What about medications for opiate recovery and mental illness?

What about
medications for
opiate recovery and
mental illness?
Maria Muzik, M.D., M.S.
Assistant Professor of Psychiatry,
University of Michigan Department of Psychiatry & Comprehensive Depression Center
Director, Women and Infant Mental Health Clinic,
Attending Physician, Comprehensive High Risk OB Clinic for Women with Substance Use
Disorders
Assistant Research Scientist, Center for Human Growth & Development University of Michigan
© 2015 PSI
RISK BENEFIT RATIO
Risks of
Untreated
Illness
versus
Risks of
Medical
Treatment
NO RISK-FREE ZONE!!!
It is always about harm reduction
“Risk of Medical Treatment”
Awareness started in 1960s
• Prior belief in “placental barrier” protecting the child
• thalidomide and diethylstilbestrol (DES), amplified public sentiment about
the need for protecting the fetus from risks from drug use.
• Thalidomide was approved in 1958 as a sedative and antidote for nausea in
early pregnancy. By 1962, rare set of deformities, mostly limb
malformations, were caused by the drug and 8,000 children had been
affected
• DES was a synthetic hormone prescribed in the 1940s and 1950s to prevent
miscarriage. By the late 1960s and 1970s, known that the daughters of
women who had taken DES during pregnancy developed a rare
adrenocarcinoma of the vagina.
• Since then massive concern which licit and illicit drugs as possible
teratogens, and the activities, intake, diet and behaviors of pregnant
women have been under close scrutiny ever since.
Lester, Barry M.; Andreozzi, Lynne; Appiahm, Lindsey, "Substance use during pregnancy: time for
policy to catch up with research," Harm Reduction Journal (London,) 2004, Volume 1, Issue 5, p. 2.
What is the goal of this presentation?
• The medical community has a pretty good sense
to date what is the “current state-of-art safe and
evidence-based pharmacological treatment for
pregnant women with mental illness and
substance use disorders”
• Always the question “what is the benefit and
what the risk to mother and child?”
• Medical/clinical science should guide treatment
decisions rather than access barriers
Mental Illness and
Substance Use
Disorders
Psychosocial
Stress/Trauma
Genetics
Physical Illness
Maternal and
Fetal Health
Prescribed
medicines for
physical illness
(e.g. Steroids)
Antidepressants
Anxiolytica
Mood Stabilizers
MAT
(MET, BUP)
How prevalent is the problem?
• Mental health
–
–
–
–
Depression
Anxiety
Bipolar Illness
PTSD
6-15% , 40% and more (high-risk)
GAD 8-10%; OCD 4% in pp
0.01% new; 75% relapse risk
3-7%
• Substance Use
– Opioid Use Disorders 6% in pregnant (11% non-preg)
• Prescription pain pills
• Heroin
– Alcohol Use Disorders 0.3 % heavy use, 2.7% binge
– Tobacco Use
16-17%
Ross & McLean, J Clin Psychiatry, 2006; Evans J, et al. BMJ. 2001;323:257-260 ; SAMHSA, Results from the 2013
National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-48, HHS Publication No.
(SMA) 14-4863. Rockville, MD
The Campaign to Change Direction is a national initiative
designed to change the culture of mental health in America.
The Campaign encourages us all to learn and share the Five
signs of emotional suffering:
1. change in personality
2. agitation (angry, irritable, moody, anxious)
3. withdrawal (isolation)
4. decline in personal care (maybe engage in risk behaviors)
5. hopelessness (overwhelmed)
http://www.changedirection.org/
http://www.changedirection.org/know-the-five-signs/
Bipolar Disorder/mania
+
Mood
-
Euphoric or irritable Mood
Distractability
Indiscretion
Grandiosity
Flight of ideas – incoherent, out of touch
with reality
Active: High energy
Sleep: No need
Talkative-pressured speech
What is postpartum
psychosis/Bipolar?
