What If This Was The Message?

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1 Association of Single-Nucleotide Polymorphisms, Buprenorphine vs Methadone Maintenance Therapy, and Second/Third Trimester Dose Reduction Strategies with Clinical Outcomes of Neonatal Abstinence Syndrome John B. Standridge, M.D. DFASAM Medical Director, Council for Alcohol and Drug Abuse Services, Inc. Clinical Professor, University of Tennessee College of Medicine Chattanooga Addiction Medicine Physician, Personal Medicine LLC More People Died Of Opioid Overdoses Last Year Than Ever Before Heroin and prescription painkillers drive the overdose epidemic, the CDC finds. 12/18/2015 There were a total of 28,647 overdose deaths, the CDC reported, with nearly two-thirds of overdose deaths related to opioids other than heroin. 28, = 78.5 overdose deaths daily in the US. Drug Overdose Total = 47,055 There has been a distressing rise in neonatal abstinence syndrome as a result of women being exposed to opioids during pregnancy. Misuse by older adults also has become an increasing concern. What If This Was The Message? U.S. CONSUMPTION OF OPIOID PAINKILLERS TENNESSEE OPIATE OD FATALITIES TOTAL , ,302 Although the U.S. comprises less than 5 percent of the world s population, it consumes 80% of the global opioid painkillers and 99% of the global supply of hydrocodone. hydrocodone world USA 143 painkiller prescriptions per 100 people Overdose deaths have overtaken car crashes as the leading cause of accidental death, with nearly 80 people dying from opioid-containing overdoses every day and 2.1 million people addicted to opiates Acute Pain Number of people needed to treat for one person to get 50% pain relief Oxycodone 15 mg Oxycodone 10 mg + acetaminophen 650 mg Naprosyn 500 mg 0 Ibuprofen 200 mg + acetaminophen 500 mg NNT Cochrane Collaboration Also see Pediatrics Feb;135(2): Chronic Pain May 30, 2016 Proceedings of the National Academy of Sciences. OPIOID-INDUCED HYPERALGESIA A University of Colorado study shows that morphine treatment after nerve injury doubles the duration of pain. Opioids signal at an immune receptor expressed in the spinal cord and elsewhere, that recognizes opioids as something that s foreign that needs to be eliminated. It triggers an immune response causing the release of pain molecules that increase the perception of pain in the brain. A glial cell signaling cascade produces a cell signal from a protein called interleukin-1beta (IL-1b), which increases the activity of painresponsive nerve cells in the spinal cord and brain. That can cause increases in pain duration lasting several months. 1

2 Neonatal Abstinence Syndrome is a growing and very expensive burden to society and governmental resources. Methadone dose and neonatal abstinence syndrome-systematic review and meta-analysis. Addiction Dec;105(12): ,139 neonates AIM: To determine if there is a relationship between maternal methadone dose in pregnancy and the diagnosis or medical treatment of neonatal abstinence syndrome (NAS). METHODS: PubMed, EMBASE, the Cochrane Library and PsychINFO were searched for studies reporting on methadone use in pregnancy and NAS ( ). The relative risk (RR) of NAS was compared for methadone doses above versus below a range of cut-off points. Summary RRs and 95% confidence intervals (CI) were estimated using random effects meta-analysis. Sensitivity analyses explored the impact of limiting meta-analyses to prospective studies or studies using an objective scoring system to diagnose NAS. RESULTS: A total of 67 studies met inclusion criteria for the systematic review; 29 were included in the meta-analysis. Any differences in the incidence of NAS in infants of women on higher compared with lower doses were statistically non-significant in analyses restricted to prospective studies or to those using an objective scoring system to diagnose NAS. CONCLUSIONS: Severity of the neonatal abstinence syndrome does not appear to differ according to whether mothers are on high- or low-dose methadone maintenance therapy. 2

