Bethesda, MD Association for Medical Education and Research in Substance Abuse November 1, 2012 Betty Ford Award Plenary Address

Treating Opioid-dependent Women during Pregnancy: How Research Findings Can Inform Clinical Practice 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 2 medications, methadone and buprenorphine. Neither medication is approved for use in pregnant women. Both 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

Acknowledgements

     

Study patients and infants Staff at the Center for Addiction and Pregnancy, Behavioral Pharmacology Research Pharmacy and Nursing staff Johns Hopkins University Co-Investigators:

–

Drs. Donald Jasinski, Lauren Jansson, Robert Dudas, Lorraine Milio, Martha Velez, Vickie Walters, Eric Strain, George Bigelow National Institute on Drug Abuse

–

R01 DAs: 015764, 015738, 017513, 015778, 018410, 018417, 015741, 15832 Maternal Opioid Treatment: Human Experimental Research (MOTHER) Site PIs and investigative teams Reckitt-Benckiser Pharmaceuticals Inc. for active and placebo Subutex tablets

4

Outline

•

Historical and current context of opioid use and opioid agonist treatment during pregnancy

•

Comparison of methadone v. buprenorphine: maternal and neonatal outcomes

♦

Primary and secondary outcome findings

♦

Latest key secondary analysis study results

♦

Impact of behavioral intervention for smoking cessation

•

Clinical implications and unanswered questions

5

Historical Context

• • •

Concern over pregnant women using substances in the United States has been an important health issue in the United States for more than a century: In the 1800s, 66 –75% of individuals with opium use disorders were women The most common substance source of opium for women was medical prescriptions to treat pain During the late 1800s physicians recognized the neonatal opioid withdrawal syndrome, and the need to treat the newborns of mothers who had taken opium during pregnancy with morphine in order to prevent morbidity and mortality Kandall, Substance and shadow, 1996. Earle, Medical Standards, 1888.

6

Historical Context

♦ ♦ ♦ ♦ ♦

By the 1900s physicians becoming better educated about the drawbacks of prescribing narcotics, and legitimate supplies of narcotics then shrank Women unable to stop using substances were forced to seek them from illegitimate sources Passage of the Harrison Narcotic Act of 1914 greatly changed narcotic prescribing and dispensing practices, requiring that addictive substances needed to be prescribed by a licensed health professional Some enlightened physicians treated opioid addiction with morphine In 1919, this practice was prohibited by the Supreme Court

►

Result: Segregation of the treatment of substance use disorders from general medical practice Kandall, Substance and shadow, 1996.

7

Historical Context: Methadone

• • • • •

Schedule II opioid Synthetically derived μ opioid receptor agonist Antagonist at NMDA receptors Half-life estimated to fall in the range of 24-36 hours

8

Historical Context: 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

9

Historical Context

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. Neonatal abstinence syndrome. In: R.A. Hoekelman, S.B. Friedman, N.M. Nelson and H.M. Seidel, Editors, Primary Pediatric Care (2nd ed.), Mosby Year Book, St. Louis, MO 1992):1367 –1378.

10

Historical Context

40 years of documented benefits of methadone during pregnancy



Prevention of erratic maternal opioid levels lessens fetal exposure to repeated withdrawal episodes

 

Reduces fetal exposure to illicit drugs Decreases risks to fetus of infection from HIV, hepatitis and sexually transmitted infections



Reduces the incidence of obstetrical and fetal complications



Improves newborn outcomes Review by Kaltenbach et al., Obstet Gynecol Clin North Am 1998.

11

Historical Context

   

In the 1970s , a positive relationship between maternal methadone dose and NAS severity was reported Thus, early recommendations were to maintain pregnant women on methadone doses between 20 to 40 mg per day Subsequently, 3 decades of research have shown an inconsistent relationship between maternal methadone dose and NAS severity Only in the last 10 years have pregnant women been appropriately medicated using the same principles as those used for non-pregnant patients Review by Cleary et al., Addiction. 2010.