 New-onset
or relapse of  Delusions/hallucinations
bipolar spectrum
 Suicidal thoughts
disorder (depression
with psychosis or mania)
 Major loss of functioning
 Labile mood
 Rapid decline over 1-2
weeks
 Extremely disturbed
mood
 Psychiatric emergency
 Highly agitated
 Inpatient stabilization,
medications, therapy,
 Severely disturbed
ECT, family support
sleep
Bipolar ≠ baby blues
 80%
of women
 Labile
mood
 Tearful
 Mildly
disturbed sleep
 No
major change in functioning
 Begins 2-4 days after birth; maximum at end of
first week
 Resolves by second week
 Physiologic
reaction to birth experience,
physical exhaustion and/or hormonal changes
 No
treatment necessary, except if severe and >14
days
 PTSD

2%
 24%
 40%
in pregnancy/postpartum
- low risk
- in high risk pregnant women (teens,
poverty)
- in low SES sample of women exposed
to IPV and other trauma in pregnancy;
Co-morbid PTSD+Depression 6x in trauma samples
Co-morbidity with Substance Use Disorders high
 80% of women with substance use disorders have a
lifetime history of trauma
 30% to 59% have posttraumatic stress disorder (Cohen
and Hien, 2006).
Substance Use
SCREEN
Trauma/Stress
PTSD
Maternal and
Fetal Health
Depression
TREAT COMPREHENSIVELY
& MULTIMODALY
RISK BENEFIT RATIO
Risks of
Untreated
Illness
versus
Risks of
Medical
Treatment
NO RISK-FREE ZONE!!!
It is always about harm reduction
What are areas of concern of
untreated illness ?
• Maternal concerns
– poor nutrition and weight gain
– Poor follow through with prenatal care
– Pregnancy complications (e.g., gestational
diabetes, preeclampsia, infections (HIV,
Hep C)
– unhealthy coping strategies (smoking, alc)
– Illness progression and death (e.g., suicide
or accidental overdose)
What are areas of concern of
untreated illness?
• Fetal concerns
– Spontaneous fetal demise
(miscarriage/stillbirth)
– Preterm birth
– Fetal/ congenital anomalies
– IUGR
– LBW/SGA
– Neonatal Effects (e.g., NAS)
– Neurodevelopmental longer-term effects
Teratogenicity

Baseline population risk for any malformation is 24% among healthy, unexposed women

Any medicine risk must be measured against this
baseline risk
Untreated Illness
Risk
Depression/Anxiet
y
Illicit Opiate Use
Mother’s pregnancy
course
Preeclampsia, GDM, poor
nutrition/weight gain;
poor PNC; smoking/alc;
suicide 1
Preeclampsia, HIV/HepC;
poor nutrition/weight
gain; poor PNC;
smoking/alc;
suicide/accidental OD
Cycles of withdrawal and
relapse/placenta insuff ,
hemorrhage16,18
Fetal death
no reports
PTB
yes, 20% 3,4,5
IUGR/LBW/SGA
yes
Fetal/cong anomalies
Neonatal effects
Neurodevelopment
3,4
? (maybe)
yes 6,20
yes,but (emotional and
behavior problems) 7
Fetal distress16,18
yes, >25% 13
yes16,18
? (maybe)
NAS 96% 16
(shorter)
maybe (ADHD,
cognition)17
Neonatal Effects in Untreated Depression
Infant Effects in Untreated Depression
Author(s)
Child
Age
N
Results
Tse et al.
2010
36 mo
1030
Antenatal depression did not predict child cognition
Hanington
et al. (2011)
42 mo
6914
Maternal and paternal depression and marital conflict during
pregnancy were both associated with adverse child outcome after
adjustment for postnatal risk factors
Barker et al. 7-8 yrs
ALSPAC
3298
Antenatal depression associated with an increase in child
externalizing difficulties and a decrease in verbal IQ
Austin et al. 4-6 mo
970
Antenatal depression did not predict infant temperament.