3 Methadone dose and neonatal abstinence syndrome-systematic review and meta-analysis. Addiction Dec;105(12): COMMENTARY: The authors acknowledged that the lack of blinded assessment of NAS meant that the diagnosis of NAS was potentially biased by knowledge of the maternal methadone dose in the majority of studies. In addition, most studies did not assess the effect of potentially confounding factors on the incidence of NAS. Many of the included studies were small, with around half of the studies including less than 50 neonates. These quality concerns reduce the reliability of the results of the included studies, although they were mitigated by the use of sensitivity analyses restricted to the better quality studies in the review. This was a well-conducted systematic review and the authors' conclusions are likely to be reliable. However, it should be noted that no evidence of a statistically significant difference does not necessarily mean that there is no difference. Methadone dose and neonatal abstinence syndrome-systematic review and meta-analysis. Addiction Dec;105(12): FURTHER ANALYSIS: Using a range of cut-off points, there was no statistically significant difference in the incidence of NAS between lower and higher methadone dosage groups for most cut-off values, with the exception of the cut-off values of 20mg (RR 0.52, 95% CI 0.33 to 0.81; 10 studies; Ι²=67%) and 40mg (RR 0.69, 95% CI 0.51 to 0.94; nine studies; Ι²=65%); corresponding to a 48% reduction in the risk of NAS for pregnant women taking methadone at a dose of 20mg or less and a 31% reduction in the risk of NAS for pregnant women taking methadone at a dose of 40mg or less. There was substantial statistical heterogeneity for most of the comparisons. In sensitivity analyses that included only studies that used an objective scoring system and prospective studies only, the results were no longer statistically significant for the cut-off values of 20mg and 40mg. Nineteen studies found a relationship between methadone dose and the incidence, severity or duration of NAS, 18 did not find such a relationship and 30 studies did not report on the relationship between methadone dose and NAS. The Effect of Methadone Dose Regimen on Neonatal Abstinence Syndrome. Journal of Addiction Medicine McCarthy, John J. MD; Leamon, Martin H. MD; Willits, Neil H. PhD; Salo, Ruth PhD Objectives: To evaluate the effects of a multiple daily dose methadone regimen in pregnancy on neonatal outcomes. Methods: Although methadone maintenance has been the standard for the treatment of opioid dependence in pregnancy, there is no consensus on proper dosing. Single daily dosing is the most common strategy. Because of accelerated metabolism of methadone in pregnancy, this regimen may expose mother and fetus to daily episodes of withdrawal and possibly contribute to more severe Neonatal Abstinence Syndrome (NAS). This study reports on a protocol that increased both methadone dose and dose frequency in response to maternal reports of withdrawal. The Effect of Methadone Dose Regimen on Neonatal Abstinence Syndrome. Journal of Addiction Medicine McCarthy, John J. MD; Leamon, Martin H. MD; Willits, Neil H. PhD; Salo, Ruth PhD Results: Treatment of NAS was needed in 29% of neonates, compared to a published rate of 60% to 80%. The mean methadone dose was 152 mg at delivery, divided into 2 to 6 doses per day. Ninety-two percent of mothers were free of illicit drug use at delivery. There was no relationship between methadone dose and treatment of NAS. Female babies had a treatment rate of 16% versus 38% for male babies. Beyond abstinence symptoms, cohort outcomes in terms of gestational age, birth weight, prematurity, Caesarian sections, and breastfeeding equaled or approximated US population norms. Conclusions: The protocol was associated with low rates of treatment of NAS and high rates of maternal recovery. High rates of treatment for NAS reported in methadone-exposed neonates might relate in part to iatrogenic factors and be reduced through the use of divided daily doses and protocols that minimize maternal withdrawal. Neonatal