12

Historical Context

Methadone Dosing during Pregnancy



Often methadone dose needs adjustment upwards as gestational age increases



Greater plasma volume



Increased renal blood flow



Induction of CYP3A



Possible contribution of CYP3A7 from fetus

12

Pond et al., 1985; Swift et al., 1989; Jarvis et al., 1999; Wolff et al., 2004

13

Historical Context

Fetal Physiologic Effects of Maternal Methadone Administration Trough mean

    

Heart Rate HR Variability # Accelerations Movement Bouts 136.5

5.9

3.6

66.8

Movement Duration 26.9



Motor Activity Total 1627.8 Peak mean 128.3* 3.7* 0.5* 63.6

13.7* 880.1* * p < .05

Jansson et al., 2005

13

14

Historical Context

140 120 100 80 60 40 20 0 Days Retained in CAP Treatment 122 14 104 30 95 100 80 60 40 20 % Mothers with Positive Urine Drug Screen at Delivery 53 57 3 meth taper (n=67) 3 meth taper+MM (n=8) 7 meth taper (n=28) 7 meth taper+MM (n=20) MM (n=52) 33

MM = Methadone Maintenance

23 15 0 Methadone Tapering v. Maintenance



Guidance regarding tapering v. maintenance was based largely on sound clinical judgment



Methadone maintenance facilitates retention of patients and reduces drug use



Biggest concern with methadone during pregnancy is the potential for occurrence of a neonatal abstinence syndrome Jones et al., 2008.

14

15

Historical Context: Summary



For over 4 decades methadone has been the recommended standard of care for treating opioid-dependent pregnant patients



Methadone maintenance is superior to tapering for pregnant patients



Maternal methadone dosing may need to be increased as gestational age advances



Fetal heart rate and variability as well as fetal movements are reduced following single daily dosing of methadone



NAS is an expected yet treatable complication in methadone exposed infants

15

16

Current Context

100 80 60

National Survey on Drug Use and Health 2008/9

Past Month Use

Any Illicit Drug Marijuana Cocaine Opioids Alcohol Tobacco

40 20  0

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; Patrick et al., JAMA, 2012.

17

Current Context

Weighted National Estimates of the Rates of Maternal Opiate Use per 1000 Hospital Births per Year 5.63

6 5

  

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. 4 3 2 1 1.2

1.25

2.2

0 2000 2003 2006 2009 100

in the United States —one infant every hour—suffers from neonatal abstinence syndrome (NAS)

Low Birthweight, Respiratory Diagnoses, and Medicaid Coverage in 2009 Weighted National Estimates of the Rates of NAS per 1000 Hospital Births per Year 78.1

80 4 3.4

60 3 45.5

40 30.9

1.8

19.1

2 1.5

20 7 1.2

0.7

1 0 Low Respiratory Medicaid Birthweight Diagnoses Coverage NAS neonates non-NAS neonates 0 2000 2003 2006 2009

18

Current Context

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.

19

Current Context

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.

20

Current Context

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 century vital sign in the early 21 st



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.

21

Current Context

Issues facing pregnant drug users and their children

     

Exposure to violence and trauma Generational drug use Lack of formal education Lack of job acquisition and maintenance skills Gender inequality/male focused 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

22

Current Context

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

22

Stable caregiver and environment



Nutrition

22

23

Current Context



Comprehensive Care

Interdisciplinary approach

–

Psychiatry

– – – – –

Psychology Obstetrics Pediatrics Nursing Social Work



Multiple modalities

–

Medically-assisted withdrawal and aftercare

–

Methadone with behavioral treatment

23

24

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

24

25

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 24-60 hours Reviews in Jones et al., Drugs, 2012, and Addiction, 107 (Suppl. 1), 5 –27.

26

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, 107 (Suppl. 1), 5 –27.

27

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, 107 (Suppl. 1), 5 –27.

28

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, 107 (Suppl. 1), 5 –27.

29

PROMISE Study

% Treated for NAS 50 40 30 20 10 120 100 80 60 40 20 Morphine drops Birth weight (gm) 5000 4000 3000 2000 1000 Neonatal length of stay 10 * P=.021. p = .021

8 6 4 2



PROMISE study combined with double-blind RCT in Vienna (Fischer et al., 2006) provided preliminary data 0 20 15 10 5 0

■

Methadone (n=11) % NICU treatment APGAR at 1 minute 0

■

Buprenorphine (n=10, 1 twin set) 0 APGAR at 5 minutes Length (cm) Head circumference (cm) 10 10 80 50 8 8 60 40 6 6 30 40 4 4 20 20 2 2 10 0



The advancement of treatment research for opioid-dependent pregnant women may be best served through a multisite international network able to conduct randomized controlled trials 0 0 0 0 Jones et al., Drug Alcohol Depend, 2005.

