WELCOME! Identifying and Managing Neonatal Abstinence Syndrome. ALICE ORDEAN MD, CCFP, MHSC, FCFP, ABAM Dip. Wednesday, March 11, pm to 1pm

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1 WELCOME! Identifying and Managing Neonatal Abstinence Syndrome ALICE ORDEAN MD, CCFP, MHSC, FCFP, ABAM Dip. Wednesday, March 11, pm to 1pm

2 Identifying and Managing Neonatal Abstinence Syndrome ALICE ORDEAN MD, CCFP, MHSC, FCFP, ABAM Dip. Medical Director, T-CUP, St. Joseph s Health Centre Associate Professor, DFCM, University of Toronto March 11, 2015

3 Outline Prevalence of perinatal opioid use and NAS Approach to comprehensive management of prenatal opioid use disorders Approach to identification and management of NAS Supportive measures Pharmacotherapy

4 Prevalence of Opioid Use Disorder in General Population Annual prescribing of opioids increased from 1991 to 2007 from 458 to 591 per 1000 individuals (increase of 29%) Treatment for prescription opioids in addiction services increased from 10.6% in 2005/6 to 18.6% in 2010/11 OPICAN study, 2005 demonstrated that type of illicit opioid use varies by province: prescription opioid misuse more common in Toronto

5 Prevalence of Opioid Use Disorder in General Population (2) CADUMS, 2011 (Canadian Alcohol and Other Drug use Monitoring Survey) revealed that 1 in 6 Canadians reported past year prescription opioid use abuse rates ~5% CAMH Monitor, 2013 found that 22% of Ontario adults reported past year use of prescription opioid pain relievers, ~3% use for non-medical purposes

6 Prevalence of Opioid Use Disorder during Pregnancy Prevalence of opioid use during pregnancy varies by population studied (geographical location) & method for detection (self-report vs. toxicology) Availability of perinatal Canadian data limited 2010 U.S. National Survey on Drug Use and Health: 4-5% of pregnant women reported illicit drug use in past 30 days, 0.1% heroin use and 1-2 % non-medical use of prescription opioids

7 Rates of neonatal abstinence syndrome (NAS) Data source Canadian Institute for Health Information (CIHI)

8 NAS Bed Utilization: Ontario Year Number of infants with NAS diagnosis Average length of stay (days) Beds per day utilized across province for NAS Comparison to healthy term newborn average LOS in 2004 was 1.4 days Data source - Canadian Institute for Health Information (CIHI)

9 NAS Bed Utilization: Summary ~3 % of neonatal beds occupied by infants diagnosed with NAS Average length of stay (LOS) for these neonates is 15 days versus 1.4 days for a term newborn Range of LOS highly variable, >42 days in some hospitals Some centers with interest/need/expertise can have 10-20% of newborns in special care nursery (SCN) with diagnosis of NAS

10 Polysubstance Use Pregnant women with opioid use disorder also report oregular alcohol and cigarette smoking ocomorbid drug use: o Benzodiazepines o Cocaine o Marijuana

11 High incidence of concomitant illicit drug use during pregnancy Canadian national cohort of 102 opioid-dependent pregnancies, receiving care at 3 integrated care programs in Vancouver, Toronto and Montreal Demographics: 29.7 years, 64% white, 50% single, 61% on social assistance 50% on methadone prior to conception, other half initiated during pregnancy at mean of 21 weeks gestational age Ordean et al. Can Fam Phys 2013

12 High incidence of concomitant illicit drug use during pregnancy(2) At first visit, pregnant women reported 46% heroin use, 27% prescription opioid use Geographical differences: prescription opioid use more common in Toronto (48%), heroin use more frequent in Vancouver (80%) and Montreal (50%) Polysubstance use: 87% nicotine, 44% cocaine, 25% alcohol, marijuana, benzodiazepines By delivery, significant reductions in heroin (16%) and prescription opioids (10%), cocaine (19%), marijuana (7%) and alcohol (5%) use