Abstinence Syndrome after Methadone or Buprenorphine Exposure NEJM Dec:363;24, Background Methadone, a full mu-opioid agonist, is the recommended treatment for opioid dependence during pregnancy. However, prenatal exposure to methadone is associated with a neonatal abstinence syndrome (NAS) characterized by central nervous system hyperirritability and autonomic nervous system dysfunction, which often requires medication and extended hospitalization. Buprenorphine, a partial mu-opioid agonist, is an alternative treatment for opioid dependence but has not been extensively studied in pregnancy. Results Treatment was discontinued by 16 of the 89 women in the methadone group (18%) and 28 of the 86 women in the buprenorphine group (33%). A comparison of the 131 neonates whose mothers were followed to the end of pregnancy according to treatment group (with 58 exposed to buprenorphine and 73 exposed to methadone) showed that the former group required significantly less morphine (mean dose, 1.1 mg vs mg; P<0.0091), had a significantly shorter hospital stay (10.0 days vs days, P<0.0091), and had a significantly shorter duration of treatment for the neonatal abstinence syndrome (4.1 days vs. 9.9 days, P< ) (P values calculated in accordance with prespecified thresholds for significance). There were no significant differences between groups in other primary or secondary outcomes or in the rates of maternal or neonatal adverse events. Conclusions These results are consistent with the use of buprenorphine as an acceptable treatment for opioid dependence in pregnant women. Neonatal Abstinence Syndrome after Methadone or Buprenorphine Exposure N Engl J Med 2010; 363: December 9, 2010 Buprenorphine treatment in pregnancy: less distress to babies NIH study compares buprenorphine to methadone in opioid addicted pregnant women Compared to methadone, buprenorphine resulted in similar maternal and fetal outcomes, yet had lower severity of NAS symptoms, thus requiring less medication (1.1 versus 10.4 milligrams) and less time in the hospital for their babies (10 versus 17.5 days). The Maternal Opioid Treatment: Human Experimental Research (MOTHER) was one of the first to prospectively follow opioiddependent pregnant women from enrollment until at least 28 days after giving birth. The eight-site international study included 131 mothers and their newborns. Dr. Hendree Jones, the primary study author said, "We were pleased to be able to identify a medication that lessens the withdrawal distress to newborns, and gets them out of the hospital more quickly." 3

4 Journal of Addiction Medicine: published ahead of print Methadone and Buprenorphine for Opioid Dependence During Pregnancy: A Retrospective Cohort Study. Meyer, Marjorie C. MD; Johnston, Anne M. MD; Crocker, Abigail M. PhD; Heil, Sarah H. PhD Objectives: To compare maternal characteristics, prenatal care, and newborn outcomes in a cohort of opioid-dependent pregnant women treated with methadone versus buprenorphine. Methods: In a retrospective cohort study, 609 pregnant, opioiddependent women were treated with methadone (n = 248) or buprenorphine (n = 361) between 2000 and 2012 at a single institution. Results: Mothers treated with buprenorphine were more likely to start medication before or earlier in pregnancy, had longer gestation, and gave birth to larger infants. Newborns of buprenorphine versus methadone-maintained mothers required treatment for neonatal abstinence significantly less often and for a shorter duration. Journal of Addiction Medicine: published ahead of print March 2015 Methadone and Buprenorphine for Opioid Dependence During Pregnancy: A Retrospective Cohort Study. Meyer, Marjorie C. MD; Johnston, Anne M. MD; Crocker, Abigail M. PhD; Heil, Sarah H. PhD Results: Mothers treated with buprenorphine were more likely to start medication before or earlier in pregnancy, had longer gestation, and gave birth to larger infants. Newborns of buprenorphine versus methadone-maintained mothers required treatment for neonatal abstinence significantly less often and for a shorter