29

30

Location of MOTHER Study Sites

Lead Site Johns Hopkins U PI: H Jones Brown U PI: B Lester Thomas Jefferson U PI: K Kaltenbach U Vermont PI: S Heil U Vienna PI: G Fischer U Toronto PI: P Selby Vanderbilt U PI: P Martin Wayne State U PI: S Stine Coordinating Center PI: A Arria * * * * * * * *

31

MOTHER Study: Participants

        

Eligibility

18 to 40 years of age Gestational age 6 to 30 weeks Opioid-dependent (DSM-IV, SCID I) Opioid-positive urine Single-fetus pregnancy Plan to deliver at site hospital No medical or other conditions contraindicating participation No pending legal action potentially preventing participation Without benzodiazepine or alcohol disorders Jones et al., N Engl J Med, 2010.

32

MOTHER Study: Design

MOTHER Experimental Design

Cocaine + Early EGA Late EGA Cocaine Buprenorphine Initial consent Screening Medical clearance Early EGA Late EGA Methadone

•

Randomized clinical trial

–

8 sites

–

Double-blind

–

Double-dummy

– –

Stratified Parallel group

–

Flexible dosing:

♦

20 to 140 mg methadone

♦

2 to 32 mg buprenorphine

 

Pre-delivery



Induction Daily dosing Weekly assessments 28 days Post-delivery Jones et al., N Engl J Med, 2010.

33

Refused participation (n=243)

MOTHER Study: Screening

Screened (N=1,074) at 8 sites Excluded (n=656) Randomized (n=175) at 7 sites Failed to meet inclusion criteria (n=557)



27% outside EGA range (n=149)



22% benzodiazepine use (n=124)



19% medical reason (n=105)



10% alcohol use (n=57) Jones et al., N Engl J Med, 2010.

34

Buprenorphine (n=86)

MOTHER Study: Randomization

Randomized (n=175) at 7 sites Methadone (n=89) Completed (n=58) Premature discontinuance (n=28) 20 Dissatisfied with medication 2 Completed (n=73) Premature discontinuance (n=16) Jones et al., N Engl J Med, 2010.

35

MOTHER Study: Baseline Comparisons

MOTHER Results Baseline: Completers

Maternal age in years Race White Black Other Years of education Employed Legal status (uninvolved) Estimated weeks of gestational age at study entry

Total Sample (N=131)

% or Mean (SE) 26.6 (.5)

Methadone (n=73)

% or Mean (SE) 27.7 (.7)

Buprenorphine (n=58)

% or Mean (SE) 25.3 (.7) 87.8% 9.2% 3.1% 11.3 (.2) 16.0% 83.2% 18.7 (.5) 84.9% 13.7% 1.4% 11.3 (.3) 13.7% 79.5% 18.7 (.8) 91.4% 3.4% 5.2% 11.3 (.2) 19.0% 87.9% 18.7 (.7)  

Randomized participants compared by study condition had no statistically significant differences in baseline characteristics Completers compared by study condition had similar results Notes: Site was a blocking factor in all analyses; Bonferroni’s principle was used to set family wise α = .0045.

Jones et al., N Engl J Med, 2010.

36

100 Treated for NAS [Yes] 75 50 25 0

MOTHER Study: Primary Outcomes

15 10 5 0 25 NAS peak score 20 20 Days of infant hospital stay 15 10 5 0 p = .00012

■

Methadone

■

Buprenorphine Total amount of morphine for 15 NAS (mg) 10 5 0 p = .00000012

50 Head circumference (cm)

•

Compared with methadone exposed 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 40 30 20 10

•

Both medications in the context of comprehensive care produced similar maternal treatment and delivery outcomes 0

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.

37

MOTHER Study: Secondary Outcomes

Medication dose at delivery, mg 100 75 50 25 0 Normal presentation [Yes] 100 75 50 25 0

■

Methadone 50 40 30 20 10 50 40 30 20 10 0 Premature discontinuance [Yes] Cesarean section [Yes] Drug screen at delivery [Positive] 100 Medical complications at delivery [Yes] 25 20 80 60 15 40 10 20 5 0

■

Buprenorphine 10 Maternal weight gain, kg Number of prenatal 10 obstetrical visits 8 8 6 6 4 0 4 Amount of voucher Money earned for drug-negative tests, US$ 2000 1500 1000 500 2 2 0 0 0 0

Note:

Bonferroni’s principle was used to set familywise α = .003125 (nominal α = .05/16) for the secondary outcome measures.



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 Jones et al., N Engl J Med, 2010.

