Carl Christensen, MD October 23, 2017 ccmdphd@mac · Methadone vs. Buprenorphine: the MOTHER study...
Transcript of Carl Christensen, MD October 23, 2017 ccmdphd@mac · Methadone vs. Buprenorphine: the MOTHER study...
CarlChristensen,[email protected]
PregnancyandAddiction 1
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Addiction and Pregnancy 2017
Carl Christensen, MD, PhD, D-FASAM
Clinical Assoc Prof, Psychiatry and OB/Gyn, Wayne State Univ School of Med, Detroit Mi
Medical Director, Mich Health Professional Recovery ProgramJune 15, 2017
Disclaimers
´ No Financial Relationships´ Consultant, DEA/DOJ´ Consultant, BCBS Mich´ Methadone provider,
Wayne State SOM´ Medical Director, Dawn
Farm, Ann Arbor, MI´ Buprenorphine and
naltrexone provider, A2
Qualifications:3 Carl Christensen Disclosures II
´Medications will be referred to in the generic whenever possible; will discuss FDA specific formulations
´We will be discussing off label use of buprenorphine and methadone; neither of these are approved by the FDA for use of opioid dependence in pregnancy
WHY TALK ABOUT THIS?
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WHY TALK ABOUT THIS?
Addiction and Pregnancy 12
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WHY TALK ABOUT THIS?
Addiction and Pregnancy 13
HEROIN
WHY TALK ABOUT THIS? NAS in Michigan
Addiction and Pregnancy 16
You are here…..
JAMA Pediatrics December 12, 2016 Online
NAS OPIOID USE
rural
Urban
What is Addiction? What is Addiction?
´Physiologic Dependence?
´Lack of willpower?´An “amoral”
condition?´A brain disease?Physiology of Addiction
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Physiologic Dependence: Tolerance and Withdrawal
´Tolerance: requiring increasing amounts of drug to get the same effect
´Withdrawal: the opposite effect of the drug when it is removed
´NEITHER of these imply chemical dependency (addiction)
Physiology of Addiction
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Lack of Willpower?
Physiology of Addiction 22
An “amoral” condition?
Physiology of Addiction
23 Brain disease?
Physiology of Addiction
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The Nucleus Accumbens: the Pleasure Center.Dopamine: the Pleasure DRUG
Physiology of Addiction
25VTA: the “gas tank”: supplies dopamine to the Nucleus Accumbens
Physiology of Addiction
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Frontal Cortex: inhibits the Pleasure Center (maybe)
Physiology of Addiction
27 What is the problem?
´Addiction is not a problem of drug WITHDRAWAL…..
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What is the problem?
´Addiction is not a problem of drug WITHDRAWAL…..
´It is a problem of:´CRAVING´LOSS OF CONTROL´COMPULSIVE USE ´USE DESPITE CONSEQUENCES´(the “4 Cs”)
29 Drug WITHDRAWAL: the Hindbrain
Physiology of Addiction
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Drug ADDICTION: the (primitive) Forebrain:
Physiology of Addiction
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Physiology of Addiction
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Why Can’t Addicts Stop?????
´The relapse rate after undergoing detox approaches 100%
´The relapse rate when coming off meds (buprenorphine, methadone) is 90%
´But: their withdrawal is gone.´SO: why do they relapse?????
Physiology of Addiction
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Normal VolunteersRed: good blood flow
Physiology of Addiction
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Non users
Cocaine users, 10 days sober
Cocaine Users, 100 days sober
High blood flow
Low blood flow
How Longto recover
fromMethamphetamine?
[C-11]d-threo-methylphenidate
Volkow et al., J. Neuroscience, 2001.
low
high
Normal Control
Methamphetamine Abuser(1 month abstinent)
Methamphetamine Abuser (14 months abstinent)
Treatment of Opioid Dependence (without) Pregnancy
Medication Assisted Therapy (MAT):Agonists vs. Antagonists
Drug Type AnalogyMethadone Full Agonist High OctaneBuprenorphine* Partial
AgonistLow Octane
Naltrexone Antagonist Water
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Medication Assisted Therapy (MAT):Methadone
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Medication Assisted Therapy (MAT buprenorphine
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Medication Assisted Therapy (MAT naltrexone
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BOTTOM LINE: (non-pregnant)
´In both controlled and retrospective studies, the success rate for most medications is between 40 and 60% (one to two years).