duration. Methadone n=248 Buprenorphine n=361 EGA (weeks) Preterm (EGA <37 weeks) 17% 10% Birth Weight (grams) Infants Treated for NAS 42% 23% Journal of Addiction Medicine: published ahead of print Methadone and Buprenorphine for Opioid Dependence During Pregnancy: A Retrospective Cohort Study. Medication Dose at Delivery Meyer, Marjorie C. MD; Johnston, Anne M. MD; Crocker, Abigail M. PhD; Heil, Sarah H. PhD Conclusions: These data suggest pregnancy outcomes with buprenorphine to treat opioid dependence during pregnancy in clinical practice are as good and often better than outcomes with methadone. These results are consistent with efficacy data from randomized clinical trials and further support the use of buprenorphine for the treatment of opioid dependence during pregnancy. Neonatal Abstinence Syndrome after Methadone or Buprenorphine Exposure Methadone and Buprenorphine for Opioid Dependence During Pregnancy: A Retrospective Cohort Study. Methadone Buprenorphine 78.2 mg 16.2 mg 87.4 mg 15.4 mg Association of OPRM1 and COMT Single-Nucleotide Polymorphisms With Hospital Length of Stay and Treatment of Neonatal Abstinence Syndrome MAIN OUTCOMES AND MEASURES: Primary outcome measure was length of hospital stay, with between-group differences expressed as β and calculated with linear regression models. Secondary outcome measures included need for any medical treatment for NAS and treatment with 2 or more medications. RESULTS: Infants with the OPRM1 118A>G AG/GG genotype had shortened length of stay (β = -8.5 days; 95% CI, to -2.1 days; P =.009) and were less likely to receive anytreatmentthan AA infants (48% vs 72%; adjusted odds ratio, 0.76; 95% CI, ; P =.006). The COMT 158A>G AG/GG genotype was associated with shortened length of stay (β = days; 95% CI, to -3.4 days; P =.005) and less treatment with 2 or more medications (18% vs 56%; adjusted odds ratio, 0.68; 95% CI, ; P =.001) than the AA genotype. Associations with the ABCB1 SNPs were not significant. CONCLUSIONS AND RELEVANCE: Among infants with NAS, variants in the OPRM1 and COMT genes were associated with a shorter length of hospital stay and less need for treatment. These preliminary findings may provide insight into the mechanisms underlying NAS. JAMA. 2013;309(17):

5 Detoxification from opiate drugs during pregnancy Jennifer Bell, MD, Craig V. Towers, MD, Mark D. Hennessy, MD, Callie Heitzman, RN, Barbara Smith, Katie Chattin Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Tennessee Medical Center, Knoxville, TN Results Over 5.5 years, 301 opiate-addicted pregnant patients were fully detoxified during pregnancy with no adverse fetal outcomes related to detoxification identified. There were 94 patients who delivered newborns treated for neonatal abstinence syndrome (31%). There was an 18.5% rate of neonatal abstinence syndrome in the 108 acutely detoxified while incarcerated, a 17.4% rate of neonatal abstinence syndrome in the 23 who had inpatient detoxification with intense outpatient follow-up management, a 17.2% rate of neonatal abstinence syndrome in the 93 who went through slow outpatient buprenorphine detoxification, but a 70.1% rate of neonatal abstinence syndrome in the 77 who had inpatient detoxification without intense outpatient follow-up management. Conclusion With these data and other published studies, more than 600 patients have been reported to detoxify from opiates during pregnancy with no report of fetal harm related to the process. These data highly suggest that detoxification of opiate-addicted pregnant patients is not harmful. The rate of neonatal abstinence syndrome is high but primarily when no continued long-term follow-up occurs. Once a patient is drug free, intense behavioral health follow-up is needed for continued success. Association of OPRM1, COMT and Other Single-Nucleotide Polymorphisms, Buprenorphine vs Methadone Maintenance Therapy, and Third Trimester Dose Reduction Strategies With Hospital Length of Stay and Treatment of Neonatal Abstinence Syndrome John B. Standridge, MD; Principle Investigator The primary objective of this study