buprenorphine Basic tenets of treatment are the same Pharmacologically different Schedule II vs. Schedule III Different systems of care Cost

23 MAT with Methadone Issues Specific to Methadone Regulatory Schedule II Drug (may only be prescribed for MAT within an OTP except for hospitalization for medical condition) Induction Dose

24 Methadone Induction USA Regulatory Issues (42CFR 8.12) Documented opioid dependence for a minimum of 1 year- pregnant women are exempt but must certify pregnancy First dose 30mg If withdrawal symptoms persist after 2-4 hours, initial dose can be supplemented with another 5-10mg Maximum daily dose 40mg unless documented by physician that dose was insufficient to control withdrawal

25 MAT with Buprenorphine Issues Specific to Buprenorphine Regulatory Schedule III Drug Transition from methadone to buprenorphine Induction

26 Buprenorphine Induction Does not have the same regulatory restrictions Typically takes place over a 3 day period, beginning with 2mg or 4mg, usually with a maximum dose of 8 mg Day 1 12 mg Day 2 16 mg Day 3

27 Buprenorphine Induction Dependence on short-acting or long acting opioids is issue Short-acting: minimum of hrs between use and buprenorphine administration and exhibit early signs of withdrawal Long-acting: taper to 30mg for a minimum of 1 week. Last dose of methadone 24hr before buprenorphine and experiencing withdrawal As such transition from methadone is especially difficult tin pregnant women

28 Medication Dose Dose should be based on the same criteria as nonpregnant patients Pregnant women may develop symptoms of withdrawal as pregnancy progresses and may require dose increase in order to maintain the same plasma level (Jones et al., 2005*) Split dose regimen may be used to facilitate steady state maintenance (often difficult to implement) Increasing the daily medication regimen (2-6 doses per day) has been found to reduce the need for NAS treatment significantly to 29% (McCarthy et al., 2015*)

29 Medication Dose Dose should NOT be reduced during pregnancy to avoid NAS No clear evidence of association between maternal dose and severity of NAS (Jones et al., 2013c*, Jones et al., 2014a*) Non-therapeutic maternal dose may promote supplemental drug use and increase risk to fetus

30 Medication Dose Conclusion: As gestation increases, higher doses of methadone and possible buprenorphine appear to be needed Klaman et al., 2017

31 MAT and the Fetus* MOTHER study designed to assess the efficacy of buprenorphine for reducing NAS relative to methadone Randomized Clinical Trial Double-blind Double-dummy Flexible dosing mg methadone 2-32mg buprenorphine

32 Summary of MOTHER Fetal Results Buprenorphine exposed fetuses had higher levels of fetal heart rate variability, more fetal heart rate accelerations and greater coupling between fetal heart rate and fetal movement than methadone exposed fetuses At 24 and 28 weeks gestation, buprenorphine exposed fetuses displayed less motor activity suppression and longer duration of movement than methadone exposed fetuses (Jansson et al. 2011*)

33 Summary of MOTHER Fetal Results Methadone exposed fetuses were more likely to have a nonreactive (abnormal) non-stress test, fewer heart rate accelerations, and lower biophysical profile scores (more negative) than buprenorphine exposed fetuses (Salisbury et al. 2012*) Conclusion: Buprenorphine appears to have a less sedating effect than single daily dosing of methadone. Split dosing of methadone in the 3 rd trimester may also have a less suppressive effect Klaman et al. 2017

34 MAT and Pain Medication during Pregnancy, Delivery, and Postpartum* Individuals with long term exposure to opioids experience tolerance(reduced analgesia) and hyperalgesia (increased sensitivity to pain) Pregnant and postpartum women receiving MAT or with a long history of exposure to opioids often require higher doses of opioid analgesia during labor, delivery, and postpartum (Alford et al., 2006*; Meyer et al., 2007*, 2010*)

