John McCarthy, M.D.Medical Director, BAART/Bi-Valley Medical Clinic, SacramentoAssociate Professor of Psychiatry, UC Davis
Part 1: OpiateAddictionandPregnancyPart 2: MethadonevsBuprenorphine:What Goes?
Pregnancy is Politics!!
Open Letter to the Media and Policy MakersRegardingAlarmistand Inaccurate Reportingon PrescriptionOpiate Use by Pregnant WomenMarch 11,2013NationalAdvocates for Pregnant Women, 15 West 36th Street, Suite 901, New York, NY 10018
Dr. Bob Newman and the NationalAdvocatesfor Pregnant Women(NAPW)
Between 2000-2009 antepartum opiate use increased five fold in pregnant women (Patrick et al JAMA 2012)Neonatal abstinence increased nearly three fold. (Patrick et al)Most of this increase reflects prescription opiate abuse/addiction.The average age on admission to Bi-Valley programs went from 42 to under 30 years in the space of about 5 years. About 40% of young admissions are women
Perinatal Complications of Heroin Addiction in the Pre-Methadone Era
Fetal and neonatal mortality from untreated heroin addiction was 10% (Frickerand Segal, 1978)Fetal and neonatal demise from maternal heroin addiction was 4 times general population: 12 stillbirths and 25 neonatal deaths among 792 cases. Autopsy: focal CNS hemorrhages from fetal hypoxia during opiate withdrawal (RementeriaandNunag1973)During severe withdrawal, oxygen supply goes down, oxygen demand goes up
Is it to protect the fetus from methadone?Meaning use low doses and/or reduced doses and have the mother tough it out or even relapse to drug use.Or is it to protect the fetus from withdrawal?Meaning treat maternal withdrawal with dose increases to protect the fetus fromintrauterineabstinence and have a mother who is not chronically sick.
What is the Goal of Methadone Dosing in Pregnancy?
A recent meta-analysis of the relationship of methadone dose to neonatal abstinence syndrome (NAS) reviewed 67 studies (Cleary: 2010).The last research studyofhuman fetal opiate abstinence was in 1975 (Zuspan)The first summary of intrauterine abstinence syndrome (IAS): 2011 McCarthy (J Maternal Fetal Neonatal Medicine)
When the mother is in withdrawal then the fetus is in withdrawalThis is true for the second trimester onward, probably not in the first trimester.
Fetal Stress: TheZuspanStudy (1975)
Zuspanetal, reportingon theeffects ofa 1973FDAmandate that forced a 21-daywithdrawal onall pregnantwomen, documented one fetal death during withdrawalwhichthey attributed tothis process “since violentintrauterinemovements precededthe stillbirth”They reportedknowledgeof foursimilardeaths.
Fetal Stress: TheZuspanStudy (1975)
Theythen used serial amniotic fluid amine assays to monitor thefetus duringwithdrawal. Aftermethadone decreasesof 5 and 3 mg,epinephrine and norepinephrinevalues were 8–10 times higher than baseline.Becauseof theevidence of fetal stress, the dose was increased andfetal catecholamine levelsimproved. Maternal catecholamine levelswere normal,indicating apurely fetal stress response.Theauthors recommendedagainst detoxificationduringpregnancy,unlessa scientific means is availableto monitorfetal homeostasis.
