Opioid Dependence in Pregnancy James J. Nocon, M.D., J.D. Indiana University School of Medicine Chairman, Indiana Prenatal Substance Abuse Commission Director, Prenatal Recovery Clinic Wishard Memorial Hospital 1001 West 10th Street, F5102 Indianapolis, Indiana 46202 jnocon@iupui.edu October 7, 2011

Objectives Review Opioid Pharmacology Types of Opioid Dependence Managing Opioid Dependence Prenatal Intrapartum Breast Feeding Effects on the fetus and newborn Withdrawal

Pregnancy Enhances Recovery Pregnancy makes a difference in long-term recovery. After one year of treatment: 65.7% of women who entered treatment while pregnant used no drugs, while Only 27.7% of non-pregnant women remained drug free. (p<0.0005) Peles E, Adelson M. Gender Differences and Pregnant Women in a Methadone Maintenance Treatment (MMT) Clinic. J Addictive Diseases 2006; 25: 39-45. 3 3

America Has Never Been Drug-free Most commonly used drugs in order of frequency: 1800 to 2000 21st Century: 2002-2007 Cocaine – the 7% solution Cannabis (THC) (2737 B.C China) Laudanum – tincture of opium; Morphine – from the Civil War Methadone – developed in Nazi Germany prior to WWII Alcohol –how the West was won Amphetamine -1887; used extensively in WWII to keep soldiers alert; the US military uses with airmen today in Iraq Methamphetamine -1893 Methylenedioxy-methamphetamine (MDMA) Developed by Merck in 1912 as an appetite suppressant; today it’s called ecstasy Cocaine 52 Cocaine and THC 59 THC 49 Methadone 42 Other Opiates 27 Alcohol 10 Other Combinations 48 (opiates/amphetamines) Based on 287 pregnant patients treated from 2002 to 2007.

What’s the Difference Between Opioids and Opiates? Alkaloids derived from the opium poppy Morphine, Codeine, Thebaine Opioids All Opiates, plus: Semi Synthetics – derived from the alkaloids (thebaine): hydrocodone; oxycodone; heroin Synthetics: methadone; fentanyl; nubain; buprenorphine

Changes In Opioid Use Percent of pregnant patients dependent on opioids referred to an Indiana Substance Use Program: 2002-2007: 69/287 patients: 24% 2008: 69.3% 2009: 79.1% 2010: 75.5% Includes heroin, opioid dependent chronic pain patients, opioid poly-substance users, methadone and buprenorphine maintenance.

Opioid Abuse Skyrockets Opioid prescription abuse is the fastest rising addiction and public health problem in the United States. Over 2,000 deaths per week have been attributed to opioid abuse. Most of the fatalities are due to Oxycontin http://www.foodconsumer.org/newsite/Politics/32/opioid_abuse_skyrockets_061820100141.html

What’s Oxycontin? Oxycodone Most abused Rx drug: Made by Perdue Pharma Special coating allows for extended release Marketed as safe – low addictive risk Perdue Pharm sued for misbranding, among other issues. East to remove the coating – rapid onset Most abused Rx drug: Especially in Kentucky and Tennessee: “Hillbilly Heroin” OxyContin's warning label said to not crush the controlled-release tablets because of the potential for rapid release of oxycodone, which led many people to crushing the tablets and injecting or snorting the drug.

Typical Doses of “Oxy” 10 mg - white 15 mg - grey 20 mg - pink 30 mg – brown – most often prescribed 40 mg – yellow 60 mg - red 80 mg – greenish blue Addicts typically use 250 mg/day to feel normal. And 500-550 mg to get high. It sells for about $1 per milligram

PMP Restricts “Oxy” Abuse 47 states have a Prescription Monitoring Program (PMP) Inspect: http://www.in.gov/pla/inspect.htm Florida’s program in jeopardy due to lack of state funding. Lack of effective PMP allows “pill mills” to flourish as “Pain Clinics.” 41 million prescriptions for Oxy in Florida (July to Dec 2010) Only 4 million Rx for entire US.