37

38

MOTHER Study: Secondary Analysis Studies

One of the goals of the MOTHER Study was to collect comprehensive data on maternal, fetal, and neonatal behavior that could be shared with the broader research community This broad availability of the MOTHER data has allowed MOTHER Principal Investigators and other researchers to ask a variety of questions about maternal, fetal, and neonatal issues related to maternal buprenorphine and/or methadone treatment. An Addiction Supplement issue will be published shortly reporting on these studies.

The following slides present findings from a number of these secondary outcome studies, including:

     

The extent to which 32-week fetal movement and cardiac measures differ between methadone and buprenorphine before and after dosing Differences between buprenorphine- and methadone-maintained pregnant women in obstetrical and neonatal complications Liver enzymes and their relationship to buprenorphine and methadone treatment, as well as HCV status Differences in NAS signs between medications Predicting treatment for neonatal abstinence syndrome Neonatal neurobehavioral effects following buprenorphine v. methadone exposure MOTHER User’s Guide and Databases can be found at: http://www.jefferson.edu/jmc/pediatrics/mother/

39

MOTHER Study: Secondary Analysis Studies

Fetal Cardiac and Movement Parameters at 36 weeks (N=11) Primary Outcomes Methadone

n

=6

Buprenorphine

n

=5

Z

Mean (SD) FHR, bpm 133.42 (7.89) 134.58 (7.12) -0.18

FHR variability Accelerations Motor activity FM duration FHR-FM coupling, % 4.43 (0.78) 1.17 (1.17) 3.58 (1.18) 8.74 (2.71) 27.42 (13.97) 5.30 (2.16) 2.80 (3.83) 5.92 (2.95) 21.53 (13.22) 18.88 (6.90) -0.37

0.0

-2.01* -2.01* -1.10

*p < .05



Compared with methadone exposed fetuses, buprenorphine-exposed fetuses have better indications of fetal well being, 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.

40

MOTHER Study: Secondary Analysis Studies

p < .01

p = .095



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

►

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, 107 (Suppl. 1), 36 –44

41

MOTHER Study: Secondary Analysis Studies

Obstetrical and Neonatal Complications

 

Several studies have compared obstetrical outcomes for opioid dependent pregnant women in maintenance treatment with buprenorphine or methadone



Results have suggested that obstetrical outcomes are comparable between the two medications



However, only two of these studies were randomized controlled trials, both with small sample sizes This study compared obstetrical and neonatal measures between buprenorphine and methadone for outcomes that were not presented in the MOTHER primary outcomes paper Holbrook et al., Addiction, 107 (Suppl. 1), 83 –90.

42

MOTHER Study: Secondary Analysis Studies

Incidence of obstetrical/neonatal complications Premature rupture of membranes < 37 weeks EGA Gestational diabetes Buprenorphine (n=86) Methadone (n=73) 0 1 (2%) 4 (5%) 2 (3%) Placental abruption Premature rupture of membranes ≥37 weeks EGA Head sparing Meconium aspiration Placenta previa Non-head sparing Preeclampsia Sepsis 0 2 (4%) 1 (2%) 1 (2%) 0 0 0 0 3 (4%) 0 1 (1%) 0 1 (1%) 1 (1%) 0 0

•

There were few obstetrical and neonatal complications in the total sample, as well as in both the buprenorphine and methadone conditions

Holbrook et al., Addiction, 107 (Suppl. 1), 83 –90.

43

MOTHER Study: Secondary Analysis Studies

Incidence of Preterm Labor in the Two Medication Conditions 20 15 10 5 0 p < .05

■

Methadone

■

Buprenorphine p < .05

•

Maternal methadone versus buprenorphine maintenance treatment was associated with:

 

a higher incidence of preterm labor a higher percentage of respiratory distress signs in neonates

Holbrook et al., Addiction, 107 (Suppl. 1), 83 –90.

44

MOTHER Study: Secondary Analysis Studies

Liver enzymes, buprenorphine, methadone, and HCV Status



Possible relationship between buprenorphine treatment and hepatic injury or dysfunction in opioid-dependent individuals



Liver enzymes do not show much variation from normal in healthy pregnant women



However, rates of HCV infection in pregnant opioid-dependent women have been reported as high as 93%



Thus, the extent to which agonist medication, HCV exposure, or both have an effect on liver enzymes in pregnant opioid-dependent women is unknown



Liver enzymes assayed:

-

aspartate aminotransferase (AST)

-

alanine aminotranferase (ALT)

-

gamma-glutamyl transferase (GGT) McNicholas et al., Addiction, 107 (Suppl. 1), 91 –97.