Postnatal depression and antenatal anxiety did.
Davis et al.
247
Antenatal depression and elevated antenatal cortisol associated
with greater infant negative reactivity
Koutra et al. 18 mo
Rhea
Cohort
223
Antenatal depression was associated with decreased cognitive
development independently of postnatal depression
Werner et
al.
103
Neither antenatal nor postnatal depression associated with
observed infant behavioral reactivity. Antenatal cortisol predicted
infant behavioral reactivity
2 mo
4 mo
Child Effects in Untreated Depression
Author(s) Child Age
N
Results
Luoma et
al.
8-9 yrs
147 Antenatal depression predicted elevated externalizing and total
problems. Antenatal plus recurrent maternal depression
associated with worst outcome
Leech et
al.
10 yrs
636 Antenatal depression no longer predicated child
depression/anxiety after adjustment for family and child risk
factors
Hay et al.
11 & 16
yrs
121 Effect of antenatal depression on child emotional disorder was
mediated by cumulative exposure to maternal depression.
Postnatal depression predicted child IQ
Pawlby et
al. 2009
16 yrs
127 Effect of antenatal depression on adolescent depression was
mediated by cumulative exposure
Hay et al.
2010
11 & 16
yrs
121 Antenatal depression predicted violence in adolescence,
even after adjustment for other parental, prenatal, and
postnatal risk factors
Korhonen
et al.
16-17 yrs 327 Antenatal depression associated with elevated externalizing
problems and lower social competence in males. For both
genders, concurrent maternal depression associated with
behavioral and emotional problems
Important Modifiers to Impact of PPD
• Socioeconomic status: Poverty
– Lovejoy, M. C., Graczyk, P. A., O'Hare, E., & Neuman, G. (2000).
• Marital Status: Being single – absence of a healthy parenting
partner
• Lack of Father Involvement
• Mom’s age: teen moms
– Deal, L. W., & Holt, V. L. (1998).
• Child Gender
– Goodman, S. H., & Gotlib, I. H. (1999).
• Mother’s Depression Severity & Chronicity
– Brennan, P. A., Hammen, C., Andersen, M. J., Bor, W., Najman, J. M., & Williams, G.
M. (2000).
• van der Waerden et al., (2015)
– Comorbidity
• Carter, A. S., Garrity-Rokous, F. E., Chazan-Cohen, R., Little, C., & Briggs-Gowan,
M. J. (2001).
• Parenting
– Field, T. (2010)
• Trauma exposure
– Martinez-Torteya, Muzik et al., (2014)
Illicit Opiate Use in Pregnancy 16,18
• Risks are preeclampsia, premature labor and
rupture of membranes, placental insufficiency,
abruptio placentae, intrauterine growth
retardation, and intrauterine death increases
greatly with illicit opiate use during pregnancy
• Even with a successful labor and delivery,
neonates often have low birthweight and
smaller head circumference as well as
experience symptoms of opiate
withdrawal/NAS
Is it the drug or the psychosocial
exposure and lack of PNC? 16
• Difficult to detangle: poverty, poor nutrition,
homelessness, a history of domestic violence,
and lack of prenatal care
• The overlap between lack of PNC and illicit drug
use is evident in the population studied.
• Women with IDU DO NOT ENGAGE IN PNC:
– a prevalence of 4.2% IDU in mothers with adequate
PNC,
– 26.2% in women with inadequate PNC, and
– 55.2% in mothers with no PNC.
PTB in exposed to illicit drugs13
• Data form retrospective cohort study of opiateaddicted gravid women treated with methadone
who delivered a single neonate between 2000 and
2006.
• The overall PTB rate was 29.1% (75/258).
• Among women abusing 0, 1, 2, or 3 or more
supplements in addition to methadone, the PTB rate
was 24.2% (reference), 25.5% (P = .50), 47.6% (P =
.04), and 64.7% (P = .01), respectively.