Political Ideology Enables “OXY” Abuse; Intent vs. Impact Intent of Florida Governor To reduce federal government and spending. Rejects 15 million in Federal funds for the PMP. Rejects the PMP because of opposition to supporting a “government database.” Attempts to repeal Florida Law creating PMP Impact: Allows pill mills to flourish. More “pain clinics” in Florida than McDonalds. Kills 10 people per day in Florida #1 drug of abuse among 12-17 year olds

Others Enable “Oxy” Abuse Organized Crime Pharmacies Doctors Over $5,000 a day to write prescriptions in “pill mills” in Florida. Can easily make over a million dollars/year No nights, no call, just writer’s cramp. And, America has never been drug free!

What is Addiction? Great question. Like obscenity, hard to define but, I know it when I see it. Dependence Psychological: withdrawal Physical; tolerance and withdrawal Addiction: continuing the behavior in spite of the adverse and illegal consequences of the behavior.

Relationship View of Addiction If the behavior keeps me from being physically and emotionally present for those I love and those who love me. Then I have a problem with the behavior. May be alcohol, tobacco or other drugs (ATOD) May be eating, sex, gambling, etc. Hoarding?

Addiction in Women Late 19th Century: Women accounted for 2/3 of America’s opiate addicts and a large percentage of marijuana, sedative, cocaine and amphetamine addiction. Only 1 in 5 illegal drug addicts during 1914-1954 were women Approximate 15% of all pregnant women today are using alcohol, illegal and illicit drugs during pregnancy. Note: Americans constitute 4% of the world’s population and consume 2/3 of the entire drug supply.

Psychiatric Gender Issues in Maternal Addiction If sexually abused as a child: 6 times more likely to become drug addict (opiates) 4 times more likely to become an alcoholic Kendler KS, et al. Childhood sexual abuse and adult psychiatric and substance use disorders; an epidemiological and co-twin control analysis. Arch Gen Psychiatry. 2000;57:953-959. Major depression more frequent in women substance users. Prescott et al. Sex specific genetic influences on the co-morbidity of alcoholism and major depression in a population-based sample of U.S. twins. Arch Gen Psychiatry. 2000;57:803-811.

Other Women’s Issues in Addiction Alcoholic women usually have alcoholic spouses and less spousal support. (Holds true for opiates, as well) Redgrave, et al, Alcohol misuse by women. Int. Rev. Psychiatry 2003;15:256-268 Women more likely to abuse prescription drugs “My mother gave me her Xanax.” Vicodin, Lortab, Xanax and Klonopin. Bardel, et al. Reported current use of prescription drugs and some of its determinants among 35-65 year old women in mid-Sweden; a population based study. J Clin Epidemiol. 200 53;637-643 17

The Pathophysiology of Addiction Just as alcohol, tobacco, and drugs activate the pleasure circuit in the brain, so do many behaviors such as sexual activity, winning a contest, gambling, and being praised. What drugs and behaviors have in common is the release of various neurotransmitters in nucleus accumbens in the brain: Dopamine – creates the “buzz.” Serotonin – sense of well being. Endorphins – euphoria. GABA (gamma amino butyric acid) – satiety and somnolence (sleepy after a big meal or sex) As repeated use of the drug or behavior depletes the dopamine, more activity is required to get the same effect. “Tolerance.” There comes a point when the affected person becomes an addict, as if a switch in the brain is flipped, and the person no longer has the ability to make free choices about the continued use of the drug. Leshner AI. Addiction is a brain disease, and it matters. Science 1997;278:45-47 18 18

Pleasure in the Brain http://thebrain.mcgill.ca/flash/index_i.html Ventral Tegmental Area Nucleus Accumbens – dopamine rich center in the limbic area Prefrontal Cortex – short term memory Amygdala – moderates emotional influences on memory – fear response MFB: medial forebrain bundle These are the primary centers involved in pleasurable sensations. Often referred to as “the Pleasure Circuit”