13 Opioid Use Disorder DSM V Criteria Problematic pattern of opioid use leading to clinically significant impairment 2 or more of the following within 12 months: 1. Opioids taken in larger amounts or over longer period than intended 2. Persistent desire to cut down 3. Great deal of time spent in activities to obtain, use or recover from its effects 4. Craving to use 5. Failure to fulfill major role obligations work, home

14 Opioid Use Disorder DSM V Criteria (2) 6. Continued use despite social or interpersonal problems 7. Important social, occupational or recreational activities given up 8. Recurrent opioid use in physically hazardous situations 9. Continued use despite physical or psychological problems 10. Tolerance 11. Withdrawal

15 Risks of Antenatal Opioid Use Consequences of antenatal opioid use due to repeated cycles of intoxication and withdrawal Prescription opioid misuse associated with: Intrauterine growth restriction Increased risk of spontaneous abortion Increased risk of prematurity and low birth weight leading to increased neonatal morbidity & mortality rates Increased risk of SIDS (sudden infant death syndrome)

16 Risks of Antenatal Opioid Use (2) Infants exposed to any regular use of opioids such as methadone, morphine, codeine, oxycodone and heroin in utero develop a physical dependence on these substances As a result, infant is at risk of developing withdrawal symptoms and signs after birth when no longer exposed to any opioid Neonatal opioid withdrawal can occur in 55-94% of infants exposed to opioids in utero

17 Approach to Care for Opioid Use Disorder in Pregnancy Engagement and retention in care Opioid withdrawal management Opioid agonist treatment (OAT) during pregnancy o Methadone: maintenance vs. detoxification o Buprenorphine o Morphine (slow-release) Comprehensive care including antenatal care and social services

18 Pregnancy: Window of Opportunity Pregnancy represents a window of opportunity, a teachable moment when women have an increased perceived risk of harm Pregnant women are more likely to access long-term substance abuse treatment programs (e.g. methadone maintenance programs) and more likely to re-access detoxification programs due to interest in stopping drug use for child s health and fear of child protection services

19 Integrated Care Program Comprehensive programs that combine pregnancy care with substance use treatment in one location - one-stop shop model Meta-analysis found that women in integrated programs had improved neonatal outcomes (higher birth weight, fewer birth complications) and maternal outcomes (fewer positive drug screening, more prenatal visits & fewer preterm births) Milligan et al., Addiction Research and Theory, 2011.

20 Opioid Agonist Treatment Current standard of care for opioid use disorder in pregnancy is methadone maintenance treatment (MMT) Due to limited experience with use of buprenorphine during pregnancy, its use can be considered after discussion of benefits and risks of buprenorphine Structured opioid-prescribing (eg. use of other sustained-release opioid preparations) can be last option if no access to methadone or buprenorphine

21 Rationale for OAT Substitute for heroin or prescription opioids Accumulates in tissues with repeated daily oral administration Relieves opioid withdrawal and reduces cravings for opioids by blocking euphoric effects of self-administered illicit opioids (cross-tolerance) leading to reduced illicit drug use Once stabilized on a dose, subsequent doses should not cause sedation, analgesia, or euphoria Allows normal function to perform mental & physical tasks

22 Rationale for OAT in Pregnancy Decreased complications due to repeated cycles of intoxication and withdrawal (e.g., miscarriage, premature labour, fetal death) Reduced rates of prematurity, low birth weight & infant mortality Improved prenatal care & nutrition Decreased risk of Hepatitis C & HIV (since reduces needle & paraphernalia sharing

23 What is methadone? Oral synthetic opioid Effects similar to morphine Dispensed as a liquid solution made by dissolving methadone in orange drink (to prevent injection) Well-absorbed from gastrointestinal tract Peak effect at 2-4 hours Long duration of action: hours

24 Methadone Side-Effects Constipation* Sweating* Weight gain Decreased libido, fatigue* Decreased level of consciousness, respiratory depression with excessive doses Neonatal withdrawal * increased during pregnancy!