35 MAT and Pain Medication during Pregnancy, Delivery, and Postpartum Opioid agonist-antagonist medications (e.g. nalbuphine or butorphanol) should be avoided in women receiving MAT due to the risk of precipitated withdrawal (Cassidy and Cyna, 2004*; Jones et al., 2014b*) Conclusion: Postpartum women with OUD may need greater amounts of pain relief medication compared with women without such opioid experience Klaman et al., 2017

36 Methadone and Buprenorphine: Breast Milk* Concentrations of both buprenorphine (Ilett et al., 2012*) and methadone (Jansson et al., 2008b*) in breast milk are quite low, and pose little risk for neonates

37 Methadone and Buprenorphine: Breastfeeding* Women maintained on methadone or buprenorphine should be encouraged to breastfeed unless contraindicated (WHO, 2014*) It has been found that breastfed infants maintained on methadone or buprenorphine had shorter lengths of hospital stay and need for pharmacotherapy for NAS (Wachman et al., 2013*)

38 Methadone and Buprenorphine: Breastfeeding Conclusion: Breastfeeding among women not using other substances and maintained on methadone or buprenorphine can encourage and promote maternal-infant bonding and likely have mitigating effects on NAS severity Klaman et al., 2017

39 Methadone and Buprenorphine: NAS Prevalence rates reported in research vary greatly: 55-94% (McQueen, NEJM 2016) 27-91% (Kocherlakota, 2014*) Why such inconsistency Inclusion criteria differ Wide variability in the measurement of NAS Differences in NAS treatment initiation and weaning protocols

40 Methadone and Buprenorphine: NAS Current consensus is NAS is similar for methadone and buprenorphine However, buprenorphine exposed infants require Less morphine to treat NAS Less time for treatment of NAS Less time in the hospital (Jones et al., 2010b*)

41 NAS Medication Treatment Protocol* Oral morphine sulfate and methadone are currently the recommended medications for the treatment of NAS (Hudak and Tan, Pediatrics, 2012) Buprenorphine has just been reported to more efficacious than morphine (Kraft et al., NEJM, 2017) Clonidine or phenobarbital may be used as second line medications (Agathe et al., 2009)

42 Methadone and Buprenorphine: NAS Signs and Time Course* Secondary analysis of MOTHER data found Undisturbed tremors and hyperactive MORO occurred more often in the methadone exposed group Nasal stuffiness, sneezing, and loose stools occurred more often in the buprenorphine exposed group (Gaalema et al., 2012*)

43 Other Factors Affecting NAS* Cigarette smoking has been found to be related to severity of NAS (Jones et al., 2013b*) The presence of selective serotonin reuptake inhibitors and/or benzodiazepines exacerbate NAS (Kaltenbach et al., 2102*)

44 Rooming-in to Reduce NAS* Recent research has found that the first line approach to managing NAS may be a rooming in model that minimizes stimulation, maximizes maternal-infant contact, and encourages breastfeeding (Abrahams et al., 2010*; Holmes et al., Pediatrics, 2016)

45 Neonatal Abstinence Syndrome Conclusion: NAS severity may be less with buprenorphine than with methadone; however, other factors such as tobacco use, maternal benzodiazepine use, dyad genetics, NAS medication regimens, and hospital protocols determining where infants reside (e.g. NICU or rooming-in) may alter this relationship Klaman et al., 2017

46 Overall Conclusion of RAM Literature Review Both methadone and buprenorphine provide effective treatment for OUD For mother, medications provide benefits to support behavioral change For the fetus, buprenorphine appears less sedating For the neonate, buprenorphine produces a less severe NAS NAS is only one aspect of the risk/benefit assessment MAT should be provided in the context of a comprehensive care program that is responsive to women and the maternal/fetal/infant dyad

47 Keep a mother in mind in order for her to keep her child in mind Meeting the needs of pregnant and parenting women with opioid use disorder includes not only medication treatment and care of the opioid exposed newborn but requires a comprehensive model of care that addresses the complex array of biopsychosocial problems associated with maternal addiction