Continuous Use of Drugs Changes Brain Cells Dopamine System Cocaine inhibits transporters Amphetamine affects receptor and neurotransmitter release Serotonin Hallucinogens inhibit receptors GABA/NMDA Etoh inhibits and facilitates receptor function Opiates have negative effect (Morphine; Heroin)

Pathophysiology: Addiction Changes Brain Cells Addiction is a “double whammy.” Tolerance - The brain needs more and more of the drug in order to get the same effect. And in this process, the brain cells are actually altered. Drugs reduce fear response in Amygdala and Prefrontal cortex – person uses more drug with less fear of consequences. McCann UD, Szabo Z, Scheffel U, Dannals RF, Ricaurte GA. Positron emission tomographic evidence of toxic effect of MDMA ("Ecstasy") on brain serotonin neurons in human beings. Lancet 1998 Oct 31;352(9138):1433-7. Do you have a reference for the picture?

You Know You Are Addicted When you will do anything including breaking the law to obtain the drug, Just to feel normal.

An Important Digression: Alcohol and tobacco cause more fetal damage than all the other drugs combined including all the known teratogens.

Strong Link Between Alcohol/Nicotine Use and Use of Illicit Drugs Among Women using BOTH Alcohol and Nicotine in the pregnancy • 20.4% used Marijuana • 9.5% used Cocaine Women NOT using Alcohol or Nicotine • 0.2% used Marijuana • 0.1% used Cocaine Alcohol and Nicotine use is also a marker for other drug use. 24

Opiate Use In Pregnancy Derived from Poppy, Papaver Somniferum, 4000 BC Morphine 1806 Codeine 1832 Heroin 1898 (Bayer) – was the drug of choice for obstetrical analgesia immediately post WWII Methadone 1930 (Bayer) – synthetic opioid Other Commonly Used drugs Marijuana noted in China 2737 BC – Major Cash crop in Jamestown 1611 Cocaine - Spanish taxed it use 1569 Amphetamine marketed by Smith Kline in 1887.

Most Common Opiates Used by Pregnant Patients Hydrocodone: Vicodin; Lortab Oxycodone: Oxycontin: Percocet Methadone Heroin Opiates were mostly Category B Drugs Animal studies appear to pose no risk, but Definite risk established in humans Visual defects confirmed in human studies with methadone.

Maternal Treatment with Opioid Analgesics and Risk of Birth Defects National Birth Defects Prevention Study, case-control study for infants born October 1, 1997, through December 31, 2005, in 10 states Therapeutic opioid use was reported by 2.6% of 17,449 case mothers and 2.0% of 6701 control mothers. Treatment was statistically significantly associated with: 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) in infants http://www.ajog.org/article/S0002-9378(10)02524-X/abstract

Methadone: Visual Problems Reduced acuity (95%), Nystagmus (70%), Delayed visual maturation (50%), Strabismus (30%), Refractive errors (30%), and Cerebral visual impairment (25%). Hamilton; Ophthalmic, clinical and visual electrophysiological findings in children born to mothers prescribed substitute methadone in pregnancy. Br J Ophthalmol doi:10.1136/bjo.2009.169284

Opiate Pharmacology Bind to receptors Mu: analgesia; euphoria, respiratory depression, constipation, sedation, miosis Kappa: dysphoria, sedation, psychotomimetic Delta: unknown Rate of Excretion faster than withdrawal Morphine excreted within 72 hours Methadone takes 4-5 days. Clinical relevance is patient in withdrawal may have negative UDS. Withdrawal in Adult: 6-24 hours from last dose Morphine: 3-7 days duration Methadone: 10-20 days or more

Opiate Agonists Morphine/Codeine/Dilaudid and Derivatives Methadone Specificity for Mu receptor Metabolized by liver ½ life 2-4 hours 90% excreted in urine/24 hrs Methadone 90% bound to protein ½ life 20-40 hours Slow release into blood

Opiate Antagonists Naloxone - Narcan Naltrexone - Vivitrol Very strong affinity for Mu receptor Rapid competitive antagonist – 2-4 minutes Lasts about 45 minutes “Jump starts” withdrawal Naltrexone - Vivitrol Binds more slowly ½ life 4 hours Used in alcohol and opiate treatment.