Prescribed Opiate Use in Pregnancy 8,9
• Large review article 2015 8
Mahsa M. Yazdy, Rishi J. Desai, and Susan B. Brogly. Prescription Opioids in
Pregnancy and Birth Outcomes: A Review of the Literature. J Pediatr Genet.
2015 Apr 1; 4(2): 56–70.
• Reviewed effects of tramadol, oxycodon, codein,
hydrocodon, fentanyl
• Basically no effects on fetal death
• Some minimal effects on PTB, LBW/SGA in comparison to
unexposed
• National Birth Defects Prevention Study9
conoventricular septal defects (OR: 2.7;95% CI: 1.1, 6.3),
atrioventricular septal defects (OR: 2.0; 95% CI: 1.2,
3.6),
hypoplastic left heart syndrome (OR: 2.4; 95% CI:
1.4, 4.1),
spina bifida (OR: 2.0; 95% CI: 1.3, 3.2), or
gastroschisis (OR: 1.8; 95% CI: 1.1, 2.9)
Substance Use
Trauma/Stress
MAT
(MET, BUP)
PTSD
Maternal and
Fetal Health
Depression
Antidepressants
Anxiolytica
Mood Stabilizers
Medications for Mood and Anxiety
Antidepressants
• SSRI (Zoloft, Celexa, Lexapro,Paxil, …)
• SNRI (Effexor, Cymbalta)
• Wellbutrin
• Remeron
Medications for Anxiety and Sleep
• Benzodiazepines (Ativan, Klonopin)
• Buspar
• Trazodone, Ambien
Mood Stabilizers
• Lamotrigine, Lithium, Valproic Acid
• Second Generation Antipsychotics (Abilify, Geodone,
Seroquel, Zyprexa)
Medication Assisted Treatments
Methadone
• Since 1970s
• Full agonist, long-acting, 24 hours
• daily dosing in federally regulated clinics plus treatment resources;
Buprenorphine
• partial mu opioid receptor agonist and a kappa opioid receptor
antagonist
• daily/bid dosing; because partial agonist /antagonist less respiratory
depression risk (but danger in combo w/ alcohol and benzos);
• since 2002 office-based Rx if MD special training for Rx (as tablet or
film); in pregnancy even more favorable to methadone (MOTHER
study, 2010)
Naloxone
• antagonist; lacks bioavailability when sublingual, but active when iv
or snorted ( in combo w/ buprenorphine as suboxone to reduce
diversion/misuse; mono = Narcan)
Medication
Treatment
Maternal course of
pregnancy
Fetal death (miscarriage
or stillbirth)
PTB
Antidepressant
Anxiolytics
Methadone
Buprenorphine
More likely to get PNC
Better pregnancy health
More likely to get PNC
Better pregnancy health
no increase above
base rate (6/1000) 12
yes (11-20%) 1,12
MET=BUP14
20-30/1000
yes 10% BUP, 14% MET 14
but clinically irrelevant (by ½ week)
IUGR/LBW/SGA
yes/no
1,12
yes (but less with BUP) 14
but clinically irrelevant by 75g
Fetal/cong anomalies
Neonatal effects
Neurodevelopment
no SSRI 21 (? paxil) 10
yes with SGA2
no (1.3%) 14
NAS 30% 11,20
NAS 96%, BUP<MET14
? /most likely no
Maybe (ADHD, memory,
cognition) 19
Antidepressants: Broad Strokes
• Previously, most antidepressants were
category C (“risk cannot be ruled out”):
– SSRIs (except paroxetine-formerly category D)
– SNRIs
– TCAs
– Typical and Atypical Antipsychotics
– mirtazapine (Remeron)
– bupropion (Wellbutrin)
– trazodone
The Paroxetine Controversy
• In 2005 GSK analyzed own data on n=815 exposed
infants
– 1.5 to 2-fold increased risk for atrial and ventricular septal defects
– Paroxetine  FDA Category D
• Since 2005, there have been multiple contradicting
studies:
–
–
–
–
Increased risk for unspecific malformations
Increased risk for specific cardiac malformations
No risk for malformation (risk 0.7%)
Risk is dose-dependent (>25mg daily) and only when exposed
in first trimester
Antiepileptics and Antipsychotics:
Broad Strokes
• Typicals/Atypicals: formerly category C
– Most studied and best safety record