´When patients come off the medication, they relapse.
´Relapse may be associated with an increased chance of overdose and death.
Physiology of Addiction 59
Benefits of MethadoneSalsitz, ASAM, 2012
´Reduction in death rates (Grondblah, 1990)´Reduction in IVDU (Ball & Ross, 1991)´Reduction in # of crime days (Ball & Ross)´Reduced HIV seroconversion / HCV conversion´IMPROVED OUTCOME AFTER INCARCERATION
Ball 1988: reduction in IVDU
ORT: yes or no??? 61
Ball 1988: reduction in IVDU
ORT: yes or no??? 62
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Ball 1988: resumption of IVDU!
ORT: yes or no??? 63
Ball 1988: resumption of IVDU!
ORT: yes or no??? 64
Problems with methadone
´Requires initial daily dosing first 90 days.´Must be “clean” for 2 years before you can increase
take homes!´Methadone clinics may be a source of “wet faces and
wet places”´Stigma
´Judges will often try and force moms off methadone-now forbidden by the feds.
Buprenorphine
� A partial opiate agonist (less potent)◦ Less analgesic effect◦ Less respiratory depression◦ <100 documented deaths in the U.S.
(Soyka); 4000+ PER YEAR WITH METHADONE◦ Treats both pain and opiate dependency� Different formulations are approved
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Buprenorphine +/-Naloxone:
´ Available in 3 branded forms:
´Generic buprenorphine (Subutex®): sublingual OFF MARKET: Medicaid may not cover generic due to concerns about diversion.
´Bunavail®: sublingual buprenorphine + naloxone (Narcan®): prevents IV use*
´Suboxone®: sublingual buprenorphine + naloxone (Narcan®): prevents IV use*
´Zubsolv®: ditto
´ ANY of these will precipitate sudden withdrawal: only give when patient is going INTO withdrawal!
´ * not FDA approved for pain
Addiction and Pregnancy 67
Buprenorphine:
´ Formulations approved for PAIN:
´Buprenex®: parenteral, used in the hospital setting.
´Butrans®: weekly patch, 10 to 20 mcg/hr´Belbuca®: buccal film from 75 – 900 mcg/24 hr.
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What Formulation Should You Use?
´Generic buprenorphine avoids naloxone.´It is more susceptible to diversion´Use whatever their insurance will pay for!!
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Buprenorphine long-term follow up: Fiellin, 2008
Concerns about buprenorphine
´It can be abused (mostly for withdrawal)´It is unsafe when combined with sedatives &
alcohol.´It is an opioid.´Relapse rates after detox exceed 90%. (Weiss,
2011)
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Vivitrol® (injectable naltrexone) for opioid dependenceThis medication is not currently used during pregnancy; but may be used following delivery.
Addiction Tx in Russia
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3160743/
Kupitsky et al; Lancet 2011; 377: 1506-13
Vivitrol: abstinence (50%)
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No Vivitrol, Control Treatment (40%) No Vivitrol; No Treatment (0%)
Due to treatment
Due to Vivitrol (naltrexone)
Why the handcuffs? Vivitrol: craving
VIVITROL
CONTROL
Vivitrol: craving
VIVITROL
CONTROL
Vivitrol: concerns
´ As with methadone and buprenorphine, when the medication is stopped, relapse may lead to death due to lack of tolerance.
´ It would be very difficult to treat acute pain while on Vivitrol : suggestion is “20x normal dose”.
´ Ex: a patient underwent emergency operative laparoscopy 2 weeks after Vivitrol injection. He was treated with IV Dilaudid, 10 to 20 mg/hr.
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Doc, when can I get off this sh*t medication?Can you detox off MAT?
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Luty 2003
´101 women underwent detox during pregnancy´40 successfully detoxed.´No adverse fetal effects documented´BUT:
´ Luty et al, J Sub Abuse Treat 24 (2003); 363 - 367
ORT: yes or no??? 83
Maintenance vs. Detox? Kakko et al 2003
´40 heroin addicts were started on buprenorphine/naloxone.
´20 were “detoxed” off and offered counseling.
´20 were kept on buprenorphine/naloxone and offered counseling.
´A year later…….
ORT: yes or no??? 85ORT: yes or
no???
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ORT: yes or
no???
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Can you taper off buprenorphine without relapse?