Opiate Agonist/Antagonists Nalbuphine (Nubain) 10 mg. IV or IM q. 3 hours ; onset 2-3 min IV Neonatal half life: 4.1 hours A favorite of OB nurses – less nausea Butorphanol (Stadol) 1-2 mg. IV or IM every 4 h; onset 1-2 min IV Neonatal half life unknown Buprenorphine (Subutex/Suboxone) Long acting; long half life Used for maintenance like methadone

Pregnancy Increases Metabolism of Specific Opiates Certain enzyme systems increases the metabolism of specific opiates, especially: Methadone Hydrocodone Oxycodone This is especially true of Methadone Jarvis, M. A., S. Wu-Pong, et al. (1999). "Alterations in methadone metabolism during late pregnancy." J Addict Dis 18(4): 51-61.

Increased Opioid Metabolism Increases with each trimester, especially third 30-40 percent of patients Doses may increase by 50%. May require more drug to treat pain Methadone patient may be in chronic withdrawal by third trimester. Higher does methadone actually has better outcome. McCarthy, J. J., M. H. Leamon, et al. (2005). "High-dose methadone maintenance in pregnancy: maternal and neonatal outcomes." Am J Obstet Gynecol 193(3 Pt 1): 606-610.

Clinical Management of Opioid Dependence in Pregnancy What is the Evidence? Standard of Care Opiate Overdose Opiate Withdrawal Opiate Maintenance Chronic pain patients Methadone maintenance Buprenorphine maintenance Opiate analgesia: labor; delivery; Cesarean Neonatal Abstinence Syndrome (NAS) Breastfeeding

Opioid Use in Pregnancy This is the Evidence 2002-2010 Four Groups: 213 Patients Pain patients using only opioids – 31 Opiate dependent poly-substance patients – 45 Methadone Maintenance - 90 Buprenorphine Maintenance – 46 Subutex – 12 Suboxone - 34

Opioid Dependent Chronic Pain Patients Using Opioids Only Includes opioid/acetamenophen preparations. N = 31 Preterm Labor: 4 (12.9%) Positive Meconium (other than opiates): none Mean newborn weight: 3085.9 grams LOS (newborn): 3.3 days; range 2-21 days NAS treated: 1 Intrapartum complications: 7 No overdoses. Nicotine use (> 0.5ppd): 21 (67.7%)

Opioid Dependent Poly-substance Patients Opioids plus cocaine, or THC or benzodiazepines or all three or more N = 45 Preterm Delivery: 8 (17.7%) Positive Meconium (other than opiates): 12 (26.6%) Mean newborn weight: 2879 grams LOS (newborn): 7.8 days; range 2-89 days NAS treated: 5 Intrapartum complications: 7 One antenatal overdose – mother and fetus survived One fatal postpartum overdose Nicotine Use (> 0.5ppd): 30 (66.6%)

Opioid Only Patients Postpartum Visit Routinely at 4 weeks postpartum N=31 Did not return: 3 Returned with positive UDS for drugs other than prescribed opioids: 5 Returned “negative:” 23 (74.2%)

Opioid Poly-substance Patients Post Partum Visit Routinely at 4 weeks postpartum N=45 Did not return: 13 (28.8%) Returned with positive UDS for drugs other than prescribed opioids: 7 Returned “negative:” 25 (55.5%)