is to determine whether genomic variations in the OPRM1 and COMT genes are associated with length of hospital stay (LOS) and the need for treatment of NAS. Another primary objective of this study is to confirm the findings of the MOTHER trial, namely that neonates exposed in utero to buprenorphine required significantly less morphine, had a significantly shorter hospital stay, and had a significantly shorter duration of treatment for the neonatal abstinence syndrome as compared to neonates exposed in utero to methadone; but factoring for differences in MED. A third primary objective of this study is to generate a study protocol that allows and encourages a near-term tapering of methadone and buprenorphine prior to delivery directed at establishing best practices methodology to proactively alleviate NAS severity. A fourth primary objective of this study is to refine a NAS Risk Index by developing and using a multiplicative formulaic algorithm of genetic, social, and pharmacologic data in order to establish predictive and best practices recommendations to enhance the clinical management of NAS. SNP-NAS The SNP-NAS* study is one for which I am the principle investigator. We will collect genetic materials (cheek swabs) on opioid dependent mothers and their babies with a goal of predicting, reducing the severity, and in some cases preventing neonatal abstinence syndrome (NAS). Mothers who are currently pregnant or who delivered after January 1, 2014, are eligible. One aspect of the study of interest is the research question comparing methadone with buprenorphine relative to NAS length of stay. The MOTHER trial, published in the NEJM, suggested that buprenorphine had better outcomes, but that study did not compare equivalent doses, whereas SNP-NAS will compare equivalent doses. * SNP-NAS refers to Association of Single-Nucleotide Polymorphisms, Buprenorphine vs. Methadone Maintenance Therapy, and Second/Third Trimester Dose Reduction Strategies with Clinical Outcomes of Neonatal Abstinence Syndrome. Study Objectives Genetic variation 1. Confirm the findings of the MOTHER trial, taking into account both drug-drug and dose-dose comparisons 2. Determine whether other genetic variations are associated with NAS outcomes and treatments, maintenance treatment 3. Evaluate a protocol for near-term tapering of methadone or buprenorphine prior to delivery that alleviates NAS severity and/or neonate length of hospital stay 4. Determine whether genetic variations are associated with the mother s ability to taper successfully 5. Establish evidence-based treatment guidance, using an algorithm of clinical, phenotypic, and genetic variables, that can enhance the clinical management of opioid-dependent mothers and neonates with NAS. Humans share 99.9% of their DNA The remaining 0.1% is what sets us apart from one another Physical appearance Susceptibility to disease Response to medications We can detect the sequence of DNA and identify changes that may make one patient more susceptible to a disease, or respond differently to a medication, than another patient. Reduce trial-and-error Avoid unnecessary treatment 5

6 SNPs : Single Nucleotide Polymorphisms DNA is composed of nucleotides: SNPs are polymorphisms at the single nucleotide level Not the same as a mutation! A SNP has to be present in at least 1% of population Our DNA has ~10 million SNPs. One gene may have 1000s of SNPs Where to look? SNPs associated with drug response Pharmacodynamics: Site of action What the drug does to the body Sometimes it is necessary to look at a combination of SNPs together 31 Analgesia Violin JD et al Trends in Pharmacological Sciences. 