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Buprenorphine in opioid dependence
´ 654 patients enroll on buprenorphine for 2 weeks. ´ 50% stay abstinent.´ They are tapered off and over 90% relapse.´ 360 remain, they go back on buprenorphine for 12
weeks, ´ 50% stay abstinent.´ They taper off and 90+% relapse.´ Moral of the story: medications work as long as you take
them.
“Your Baby Will Die If You Detox”:Opioid Detox During Pregnancy
´Fetal death during pregnancy is rare.´Patients can be successfully and safely detoxed.´The lowest neonatal abstinence rates are seen
with incarcerated patients (19%).
Bell et al, AJOG 2016; 215: 374.e1-6
What is the Risk of Dying in and out of Treatment?
´Relative Risk= the risk of dying compared to someone who does NOT have opioid addiction
´RR= 1 without addiction.´If RR >1 you are more likely to die.
Mortality and M.A.T (bup and MTD)122, 885 patients: OD mortalityNO ADDICTION: RELATIVE RISK IS ONE (1)
METHADONE BURPENORPHINEIn treatment Out of treatment In Treatment Out of
Treatment
3 13 1 5
Sordo L et al. Mortality Risk during and after opioid substitution treatment: systematic review and meta0analysis of cohort studies. BMJ 2017; 357: J1550
Take Home Points:
´Mortality appears to decrease (29%) after starting medication assisted treatment .
´Mortality INCREASES after leaving treatment.´Both the first two weeks IN treatment
(methadone ) and OUT of treatment (methadone and buprenorphine) are the most dangerous periods.
Treatment of Opioid Dependence During Pregnancy
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METHADONE“the gold standard”´ Was only approved for use for
addiction in 1965; Dr. James Wardell started in Detroit in 1969.
´ TIP 40: methadone is (was) the preferred treatment in pregnancy
´ Buprenorphine was considered experimental.
´ Improvement in neonatal outcomes documented by Ed Johnson and Andre Jones.
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Maternal Opioid Treatment:Human Experimental Research
(MOTHER)
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:NEJM 2010; 363: 2320-31
MOTHER STUDY
´Double blinded, RCT´Methadone vs. buprenorphine´Contingency management (financial incentives
$$$$)´CBT (cognitive behavioral tx)´Transportation, etc.´NO polysubstance dependence x tobacco!
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MOTHER STUDY
´Patients already on methadone are admitted to research unit for detox
´6 mg MS/mg methadone (4 divided doses)´Rescue doses prn´Kept until stabilized´THIS IS NOT FEASIBLE IN CLINICAL PRACTICE!!!!!!!!!´Randomized to study meds on L & D
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Sites
´ Johns Hopkins, Baltimore MD
´T. Jefferson Univ., Philadelphia, PA
´Women & Infants, Providence RI
´Vanderbilt UMC, Nashville, TN
´St. Josephʼs Hlth Ctr. Toronto, Canada
´Wayne State Univ., Detroit, Michigan
´University of VT, Burlington, VT
´Addiction Clinic Vienna, Austria
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Methadone vs. Buprenorphine: the MOTHER study
Measure Methadone BuprenorphineAmount of MS required 10.4 1.1# of days in hospital 17.5 10Duration of treatment for NAS 9.9 4.1Birthweight 2878 3093% preterm delivery 19 7*Positive drug screen at delivery 15% 9%*Dropped out 18% 33
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MOTHER study….
´“Buprenorphine exposed neonates…exhibited fewer stress-abstinence signs, were less excitable…less hypertonia…better self-regulation and required less handling…than methadone-exposed neonates.
´Jones Finnegan & Kaltenbach Drugs 2012
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Who should NOT go on buprenorphine? Patients who are:
´Already on methadone (>35 mg)´Active hepatitis C (high LFTs)´Unable to engage in treatment´Taking benzos´Plan on mixing bup with their opiates´Are diverting´Can’t get insurance coverage
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Buprenorphine-->Methadone?´NOT necessary!´Can continue buprenorphine´Risk of NAS is decreased (severity and
duration)with buprenorphine as compared to methadone!
´Again, neither of these is APPROVED for treatment of opioid dependence during pregnancy.
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Methadone à Buprenorphine?´Methadone:
´Has a LONG half life´MOTHER study dropouts were
partially due to attempts to convert high dose methadone to buprenorphine
´Current “expert opinion” is to limit to patients on 25 – 50 mg.
´Safest course may be to remain on methadone.