Comparison of Opioid and Opioid Plus Use in Pregnancy Opioid (31) Opioid + (45) p Preterm Delivery 4 (12.9 %) 8 (17.7%) NS Low Birth Weight (<2500g) 3 8 NS Mean Birth Weight 3085 g 2879g NS Positive Meconium 0 12 (26.6%) 0.001 NAS Treated 1 5 NS Mean Length of Stay 3.3 7.8 0.01 Failed to return PP 3 13 0.01 Returned PP “negative” 23 (74.2%) 25 (55.5%) NS

Methadone Maintenance Patients N = 90 (92 babies) Preterm Delivery: 28 (30%) Mean newborn weight: 2718g LBW (< 2500g): 31/92 (33.7%) Positive meconium: 9 (10.8%) Mean LOS 30.3 days NAS treated: 80 (86.9%) Intrapartum Complications: 15 Nicotine: 51/90 (56.6%)

Methadone Maintenance Post Partum Routinely at 4 weeks postpartum N=90 (92 babies) Did not return: 28 (31.1.%) Returned with positive UDS for drugs other than prescribed opioids: 3 Returned “negative:” 59 (65.5%)

Buprenorphine Patients Subutex N = 12; Suboxone N = 34; Total N= 46 Preterm Delivery: 5 (10.9%) Mean newborn weight: 3079.5 g LBW (< 2500g): 5 (10.8%) Positive meconium: 3 (6.9%) Mean LOS: 6.78 days; range 2-49 days NAS: 8 NAS treated: 6 Intrapartum Complications 8 Nicotine: 29 (63%)

Buprenorphine Postpartum Routinely at 4 weeks postpartum N=46 Did not return: 13 (28.2%) Returned with positive UDS for drugs other than prescribed opioids: 4 (8.6%) Returned “negative:” 29 (63%)

Methadone vs. Buprenorphine Major Pregnancy Outcomes Bup. (46) Meth (90) p Preterm Delivery 5 (10.9 %) 27 (30%) 0.001 Low Birth Weight (<2500g) 4 26 0.01 Mean Birth Weight 3079 g 2718g 0.005 Neonatal Abstinence (NAS) 8 89 0.001 NAS Treated 6 80 0.001 Mean Length of Stay 6.78 30.3 0.001 Failed to return PP 13 (28.8%) 28 (31.1%) NS Returned PP “negative” 29 (65.1%) 59 (65.5%) NS See also, Kakko J, Heilig M, Sarman I. Buprenorphine and methadone treatment of opiate dependence during pregnancy: comparison of fetal growth and neonatal outcomes in two consecutive case series. Drug Alcohol Depend 2008 Jul 1;96(1-2):69-78.

The Evidence Suggests New Treatment Strategies Prevention of Withdrawal Opioid Overdose Withdrawal Detoxification Maintenance Methadone Buprenorphine Opioid dependent chronic pain patient Polysubstance Use in Chronic Pain Patient

Standard of Care: Prevention of Withdrawal Evidence based literature clearly indicates that it is imperative to prevent opiate withdrawal in pregnancy: Increased rate of preterm labor – 41% Increased incidence of abruption 12% Efforts to wean off or “detox” opiates in pregnancy carry an increased risk of harm to the fetus. This represents a shift in the standard of care from “lowest possible dose” to “appropriate” doses to prevent withdrawal.

Opiate Overdose Characterized by pinpoint pupils, respiratory depression, coma, and pulmonary edema. Establish airway. Inject Naloxone – repeat if long acting opiate present, e.g., methadone. Naloxone will not harm fetus. Treatment will precipitate a severe withdrawal. Will need to restart and modify an opioid dose For maintenance, use methadone or buprenorphine Methadone: start at 20 mg BID and increase 5-10 mg per day until stable. Buprenorphine/naloxone: start at 2 – 4 mg BID; increase by 2-4 mg every 6 hours until withdrawal is abated

Opiate Overdose Recovery Will need to restart and modify opiate dose to prevent withdrawal. Methadone maintenance – only by a federally certified clinic. But a licensed physician may legally prescribe methadone to treat withdrawal in pregnancy for an inpatient. Buprenorphine – only by a federally certified clinician.