25 MMT Components Frequency of MD visits depends on stability Each visit includes review of dose, relapse prevention counselling, urine drug testing MD requires exemption to prescribe MMT Visits to pharmacy depend on number of drinks & carries Treatment contract also required which indicates voluntary participation in MMT, rules and expectations for use of methadone

26 MMT Dose Adjustment Women who develop symptoms during pregnancy, will require dose adjustment: increased methadone dose or decreased dosing interval (i.e. split-dosing) to maintain therapeutic methadone plasma concentrations Pregnant women should be offered split-dosing when single dose treatment produces maternal withdrawal (especially towards end of dosing interval) or abnormal fetal activity patterns Dose may need to be decreased after delivery

27 What is Buprenorphine? Sublingual tablet, approved for use in Canada for nonpregnant population in 2007 Rapid absorption when placed under tongue Peak effect in 1-4 hrs, long half-life hrs Ceiling effect safer in overdose Buprenorphine showed little physical dependence & milder withdrawal with abrupt discontinuation of medication in contrast to methadone

28 Rationale for Buprenorphine during Pregnancy Partial mu-opioid agonist - relieves withdrawal symptoms & suppresses opioid cravings Numerous randomized controlled trials documented that buprenorphine produces opioid-like effects equivalent to methadone reduces opioid use (i.e. effective opioid substitution therapy) Early promising results that newborns exposed to buprenorphine had shorter & milder neonatal abstinence syndrome than with methadone reduced health care costs & beneficial for families

29 Components of Buprenorphine Maintenance No restrictions all pharmacies may dispense & all physicians can prescribe buprenorphine Recommended completion of prescribing course, oneday clinical observation of an opioid-dependency practice and ongoing continuing medical education Urine drug testing at each visit, no specific schedule recommended Pharmacy visits depends on stability can grant take home doses on faster schedule

30 BMT Dosing Adjustments Titrate dose of buprenorphine until other opioid use and cravings discontinued Buprenorphine dose may need to be adjusted during pregnancy to maintain therapeutic levels, as with methadone PROMISE trial showed increase in buprenorphine dose required during last trimester of pregnancy Dose may need to be reduced postpartum

31 MOTHER Study: NAS after Methadone vs. Buprenorphine Double-blind, double-dummy randomized controlled trial 8 sites: USA, Canada(St. Joseph s Health Centre, Toronto), and Austria 175 pregnant women with opioid dependence assigned to buprenorphine (n=86) vs. methadone (n=89) No significant between group differences including substance-use characteristics

32 NAS after Methadone vs. Buprenorphine Exposure (2) 16/89 (18%) women in MMT and 28/86 (33%) women in buprenorphine group discontinued treatment Dissatisfaction with study medication was reason for discontinuation by 71% of buprenorphine vs. 13% of methadone group Doses at study discontinuation: 87mg for methadone, 14mg for buprenorphine

33 NAS after Methadone vs. Buprenorphine Exposure (3) Percentage of neonates requiring treatment for withdrawal did not differ between groups Neonates exposed to buprenorphine required 89% less morphine, spent 43% less time in hospital (10 vs days) & 58% (4.1 vs. 9.9 days) less time in hospital receiving medication for NAS Conclusion: rates of NAS among infants exposed to buprenorphine and methadone are not significantly different but buprenorphine resulted in clinically less severe NAS

34 NAS and OAT dosing Meta-analysis & systematic review (Cleary et al. 2010) concluded that severity of NAS not related to maternal methadone dose MOTHER study sub-analysis also replicated above finding and further demonstrated that maternal buprenorphine dose was not related to NAS severity, duration of treatment for NAS or length of hospital stay

35 Neonatal Abstinence Syndrome (NAS) Clinical presentation Most significant risk of any regular, daily opioid use during pregnancy is neonatal abstinence syndrome characterized by: o o o Central nervous system hyperirritability (eg. Increased muscle tone, tremors, high-pitched cry) Gastrointestinal dysfunction (eg. Poor feeding, regurgitation, loose stools, poor weight gain) Metabolic, vasomotor & respiratory disturbances (eg. recurrent sneezing & yawning, temperature instability) Onset of symptoms and signs depends on half-life of opioid used

36 NAS Severity Several variables can affect severity Nicotine exposure: number of cigarettes smoked 24 hours prior to delivery & heavy smoking associated with higher cumulative Finnegan score, longer hospital stay Psychiatric medications: antidepressants and antipsychotics associated with longer duration of NAS treatment

37 NAS Complicated by Polydrug Use Neonatal symptoms more severe with polydrug exposure especially combinations of opioids and benzodiazepines Wachman et al. demonstrated that maternal use of methadone and psychiatric medications (including SSRIs, benzodiazepines and others) increased average length of stay from 22.9 days to 26.7, 29.1 and 28.0 days respectively Wachman et al. J Addict Med, 2011.