35(7) Pharmacokinetics: Metabolism What the body does to the drug SNPs in candidate pharmacodynamic genes have already been identified as important influences on opioid addiction risk and moderators of response to opioid therapy Where to look? Gene Disorder Serotonin 2A Receptor Alcohol abuse 6 Anxiety 7 Depression 8 Drug Abuse 9 Serotonin Transporter Alcohol abuse 10 Substance abuse 11 Catechol-O-Methyltransferase Alcohol abuse 12 Methamphetamine abuse 13 Dopamine D2 Receptor Alcohol, cocaine, nicotine dependence 14 Dopamine D1 Receptor Heroin addiction 15,16 Dopamine D4 Receptor Drug abuse 17 Dopamine Transporter Cocaine addiction 18 Dopamine Beta Hydroxylase Methylene Tetrahydrofolate Reductase Methamphetamine addiction 19 Alcohol abuse 20 Cocaine addiction 20,21 Smoking addiction 22 Bipolar disorder, depression, schizophrenia 23 Human Kappa Opioid Receptor Alcohol abuse 24 Gamma-Aminobutyric Acid Alcohol abuse 25 Methamphetamine dependence 26 Human Mu Opioid Receptor Complex regional pain syndrome 27 Heroin dependence 28 Where to look? SNPs in reward pathways have been discovered to be specifically associated with NAS severity These SNPs explained 6-15% of the variability in infant length of hospitalization Mu-opioid receptor (OPRM1) Kappa-opioid receptor (OPRK1) Delta-opioid receptor (OPRD1) Catechol-O-Methyltransferase (COMT) E.M. Wachman, M.J. Hayes, M.S. Brown, J. Paul, K. Harvey-Wilkes, N. Terrin, G.S. Huggins, J.V. Aranda, J.M. Davis. Association of OPRM1 and COMT single nucleotide polymorphisms with hospital length of stay and treatment of neonatal abstinence syndrome. JAMA, 309 (2013), pp E.M. Wachman, M.J. Hayes, R. Sherva, M.S. Brown, J.M. Davis, L.A. Farrer, D.A. Variations in opioid receptor genes in neonatal abstinence syndrome. Drug and Alcohol Dependence, 155 (2015), pp Variants in the OPRM1 and COMT genes are associated with better NAS outcomes OPRM1: Mu opioid receptor E.M. Wachman, M.J. Hayes, M.S. Brown, J. Paul, K. Harvey-Wilkes, N. Terrin, G.S. Huggins, J.V. Aranda, J.M. Davis. Association of OPRM1 and COMT single nucleotide polymorphisms with hospital length of stay and treatment of neonatal abstinence syndrome. JAMA, 309 (2013), pp Major site of action for endogenous and exogenous opioids Receptor binding results in disinhibition of dopaminergic neurons Dopamine influx = reward SNP 118A>G (Asp40Asn) : most studied variant Less binding site availability Reduced receptor density G allele (AG or GG genotypes) has been associated with opioid dependence and opioid addiction, alcohol abuse in adults G allele has been found to be associated with less severe withdrawal in NAS infants and decreased need for infant treatment O. Levran, V. Yuferov, M.J. Kreek. The genetics of the opioid system and specific drug addictions. Hum. Genet., 131 (2012), pp

7 TOXICITY TOXICITY CYP2C19 CYP2B6 UGT UGT 6/10/2016 EFFICACY Pharmacokinetic SNPs lead to metabolism abnormalities Active medication Increased inactivation of a drug Decreased inactivation of a drug e.g. Methadone Suboxone Prodrug Drug Metabolism Abnormalities Medically-assisted treatments are metabolized by enzymes subject to common polymorphisms that could greatly influence fetal exposure METHADONE CYP3A4 (other inactive metabolites) EDDP (inactive) e.g. Codeine Tramadol Hydrocodone Increased activation of a prodrug Decreased activation of a prodrug EFFICACY 38 CYP3A4 BUPRENORPHINE NORBUPRENORPHINE Buprenorphine-3-glucuronide Norbuprenorphine-3-glucuronide The MOTHER Trial: Does dose make a difference? 78.2 mg 30 mg Ceiling effect However, caution needs to be taken with dose-dose comparisons, and adjustment for CYP abnormalities. Other: Efflux pumps The ABC transporter P-glycoprotein decreases fetal exposure to compounds present in the maternal circulation Extrudes substrates from the fetal to maternal direction The ABCB1 p-glycoprotein gene has considerable genetic variability C3435T, C1236T, G2677A/T variants result in reduced efflux activity Individuals with decreased P-gp activity may be at greater risk of potential fetal exposure S.J. Hemauer, T.N. Nanovskaya, S.Z. Abdel-Rahman, S.L. Patrikeeva, G.D. Hankins, M.S. Ahmed. Modulation of human placental P- glycoprotein expression and activity by MDR1 gene polymorphisms. Biochem. Pharmacol., 79 (6) (2010), pp Determine whether genomic variations in the OPRM1 and COMT genes are associated with length of hospital stay (LOS) and the need for treatment of NAS 1. Determine whether genomic variations in the OPRM1 and COMT genes are