Opiate Withdrawal Affects Major Systems CNS – tremors, seizures Metabolic – sweating; yawning Vascular – hot flashes and chills Respiratory – increased rate; respiratory alkalosis GI – cramps, nausea, vomiting, diarrhea Drug specific effects – methadone has a prolonged withdrawal: 10 – 20 days.

Onset of Opiate Withdrawal Short Acting (heroin; morphine; vicodin): begins 6-24 hours; peak 1-3 days; lasts 5-7 days Methadone: Begins 1-3 days; peaks 3-6 days; Lasts 2 weeks or more

Opiate Withdrawal Clinical Picture Patient presents with abdominal pain, cramps and diarrhea and may complain of contractions Also has yawning, lacrimation, restlessness; may have tachycardia. UDS may be negative for opiates! Typical history reveals Rx for hydrocodone/acet. 5/500 for injuries in auto accident years ago Admits taking more than prescription allows – commonly up to 15 - 20 pills a day UDS positive for opiates; often find THC, Benzodiazepines, cocaine.

Opiate Withdrawal in Pregnancy High rate of preterm labor - 41% Increased abruption - 13% Low Birth weight – 27% Increased incidence HIV; Hep B; Hep C Current recommendation is to avoid withdrawal during pregnancy This includes “detoxification” during pregnancy. The risk of adverse events from withdrawal is far greater than from the treatment of neonatal abstinence. Lam SK, To WK, Duthie SJ, Ma HK. Narcotic addiction in pregnancy with adverse maternal and perinatal outcome. Aust N Z J Obstet Gynaecol 1992 Aug;32(3):216-21.

Opiate Withdrawal Treatment Initiate methadone or buprenorphine to stabilize withdrawal: may use oxycodone 10 mg q 4-6h for up to 72 hours to stabilize patient and then switch to methadone or buprenorphine. Phenergan 25 mg q 4-6 H for withdrawal symptoms – best for nausea, vomiting and GI symptoms Or, Phenobarbital, 30 mg TID for neurological withdrawal symptoms. Clonidine 0.1 mg TID – vascular withdrawal symptoms. Check acetaminophen levels in patients using opiate/acetaminophen compounds.

Opioid Detoxification Must be closely controlled. Benefits rarely outweigh risks. Gradual reduction to minimize withdrawal Symptomatic treatment. Phenergan 25 mg q 4-6 H for withdrawal symptoms – best for nausea, vomiting and gastrointestinal symptoms Phenobarbital, 30 mg TID for neurological withdrawal symptoms. Clonidine 0.1 mg TID – vascular withdrawal symptoms.

Opioid Maintenance Methadone Encourage patient to remain on methadone during pregnancy. Expect dose to increase up to 50% during pregnancy in about 35% of patients. Doses range from 50-150 mg. per day. Higher doses not associated with severity of NAS but improve maternal compliance with prenatal care. Patient should be encouraged to breast feed. Note: Methadone is NOT FDA approved for treatment for opiate dependence in pregnancy. McCarthy JJ, Leamon MH, Parr MS, Anania B. High-dose methadone maintenance in pregnancy: maternal and neonatal outcomes. Am J Obstet Gynecol 2005;193:606-10. Philipp BL, Merewood A, O'Brien S. Methadone and breastfeeding: new horizons. Pediatrics 2003;111:1429-30.  

Opioid Maintenance: Buprenorphine Patient must be in opioid withdrawal to start buprenorphine treatment. Inpatient: some recommend initiating treatment with buprenorphine, 2-4 mg sublingual by either tablet of film. Increase dose by 2-4 mg every 6 hours to stop withdrawal symptoms. Convert to buprenorphine/naloxone for outpatient use. Target doses rage from 4 to 24 mg per day Most pregnant patients are stable at 8-16 mg per day in divided doses.