38 NAS Premature vs. Term Infants Premature infants tend to exhibit less severe NAS than term infants Term infants have longer length of treatment, higher morphine doses for NAS treatment and as a result, longer length of stay Possible explanations for less severe NAS among preterm infants: NAS withdrawal tools designed for term infants, immature development of central nervous system, reduced total exposure to opioids and reduced placental transfer rate

39 NAS Differential Diagnosis NAS needs to be differentiated from other conditions Possible medical causes of clinical symptoms & signs need to be ruled out including: sepsis, hyperviscosity syndromes hypoglycemia, hypocalcemia hyperthyroidism intracranial hemorrhage rule out alcohol and benzodiazepine exposure

40 NAS Antenatal Care Recommendations Pregnant women should be educated antenatally about neonatal withdrawal if participating in opiate substitution programs (methadone or buprenorphine) or using other opioids on a regular basis Local variations may dictate location of infant for monitoring eg. rooming-in vs. special care nursery/neonatal intensive care unit (NICU)

41 NAS Antenatal Care Recommendations (2) The substance-using woman and her partner/family should be prepared and educated in advance for their baby s hospital experience and management of NAS. Every substance using woman should receive written materials explaining NAS, hospital stay expectations, role of the parent, and resource contacts, including the healthcare team.

42 NAS Assessment Various screening tools available for neonatal drugwithdrawal scoring Finnegan neonatal abstinence scoring system Lipsitz neonatal drug-withdrawal scoring system Ostrea tool Neonatal withdrawal inventory Neonatal narcotic withdrawal index Modified Finnegan scoring system most commonly used and best validated tool

43 NAS Assessment (2) For all opioid-exposed infants, an objective NAS scoring tool recommended: to assess severity of withdrawal symptoms and signs to determine initiation of pharmacologic treatment Scoring initiated within hours of life (every 2-4 hours) and continued depending on half-life of opioid for duration of treatment & weaning 72 hours (for short half-life) 120 hours (for longer half-life)

44 NAS MMT vs. BMT NAS profile differs between methadone (MMT) and buprenorphine (BMT) MMT had greater severity for 5 NAS signs Central nervous system hyperirritability (e.g. hyperactive Moro reflex, tremors, excessive irritability) and failure to thrive Nasal stuffiness, sneezing & loose stools more often with BMT

45 NAS MMT vs. BMT (2) Onset of symptoms around hours, with late presentations up to 5-7 days, peaks within hours Difference in median time to initiation of treatment: 36 hours for MMT and 59 hours for BMT associated with differences in pharmacokinetics & transplacental transfer

46 NAS Nonpharmacologic Measures Supportive interventions for all opioid-exposed infants o Support for mother-baby dyad (e.g., rooming in) o Self-soothing behaviors: non-nutritive sucking, swaddling to decrease arousals & prolong sleep o Cuddling, gentle handling, skin to skin contact and infant slings improve behavioural adaptation of infants with NAS

47 NAS Nonpharmacologic Measures (2) o Environmental modification to reduce sensory stimulation (eg. minimize overhead lighting, reduce noise) o Proper positioning, use of gentle firm pressure and gentle vertical rocking can support neonatal selfregulation o Frequent, smaller volume, hypercaloric feeds

48 NAS Pharmacotherapy Pharmacotherapy should be considered for treatment of NAS when supportive measures fail to adequately ameliorate signs of withdrawal and score reaches threshold for treatment Baby should be admitted to special care nursery or pediatric unit if pharmacologic treatment is indicated to allow for cardiorespiratory monitoring. Treatment indicated in up to 40-50%