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Current Management: Eleonore Hutzel Recovery Center/ Tolan Clinic, Detroit Mich
´Patients who present on SHORT acting opioids: buprenorphine
´Patients who present on long acting opioids or methadone: methadone
´Benzodiazepine use must stop immediately or they will be referred for methadone.
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Management of Labor/Postpartum in the Recovering Patient
´Labor may be a trigger for relapse´Epidurals should be encouraged´Donʼt discharge patients with short acting opiates
whenever possible!´For C/S patients: need to involve family, social work,
addictionist when dispensing opiates´RESIDENTS: Confirm EVERYTHING the patient
tells you!!
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Who is Behind the Opioid Epidemic?
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Unintentional overdose deaths involving opioid analgesics parallel per capita sales of opioid analgesics in morphine equivalents by year, U.S., 1997-2007
0100200300400500600700800
0
2000
4000
6000
8000
10000
12000
14000
'97 '98 '99 '00 '01 '02 '03 '04 '05 '06 '07Source: National Vital Statistics System, multiple cause of death dataset, and DEA ARCOS
* 2007 opioid sales figure is preliminary.
Number of
DeathsOpioid sales (mg/person)
*
0
1
2
3
4
5
6
7
8
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Rat
e
Year
Opioid Sales KG/10,000 Opioid Deaths/100,000
deaths
treatment
Rates of Opioid Sales, OD Deaths, and Treatment, 1999–2010
CDC. MMWR 2011
sales
Michigan is 10th in the US:107 prescriptions/100 people.
139 WHY do doctors over prescribe?
´The Four D’s:´Dated´Dishonest ´Duped´Disabled
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The Four D’s:
´Dishonest?´Dated´Disabled´Duped
141 The Four D’s:
´Dishonest?´Dated´Disabled´Duped
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The Four D’s:
´Dishonest?´Dated´Disabled´Duped
143 The Four D’s:
´Dishonest?´Dated´Disabled´Duped
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Pressure on Doctors?
Baker D. History of The Joint Commission’s Pain Standards: Lessons for Today’s Prescription Opioid Epidemic. JAMA, published online February 23, 2017.
“by 2004 this phrase was deleted from the accreditation standards manual”.
The Four D’s:
´Dishonest´Dated´Disabled´Duped´The 5th D: defamation
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Lembke, Anna. Why Doctors Prescribe Opioids to known Opioid Abusers. n engl j med 367;17 nejm.org october 25, 2012
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Developed for Families Against Narcoticshttp://www.familiesagainstnarcotics.org/
The Opioid Epidemic& Naloxone (Narcan®) Rescue
Naltrexone vs. Naloxone
Naltrexone´ Oral (Rivea®) or IM (Vivitrol®)
´ Slow onset
´ Long acting (hours to weeks)
´ Tightest binding to brain
´ Used for PREVENTION of overdose (FDA)
Naloxone´ IV, IM, SC or IN (Narcan®, Evzio®)
´ Rapid Onset
´ Short acting (minutes)
´ Less tightly bound
´ Used for TREATMENT of overdose (FDA)
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Naloxone formulations:(0.4 mg)
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Intranasal (I.N.): ADAPT (4mg/2mg!)154
Who is at Greatest Risk?
´Abstinence > 2 weeks: treatment; jail; relapse.´Discontinuing MAT: methadone; buprenorphine;
Vivitrol® (naltrexone). ´Mixing opioids with sedatives: alcohol,
benzodiazepines, muscle relaxers´FENTANYL
´50% of UDS samples with heroin are pos for Fentanyl
155 Fentanyl on Urine Drug ScreenPregnant Patient
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How To Do A Naloxone Rescue
´Make Sure They are Not Breathing´(always) Call 911´Do Rescue Breaths (not compressions)´Give Naloxone´Resume Rescue Breaths´Repeat Naloxone every 3 mins´To review videos: go to ccmdphd on
YouTube
157 Naloxone in Pregnancy
´“due to the risk of induced withdrawal, use of naloxone should be avoided during pregnancy and used only when absolutely necessary”
´ASAM textbook of addiction medicine
Naloxone in Pregnancy
´“That statement is no longer operative.”
´Ron Ziegler, President Nixon’s Press Secretary
Contact Information: Carl Christensen
´Email: [email protected]´Office 734 368 9871´Cell: 734 218 5317´Website: www.christensenrecovery.com
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