Opiate Dependent Chronic Pain Patient Maintain current opiate regimen – avoid withdrawal (both legal to do and meets standard of care) Hydrocodone 5/325 or 10/325 (up to 2 tabs q 6h) Oxycodone 5/325 or 10/325 (up to 2 tabs q 6h) Low rate of NAS noted with these doses Requirement of opiate may increase Pain moderators may be helpful Amytryptilene 50-100 mg h.s. Gabapentin 300 mg TID Physical Therapy – maintain mobility

Polysubstance Use Concomitant use of two or more psychoactive substances, in quantities and frequencies that cause individually significant distress or impairment. In one study, 107/287 or 37.2% of pregnant women presented for prenatal care with polysubstance use. Opiates are a common a component. As are Alcohol and Tobacco Common conditions with polysubstance use: Chronic pain conditions Fibromyalgia Bipolar Anxiety disorders

Chronic Pain Polysubstance Treatment Maintain opioid component Prevent withdrawal Reduce or eliminate benzodiazepine. Eliminate illegal substances – cocaine; THC Smoking Reduction Most require more intensive addiction counselling

Co-morbid Psychiatric Illness in Chronic Pain Patients Depression most common – 45% Substance Abuse - 19% Many chronic pain patients have been treated with a benzodiazepine and easily become dependent: especially Xanax; Klonopin Anxiety disorders – 16% (Xanax very common) PTSD (grossly under diagnosed) Bipolar – often unrecognized; be aware of aripiprazole – may cause significant HTN and Diabetes.

Reconditioning Physical Therapy in Chronic Pain Management The sine qua non of good pain management. Components: Strengthening, aerobics, etc Painful activities become comfortable Rehabilitates physically and psychologically Reduces depression and anxiety Enhances self efficacy Empowers patient to become functional

Red Flags for Abuse Lost/stolen Rx Early refills Calling unfamiliar physicians Use for psychoactive effect

Benzodiazepines Used in patients for musculoskeletal spasm and pain. Most often used for anxiety/panic disorder. Alprazolam and Clonazepam are Category D However, abrupt cessation will cause withdrawal, often severe. More prudent to prevent withdrawal. Neonatal withdrawal will often occur. Best to avoid starting benzodiazepine in pregnancy.

Analgesia and Anesthesia for Methadone Patients Epidural – labor/delivery/cesarean Spinal Can use intrathecal opiates/caines Post op pain management Use standard opiates – morphine, dilaudid Use 70-100% more or double the dose for a morphine or dilaudid pump Ibuprofen; 800 mg q 8 h as soon as tolerated Lots of stool softener

Buprenorphine Maintenance Note: Methadone is NOT FDA approved for treatment for opiate dependence in pregnancy. Buprenorphine has been found safe and effective in world-wide studies and recent studies indicate it is also safe for use in neonatal withdrawal. Easy to treat opiate withdrawals Has become standard of opiate dependency management in Scandinavia, Europe and the United Kingdom.

Buprenorphine History France 1996: buprenorphine registered to treat opiate dependence Physicians allowed to dispense by prescription 2002: Drug Addiction Treatment Act amended to allow qualified physicians to dispense buprenorphine by prescription

Buprenorphine Initial Observations Thousands treated with increasing numbers of pregnant patients Neonatal withdrawal noticed to be absent or mild Less preterm birth Normal birth weights Fischer G, Etzersdorfer P, Eder H, Jagsch R, Langer M, Weninger M. Buprenorphine maintenance in pregnant opiate addicts. Eur Addict Res 1998;4 Suppl 1:32-6.

Buprenorphine Subutex and Suboxone Buprenorphine – used for INPATIENT initiation High abuse potential for IV use Suboxone Buprenorphine/naloxone – created to eliminate IV abuse Majority of outpatients currently treated with suboxone

Buprenorphine Issues for Pregnant Patients Initial recommendation to use Subutex only – fear of effects of naloxone on fetus, specifically “intrauterine withdrawal.” Subsequent pharmological evidence reveals naloxone absorbed in extremely low dose with no evidence of harm Almost all current outpatients are treated with Suboxone. Majority of those pregnant conceived under Suboxone treatment.