associated with length of hospital stay (LOS) and the need for treatment of NAS RESULTS: Infants with the OPRM1 118A>G AG/GG genotype had shortened length of stay (β = -8.5 days; 95% CI, to -2.1 days; P =.009) and were less likely to receive any treatment than AA infants (48% vs 72%; adjusted odds ratio, 0.76; 95% CI, ; P =.006). The COMT 158A>G AG/GG genotype was associated with shortened length of stay (β = days; 95% CI, to -3.4 days; P =.005) and less treatment with 2 or more medications (18% vs 56%; adjusted odds ratio, 0.68; 95% CI, ; P =.001) than the AA genotype. Associations with the ABCB1 SNPs were not significant. CONCLUSIONS AND RELEVANCE: Among infants with NAS, variants in the OPRM1 and COMT genes were associated with a shorter length of hospital stay and less need for treatment. These preliminary findings may provide insight into the mechanisms underlying NAS. JAMA. 2013;309(17): Retrospectively, we will compare not just OPRM1 and COMT genes, but also the 12 SNPs that comprise an Opioid Risk Index validated to predict risk of opioid dependency in chronic pain patients. Additionally 128 SNPs will be analyzed individually and in combination through complex algorithm development software to identify and give weight to other genetic associations. Potentially will assess as many as 1200 mother-infant dyads with documented NAS between Jan. 1, 2015, and Dec 31,

8 % Receptor Occupancy 6/10/ Determine whether genomic variations in the OPRM1 and COMT genes are associated with length of hospital stay (LOS) and the need for treatment of NAS 2. Confirm the findings of the MOTHER trial, namely that neonates exposed in utero to buprenorphine required significantly less morphine, had a significantly shorter hospital stay, and had a significantly shorter duration of treatment for the neonatal abstinence syndrome as compared to neonates exposed in utero to methadone; but factoring for differences in MED. Is the advantage quantitative or qualitative? Outcomes to be associated with the genetic data include: Opiate(s) used during pregnancy and the week prior to delivery Dose(s) used during pregnancy and the week prior to delivery Occurrence v non-occurrence of NAS Hospital L.O.S. Total dose(s) of morphine and/or other detox regimen drugs Modified Finnegan scores, where available Neonatal Abstinence Syndrome after Methadone or Buprenorphine Exposure 78.2 mg Methadone 16.2 mg Buprenorphine Methadone and Buprenorphine for Opioid Dependence During Pregnancy: A Retrospective Cohort Study mg Methadone 15.4 mg Buprenorphine Effects of Buprenorphine Dose on μ -Opioid Receptor Availability It is difficult to know dose equivalencies of methadone relative to buprenorphine to 92% 94 to 98% Clinical guidelines have recommended patients with 90 levels of physical dependence greater than 30 mg of daily methadone should not be given acute doses of to 47% buprenorphine because of the risk of precipitated withdrawal (McNicholas, 2004) It is quite common for patients to have levels of 10 physical dependence that are higher than that 0 2 mg 16 mg 32 mg produced by 30 mg per day of methadone, so this Dose recommendation makes it problematic to consider transferring such patients to sublingual buprenorphine. Source: Greenwald, MK et al, Neuropsychopharmacology 28, , Generate a study protocol that allows and encourages a near-term tapering of methadone and buprenorphine prior to delivery directed at establishing best practices methodology to proactively alleviate NAS severity 3. Generate a study protocol that allows and encourages a near-term tapering of methadone and buprenorphine prior to delivery directed at establishing best practices methodology to proactively alleviate NAS severity Suggestions for a Buprenorphine Tapering Program Allow study participants to choose whether to maintain full current doses or to taper gradually and comfortably to some lower dose. Compare these 2 groups with regard to NAS severity outcomes. Occurrence v non-occurrence of NAS Hospital L.O.S. Total dose(s) of morphine and/or other detox regimen drugs Modified Finnegan