49 NAS Pharmacotherapy (2) 2 strategies for NAS treatment: 1. Weight-based: medication dose is based on infant s weight (mg/kg basis) 2. Symptom-based: dose is independent of infant s weight, based on NAS score Protocols vary in initial dose, dose increments, weaning dose and initiation of additional treatment

50 NAS Pharmacotherapy (3) Opioids (e.g. morphine) recommended as first-line agents for treatment of NAS Studies have documents benefits of opioids: reduce time to regain birth weight decrease incidence of severe NAS reduce duration of treatment and rate of admission to nursery Morphine is most commonly used

51 NAS Opioids Morphine preparations include: Diluted tincture of opium Preservative-free morphine solution (no alcohol/additives) Methadone is an alternative to morphine: used infrequently Buprenorphine has been shown in preliminary reports as a safe alternative treatment for NAS

52 NAS Adjunctive Treatment Clonidine Clonidine: central alpha2-adrenergic receptor reduces sympathetic outflow (eg. helps to treat tachycardia, hypertension, restlessness and diarrhea) Demonstrated effective second-line agent as an adjunct to high dose morphine to control withdrawal symptoms addition of clonidine to morphine shortens length of treatment by ~30%

53 NAS Adjunctive Treatment Phenobarbital Phenobarbital: long-acting barbiturate Indications for use: maternal polysubstance use combination of opioids with sedatives, alcohol or barbiturates Demonstrated third-line agent to reduce withdrawal severity Clonidine compared to phenobarbital showed that clonidine was associated with shorter duration of NAS treatment

54 NAS Pharmacotherapy Weaning Weaning off pharmacotherapy occurs once neonatal withdrawal symptoms stabilize occurs in inpatient setting Scoring to continue for additional hours after pharmacologic therapy has been discontinued

55 NAS Effect of Breastfeeding Methadone and buprenorphine detected in breast milk Methadone found in low concentrations Earlier studies documented that breastfed infants had lower NAS scores, lower treatment rates and shorter length of stay compared to those who are formula-fed or combination-fed More recent study confirmed trend of reduced severity and duration of NAS in breastfed methadoneexposed infants

56 NAS Effect of Breastfeeding (2) Concentration of buprenorphine in breast milk low, but due to its poor oral bioavailability, infants receive <1% of maternal weight-adjusted dose Recent study results indicated that although 70% of mothers were breastfeeding, 35% of infants required treatment for NAS; not significant difference Another study found breastfeeding buprenorphineexposed infants had lower treatment rates and shorter length of stay

57 Resources Neonatal Abstinence Working Group Convened by the Ontario Provincial Council for Maternal and Child Health (PCMCH) Goal: to address management of NAS resulting from use of opioids Outcome: developed recommendations during preconception, antenatal and postpartum stages based on research evidence and consensus

58 Future Areas of Research Determining different pathways in opioid withdrawal Optimal assessment tool for NAS Optimal protocol for NAS management (ie. weight- vs. symptom-based) Optimal medication for management of NAS Family-integrated neonatal care models

59 Thank you Any questions?

60 References Finnegan L. (2013). Substance abuse in Canada: licit and illicit drug use during pregnancy: Maternal, neonatal and early childhood consequences. Ottawa: ON: Canadian Centre on Substance Abuse. Wong S, Ordean A, Kahan M. Substance use in pregnancy. JOGC. 2011; 33(4): Ordean A, Kahan M. Comprehensive treatment program for pregnant substance users in a family medicine clinic. Canadian Family Physician 2011; 57: e Exposure to Psychotropic Medications and Other Substances During Pregnancy and Breastfeeding: A Handbook for Health Care Providers. Free from CAMH.

61 References (2) Jones HE, Kaltenbach K, Heil SH, Stine SM, et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. NEJM. 2010; 363(24): Ordean A, Chisamore BC. Clinical presentation and management of neonatal abstinence syndrome: an update. Research and Reports in Neonatology 2014; 4: World Health Organization.Guidelines for the identification and management of substance use and substance use disorders in pregnancy