quetiapine (seroquel), olanzapine (zyprexa),
haloperidol (haldol)
aripiprazole (abilify) emerging
• Lamotrigine (Lamictal): formerly category C
• Preferable to alternatives IF clinically feasible
Lithium
–
–
–
–
Formerly category D (positive evidence of risk)
Half-life is short (8-10hrs) causing peaks
Dose tid-qid to avoid peaks or use extended release
1st TM exposure: high-resolution US/fetal echo at 1618 weeks gestation
– Watch toxicity d/t pregnancy-related emesis
– In 3rd TM: renal excretion increased need to raise
dose for therapeutic level
– Labor:
• Hold dose to avoid toxicity during delivery/postpartum d/t
rapid reduction of vascular volume
• IVF throughout labor
Valproic Acid
• Formerly Category X: Contraindicated in Pregnancy
• DO NOT PRESCRIBE in a woman of childbearing age
and DEFINITELY NOT IN PREGNANCY
• Teratogenity: 10%, particularly if exposure in 1st TM
– Neural tube defect in 1st TM, dose related
– Midface hypoplasia & other facial anomalies
– Cardiac anomalies
– Folate supplementation up to 5mg daily may reduce risk
• Intrauterine Growth Restriction (IUGR)
• Mental Retardation – independent of which TM exposure
• Neonatal Toxicity
– Irritable, jittery, hypotonia, feeding difficulties, liver tox,
– hypoglycemia
© 2015 PSI
Carbamazepine
• Formerly category D (positive evidence of risk)
• Teratogenity: 6%
– Neural tube exposure 1st TM, dose related
– craniofacial & other facial anomalies
– Fetal vitamin K deficit fetal bleeding
– Worse when combination with Valproic Acid
– Oxcarbazepine (Trileptal) safer to use
• IUGR
• Neonatal Toxicity
– Transient liver toxicity
– Neonatal bleeding, administer vitamin K 1mg to baby
Benzodiazepines
• Formerly category D (positive evidence of risk)
• No evidence of congenital malformation
– Initial concern cleft lip/palate, disproven
• Lorazepam and clonazepam preferred
– Less likely to accumulate in fetus/neonate
– Alprazolam rapid on/off = unknown fetal effects
• 550 infants with normal development to 4 years out
Benzodiazepines
• “Floppy baby syndrome”
– Associated with high doses near delivery
– Neonatal apnea, hypotonia
– Not present with once-daily use
• NAS
– Increased incidence with antidepressant use
• PTB/LBW
– Inconsistent findings
– If at all, late preterm
– No control for mental illness
Medications and Breastfeeding
• Recommendations by experts derived from small
samples and case studies
• All major medical associations encourage
breastfeeding in the first 6-12 months postpartum
• All medications transferred to breast milk, but
concentrations are far less than in utero exposure
Broad Strokes
• SSRIs ok, TCAs ok
– infant levels 1-20% of mom's level based on drug
– sertraline and paroxetine have lowest concentrations
found in breast milk
• also have shorter half-lives which reduces risk for concentration
build-up
• Benzodiazepines generally ok
– infant levels 2.5-8.5% of mom's level
– longer-acting drugs and those with active metabolites
more likely to lead to infant sedation
• Lithium not recommended due to risk for neonatal
dehydration and lithium toxicity
Broad Strokes
• Valproic Acid
– Infant levels relatively low
– Theoretical risk of infant hepatotoxicity, thrombocytopenia
– Concern re: mom becoming pregnant again
• Carbamazepine
– Infant levels relatively high
– Infant monitoring recommended (drug levels, liver
enzymes, CBC)
• Lamotrigine
– Infant levels 30% mom dose, concerns about risk for SJS,
though no infant cases of this have been reported