scores Congratulations on your decision to reduce the dose of your buprenorphine during your pregnancy. Your baby should have a much better introduction to this world as a result of your efforts. Our goal with this tapering program is to reduce the dose of buprenorphine very gradually, so that it remains safe and comfortable for both you and your baby. The suggestions are not rigid, but rather very flexible. If at any time you feel uncomfortable with craving or even mild withdrawal symptoms, we encourage you to increase your dose back to a level that is comfortable and free of craving. This is an intent to taper. All that is necessary is the intention. If you cannot taper comfortably, you do not have to. Most women are motivated and able to taper comfortably to the doses suggested below. We also ask that you do not reduce your dose too fast. The following suggestion goes down on the dose at a rate of about 1 mg per week, and then only one-half mg per week. The suggested tapering program below shows a woman starting at 16 mg, but you might be on more or less than that. That is okay. You should taper from the dose you are already taking, and just use the numbers below as a guideline. Remember, if the new lower dose is not comfortable, you can raise your dose to a level that is comfortable. 8

9 3. Generate a study protocol that allows and encourages a near-term tapering of methadone and buprenorphine prior to delivery directed at establishing best practices methodology to proactively alleviate NAS severity Safety of mother-fetal dyads remains paramount Mothers will have sufficient buprenorphine to go up on doses prn discomfort, craving, or concern 16 mg alternating with 12 mg for 2 weeks, then 12 mg daily for 2 weeks, then 12 mg alternating with 10 mg for 2 weeks, then 10 mg daily for 2 weeks, then 10 mg alternating with 8 mg for 2 weeks, then 8 mg daily for 2 weeks, then 8 mg alternating with 6 mg Continue this pattern until pre-delivery dose of 4mg or so 3. Generate a study protocol that allows and encourages a near-term tapering of methadone and buprenorphine prior to delivery directed at establishing best practices methodology to proactively alleviate NAS severity The following suggestion goes down on the dose at a rate of 2.5 mg per week. The suggested tapering program below shows a woman starting at 80 mg, but you might be on more or less than that to start with. That is okay. You should taper from the dose you are already taking, and just use the numbers below as a guideline. Remember, if the new lower dose is not comfortable, you can raise your dose to a level that is comfortable. Divide your daily dose into two doses if you can. Tapering weeks 1 & 2 80 mg one day alternating with 70 mg the next day Weeks 3 & 4 70 mg daily Weeks 5 & 6 70 mg one day alternating with 60 mg the next day Weeks 7 & 8 60 mg daily Weeks 9 & mg one day alternating with 50 mg the next day Weeks 11 & mg daily for 2 weeks, Weeks 13 & mg one day alternating with 40 mg the next day Weeks 15 & mg daily for 2 weeks. Continue this pattern as long as you can comfortably until the dose is 20 mg or 30 mg every day. Do not taper completely off of the medicine. 4. Refine a NAS Risk Index by developing and using a multiplicative formulaic algorithm of genetic, social, and pharmacologic data in order to establish predictive and best practices recommendations to enhance the clinical management of NAS Case History Thanks for all you do! Patient RC felt well on 6 mg/day of buprenorphine prior to delivery after tapering gradually from 16 mg/day of buprenorphine. She delivered twin boys, 6# 1 oz and 6# 10 oz, on 7/2/15. They are nearly 25# and 21# now. They had no treatment needed for NAS. She says the buprenorphine has been extremely helpful. She graduated IOP and goes to AA meetings more often than NA. She is attending the New Way meetings. She is feeling alright on mg/day; she rarely craves or has tachycardia and anxiety. She has no time for anything but "bottles and diapers", but she is here today with the boys and her mother. She is doing well and thriving. 9