Cleary et al in a meta-analysis of 67 studies of methadone dose and NAS found 4 different approaches to dosing1. withdrawal2. maintenance on low doses3. maintenance as needed and then reduced doses4. dose increases as needed to treat maternal withdrawal
Methadone Dosing:A Clinical Quagmire
Methadone is metabolized by hepatic enzymes (3A4, 2D6) for which there issignificantgenetic diversity causing diversity in metabolic rates. The ½ life can vary between 18-36 hrs.Pregnancy accelerates methadone metabolism. It converts women into rapid metabolizers.CYP3A is consistently and significantly increased in all stages of pregnancy. It may occur before the woman is aware she is pregnant. Genetic testing is now available.The fetus is exposed only to the serum, not the oral dose. If methadone is cleared rapidly then the dose can be quite high (415mg, 70mg q4h) and yet fetal exposure quite low, (e.g90mg TID with trough methadone below detection)
Methadone Disposition in Pregnancy
May expose the fetus to daily episodes of ‘oversedation’ and withdrawalAn ultrasound studyof single and split doses by Whittmann and Segalfoundsignificant fetal behavioral abnormalitieson singledose regimens, including percent of time spentbreathing, numberof rotational body movements, and longest period offetalactivityprior to the AM dose.Thesechanges normalized on aBIDregimen.Cardiac parameters have also been shown to normalize on BID regimen
The Problem with Single Doses
Reduces or eliminates fetal methadone peaks and troughs which are not physiologic for the fetusMay allow maintenance on lower dosesBy reducing maternal withdrawal stress, it makes for a healthier pregnancyReduces maternal anxiety about withdrawalReduces risks of relapse
Advantages of Split Dosing
Average and mean dose 152mg/day, divided between 3-6 times a day.Drug of choice on admission 71% prescription opiates (hydocodoneor oxycodone), 29% heroinAverage serum level 288ng/ml (therapeutic range for trough levels is 200-600ng/ml)
Maternal Outcomes BVMCN=62
Mean gestational age 38.2 weeks (r 23-42)Full term (N=51/62) 82%Mean weight 2903grms(6lb 8oz) (r 564-3883)Full term weight (N=51) 3119gm92% of infant toxicology screens were negative for illicit drugs80% of neonates were nursed
29% were treated for NAS (N=18/62)Theliterature reports 50-80% of babies exposed tomethadone needtreatmentLOS in hospital 10 days.Rx’d22 days; notRx’d3.8 days25 female babies only 4 treated (16%) 37 male babies, 14 treated (38%)
Neonates Treated for NAS
Seiko in England reports a rate of treatment of 11%: the lowest rate of treatment ever reported.Abrahams in Vancouver reports a treatment rate of 30%Do neonates go into withdrawal from the mother? (Maternal Absence Syndrome)Do NICU environments exacerbate NAS?How necessary are NICUs for NAS management?Can NAS scoring be done with the mother present?
Mother/Infant Rooming-In Reduces Need for NAS Treatment
Dutch War Baby syndromeFetal Origins Hypothesis (Barker)Maternal stress increases fetal exposure to stress hormones, adrenalin, corticosteroids, which have been shown to have long term adverse developmental consequences for the child.
Is Stress in the Womb a Problem for the Fetus?
Both mu opiate receptor agonistsBoth cause continue physical dependence and withdrawalrisksBoth long acting with theoretical once a day dosing. But multi-dosing regimens are necessary in many patientsBoth effective treatments for opiate addictionBoth may have beneficial psychotropic effects, e.g. anti-anxiety, anti-depressant, anti-psychotic effects that are not well understood or clarified
Methadone is full opiate agonist; bup is a partial agonist with a ceiling effect on respiratory depression making bup safer in misuse or overdose situationsBup is an opiate antagonist (narcan like) when other opiates are present. It can cause severe precipitated withdrawal.Methadone has no such risks and is therefore safer for induction.Methadone is more effective in retaining patients in treatment, at least for more severe addictionsMethadone has more side effects,e.gweight gain, sweating, sedation
Although there are some studies that suggest bup has a milder withdrawal, there is no evidence that there is any greater success with continued recovery off the medicationAt low doses (like what a fetus is exposed to) both methadone and buprenorphine are full opiate agonists! Withdrawalsymptoms may be similar.Brain recovery involves endorphin and opiate receptor synthesis and a physical recovery process that may be unrelated to either methadone or buprenorphine
Bup seems to be moreabusable, especially by IV route.Addition of naloxone (Suboxone) of questionable efficacy in preventing abuse (Australian study), but that is at least the political justification.Buprenorphine is an easier treatment modality for the patient to access because regulations are minimal compared to methadone.But treatment intensity and perhaps effectiveness is better with methadone because of the added structure and counseling.