• Atypicals
– Generally ok
– Avoid clozapine due to risk of agranulocytosis in infant
Helpful Resources
• womensmentalhealth.org
– Massachusetts General Hospital's website,
contains detailed but easily understandable
information
• lactmed.nlm.nih.gov
– US National Library of Medicine's database
– Can search any medication for data re: safety in
breastfeeding
Resources for Medications in
Pregnancy and Breastfeeding
FREE
• Motherisk.org www.motherisk.org 1-877-439-2744 (free)
• LactMed: www.lactmed.nlm.nih.gov (Free)
• Organization of Teratology Information Services:
www.mothertobaby.org (formerly OTIS) Good Handouts /Free
• MGH women’s mental health program:
www.womensmentalhealth.org
• toxnet.nlm.nih.gov
PAY
• Reprotox: www.reprotox.org (you have to pay)
• Infantrisk.com (806)-352-2519 also phone app available (you have to
pay)
Medication Assisted Treatments
Methadone
• Since 1970s
• Full agonist, long-acting, 24 hours
• daily dosing in federally regulated clinics plus treatment resources;
Buprenorphine
• partial mu opioid receptor agonist and a kappa opioid receptor
antagonist
• daily/bid dosing; because partial agonist /antagonist less respiratory
depression risk (but danger in combo w/ alcohol and benzos);
• since 2002 office-based Rx if MD special training for Rx (as tablet or
film); in pregnancy even more favorable to methadone (MOTHER
study, 2010)
Naloxone
• antagonist; lacks bioavailability when sublingual, but active when iv
or snorted ( in combo w/ buprenorphine as suboxone to reduce
diversion/misuse; mono = Narcan)
Benefits of Methadone vs heroin8
• Compared with heroin-exposed neonates,
methadone-exposed neonates had higher birth
weights, longer gestations (Kandall, 1977)
• Compared with neonates exposed to illicit
opiates, methadone-exposed neonates had
higher birth weights, required longer durations of
treatment for NAS, and their mothers were more
likely to receive antenatal care (Johnson, 2003)
Benefit of treatment versus illicit use16
• 47 heroin, 32 methadone and 38 buprenorphine addicted
women were enrolled in the study.
• Birthweight and neonatal abstinence syndrome (NAS)
Results:
• Results:
• None of the women delivered before the end of 34th
gestational week.
• No perinatal death or developmental defect.
• Heroin worse than MET=BUP on BW, IUGR, placenta insuff
• NAS worst in MET
Comparison of Methadone vs
Buprenorphine --MOTHER study14
• 39 full term infants assessed at days 3, 5, 7, 10,
14-15 and 28-30 using the NICU Network
Neurobehavioral Scale (NNNS) scale
• Results: BUP infants better than MET infants
–
–
–
–
–
–
fewer Stress-Abstinence signs
less Excitable
less Over-Aroused
less Hypertonia
better Self-Regulation
required less Handling to maintain a quiet alert state
Comparison of Methadone vs
Buprenorphine plus Naloxone 15
• 62 mother-neonate dyads, 31 treated with
methadone and 31 treated with buprenorphine and
naloxone.
Results:
• Suboxone-exposed neonates had less NAS 25% versus
51% and shorter overall hospitalization (5.6 ± 5.0
compared with 9.8 ± 7.4 days; P = .02).
Breastfeeding and MAT
• Breastfeeding is an important
nonpharmacological intervention, and
according to the American Academy of
Pediatrics, mothers on
buprenorphine/methadone should be
encouraged to breastfeed (Kocherlakota,
2014).
• Minimal passage of drug via breastmilk
• Benefit for infant NAS via skin-to-skin contact;
maternal soothing /bonding
References
References
References