45

MOTHER Study: Secondary Analysis Studies

40 35 30 25 20 15 10 5 0 45 40 35 30 25 20 15 10 5 0 AST, ALT, and GGT Levels by Trimester 35 30 25 20 15 10 5 0

AST

First Second Third Post-partum

ALT Trimester

First Second ■ Third ■ Post-partum ■ ■

First Second Third Postpartum GGT

First Second Third Post-partum 

AST, ALT, and GGT decline during the course of pregnancy, and then return to baseline during the postpartum period



Participants with HCV had higher liver function levels at all time points



There was no effect of medication on ALT or GGT. However, methadone maintained participants had higher GGT levels than did buprenorphine maintained patients over the course of the study



HCV status did not moderate the effects of the medication in either group McNicholas et al., Addiction, 107 (Suppl. 1), 91 –97.

Liver function test results are in IU/L All ps < .05

46

MOTHER Study: Secondary Analysis Studies

• 53% of the total sample required treatment for NAS • Receipt of NAS treatment for infants was predicted by: – infant birthweight – greater maternal nicotine use • Total medication dose needed to treat NAS was predicted by: – Maternal use of SSRIs – higher nicotine use – fewer days of study medication received also predicted.  No variables predicted length of treatment for NAS

Kaltenbach et al., Addiction, 107 (Suppl. 1), 45 –52.

47

MOTHER Study: Secondary Analysis Studies

Incidence of NAS signs



Three signs were observed significantly more often in the buprenorphine than in the methadone condition: sneezing, loose stools, and nasal stuffiness



Two signs were observed significantly more often in the methadone than in the buprenorphine condition: undisturbed tremors and hyperactive Moro reflex



Methadone-exposed neonates had higher mean NAS total scores than buprenorphine exposed neonates Gaalema et al., Addiction, 107 (Suppl. 1), 53 –62.

48

MOTHER Study: Secondary Analysis Studies

Methadone-exposed neonates had higher mean scores for: disturbed tremors, undisturbed tremors, hyperactive Moro reflex, excessive irritability and failure to thrive Buprenorphine-exposed neonates had higher mean scores All p s ≤ 0.04

Gaalema et al., Addiction, 107 (Suppl. 1), 53 –62.

49

MOTHER Study: Secondary Analysis Studies

Time to Morphine Treatment Initiation 80 60 40 20 0 p = .01

Methadone (n = 41) Buprenorphine (n = 27)

►

There was a significant difference between medication conditions in mean time to initiation of morphine treatment for those neonates treated for NAS, with the methadone condition requiring morphine treatment earlier than the buprenorphine condition Gaalema et al., Addiction, 107 (Suppl. 1), 53 –62.

50

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

51

Smoking and Neonatal Abstinence Syndrome (NAS)

Peak NAS Score

p

< .05

9.8

10 8 6 4 2 0

4.8

Light Smoking Heaving Smoking (< 10/day) (> 20/day) n = 16 n = 13 Time to Peak NAS Score 120 100 80 60 40 20 0

37.8

p

< .05

113

Light Smoking Heaving Smoking (< 10/day) (> 20/day) n = 16 n = 13

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 opioid maintained 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

51

► duration of NAS treatment in 26 neonates of methadone maintained pregnant women but not in 12 neonates of buprenorphine-maintained pregnant women

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.

52

MOTHER Study: Cigarette Smoking

RESULTS Average number of cigarettes smoked in the past 30 days was significantly positively related to:

•

Total amount of morphine needed to treat NAS

•

Number of days neonate was medicated for NAS

•

Neonatal length of hospital stay T otal Amount of Morphine Needed to T reat NAS 6 5 4 3 2 1 0

1.5

Non Smoking

2

Below Average Smoking

3.2

Average Smoking Number of Days Medicated for NAS 10 8 6 4 2 0

3.7

Non Smoking

4.6

Below Average

6.3

Average Smoking

5

Above average Smoking

8.4

Above average Smoking 18 15 12 9 6 3 0

8,9

Non-Smoking

10,5

Below Average Smoking

13

Average Smoking

16,2

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

53

MOTHER Study: Cigarette Smoking

Neonatal Weight at Birth RESULTS Average number of cigarettes smoked in the past 30 days was significantly negatively related to: 3200 3100 3000 2900 2800

3149

Non Smoking

•

Neonatal weight at birth

•

Apgar score at 1 minute

•

Apgar score at 5 minutes

•

Maternal weight gain, study entry to delivery 10 8 6 4 2 0

8.6

Non Smoking 10 8 6 4 2 0

9.5

Non Smoking

3075 2978

Below Average Smoking Average Smoking Apgar Score at 1 Minute

8.4

8

Below Average Smoking Average Smoking Apgar Score at 5 Minutes

9.3

9 2881

Above average Smoking

7.7

Above average Smoking

8.7

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

54

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 Jones et al., under review

55

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 Tuten et al., Addiction, 2012

56

5 4 3 2 1 0 0.4

0.3

0.2

0.1

0

MOTHER Study: Secondary Analysis Studies

Hypertonia 0.8

0.6

0.4

0.2

0

■

Methadone Mean Excitability 5 4 3 2 1 0 Handling Stress-Abstinence Arousal 0.4

0.3

0.2

0.1

0

■

Buprenorphine Mean Self-Regulation 6 5 4 3 2 1 0



Neurobehavioral functioning improves during the first month of life for neonates exposed to opioid agonist medication in utero

(data not shown)



Relative to the methadone condition, the buprenorphine condition results in superior neurobehavioral functioning on several outcomes All ps < .04

Coyle et al., Addiction, 107 (Suppl. 1), 63 –73.

57

Buprenorphine

v

. Methadone: Summary of Comparisons

Benefits and Risks of Opioid Agonist Pharmacotherapy Longer treatment retention Reduced risk behaviors Greater birth weight Recommended for pregnancy Independent replication of results NAS Fetal behavior Buprenorphine

      

Methadone

       •

Both medications show similar maternal treatment outcomes

•

Data support buprenorphine’s advantage for minimizing NAS

•

Fetal behavior appears more normal with buprenorphine

•

Breastfeeding is recommended for patients who are stable on either medication

•

Longer-term outcomes are confounded by multiple factors

57

58

Conclusions

  

It is feasible to conduct multicenter randomized controlled trials examining medications to treat chronic illnesses like opioid dependence in pregnant women In terms of NAS severity, buprenorphine may have an advantage as a front-line medication option for managing opioid dependence for pregnant women who are new to treatment or maintained on buprenorphine pre-pregnancy Having more medications given in the context of comprehensive services to treat opioid-dependent pregnant women should optimize treatment options

59

Pharmacotherapy for Opioid Dependence: Unresolved Issues

►

Cost/reimbursement within the public sector is uncertain

►

Practitioners are gaining in experience with inducting pregnant women onto buprenorphine

►

Practitioners may be reluctant to continue prescribing buprenorphine during pregnancy

►

No data are available to inform selection of patients who should be maintained on which medication

►

Optimal duration of time that a patient should be maintained on either medication is unknown

►

Insufficient data are available regarding the longer term outcomes for the medications

59

60

Unanswered Questions

    

Relative safety and efficacy of buprenorphine/naloxone?

Use of methadone and buprenorphine with co-morbid alcohol and/or benzodiazepine use?

Buprenorphine induction?

NAS

–

Tools to measure

–

Medications to treat

–

Factors exacerbating and minimizing Short- and long-term outcomes

–

Growth, learning, development, behavior

61

T H E E N D

For More Information

Hendrée E. Jones, PhD email: [email protected]

voice: 1-919-485-2664 My heart and greatest joy

61

The list of references used in preparing this slide set are available upon request.

62

Outcomes with Buprenorphine + Naloxone (N=10)

Maternal

Maternal weight gain (kg) Cesarean section [yes] Analgesia during delivery [yes] † Urine drug screening at delivery [positive] ‡ Days of maternal hospital stay Began breastfeeding after delivery [yes]

Neonatal

Gestational age at delivery (in weeks) Preterm (< 37 weeks) Apgar score at 1 min / 5 min Head circumference (cm)

f

(%) 1 (10%) 6 (67%) 0 (0%) 3 (30%) 2 (20%) Birthweight (gm) Infant length (cm) Treated for neonatal abstinence syndrome [yes] 4 (40%) Total amount of morphine for NAS (mg) Days treated for neonatal abstinence syndrome Days of infant hospital stay

M

(

SD

) 7.8 (3.9) 4.1 (4.5) 37.5 (3.5) 8.0 (2.5) / 8.6 (1.3) 32.8 (1.2) 2816.1 (368.3) 46.3 (2.2) 3.5 (2.6) 6.9 (10.1) 10.1 (9.8)

Debelak et al., Am J Addict, in press.