Buprenorphine and NAS Recent evidence indicates buprenorphine safe and effective in weaning newborn from methadone with reduced length of stay when compared to morphine. Kraft WK, Gibson E, Dysart K, et al. Sublingual Buprenorphine for Treatment of Neonatal Abstinence Syndrome: A Randomized Trial. Pediatrics 2008;122:e601-607

Using Opiates In L&D Use of agonist/antagonist opiates popular because of reduced nausea and vomiting. However, Nalbuphine (Nubain) noted for excess sedation. Butorphanol (Stadol) may increase blood pressure – avoid in hypertension. Morphine best tolerated by largest group of patients.

Opioid Effects in Obstetrics Analgesic effect in labor is limited. Sedative effect is excellent. Major factor in prolonging latent phase labor. Ironically, morphine is the drug of choice for treating prolong latent phase – heavy sedation effect. Best analgesic effect is at beginning of active phase – use longer acting opiate MORPHINE Change drugs when ineffective (incomplete cross tolerance). Use adequate amounts; whatever it takes.

Dose of Opiates: Whatever It Takes. Morphine 2-5 mg. I.V. every 4 hours; onset 5 min. 10-15 mg. I.M. every 4 hours; onset 30-40 min Neonatal half life: 7.1 hours but less sedating than Nalbuphine Nalbuphine (Nubain) 10 mg. IV or IM q. 3 hours ; onset 2-3 min IV Neonatal half life: 4.1 hours Butorphanol (Stadol) 1-2 mg. IV or IM every 4 h; onset 1-2 min IV Neonatal half life unknown

Analgesia and Anesthesia for Methadone and Buprenorphine Patients Epidural – labor/delivery/cesarean Spinal Can use intrathecal opiates/caines Post op pain management Use standard opiates – morphine, dilaudid Use 70-100% more or double the dose for a morphine or dilaudid pump Ibuprofen; 800 mg q 8 h as soon as tolerated Lots of stool softener

Opiate Effects on Newborn All Opiates cause some depression but significant depression is rare. Meperidine (normeperidine): dose dependent neurobehavioral depression up to 63 hours. Nalbuphine - reduces neonatal perception to sound and tone for more than 24 hours. Morphine has the least toxic effect on fetus. Naloxone (Narcan) is the drug of choice for neonatal depression secondary to opiate sedation.

Neonatal Abstinence Syndrome (NAS) Hydrocodone babies rarely have NAS Morphine: Heroin – acute, severe but rapid – over in 72 hours Methadone – prolonged – 14-28 days with 6-8 weeks not uncommon Buprenorphine – mild and often not requiring treatment Breastfeeding assists NAS recovery

Assessment of Newborn with NAS Four Key Neurobehavioral Signs CNS signs: Irritability, excessive crying; voracious appetite Seizures GI signs: vomiting; diarrhea Respiratory signs: tachypnia; hyperpnea ANS signs: sneezing, yawning, tearing Finnegan Scale Finnegan and Kaltenbach (1992) in Hoekelman (ed) Primary Pediatric Care. St. Louis; CV Mosby 1367-1378.

Current Treatment NAS Combination therapy Oral clonidine; phenobarbital Dilute morphine drops Increase morphine dose until signs of withdrawal controlled Maintain controlling dose for 2 days Then wean morphine dose every 1-2 days. AAP Committee on Drugs. Neonatal Drug Withdrawal. Pediatrics 1998; 101: 1079-1088.

Drug Concentration in Breast Milk Milk to plasma ratio. Varies over time. When the amount of drug ingested from the milk, per unit of time, is less than the therapeutic dose (clinical effect), Then the level of exposure is low. Regardless of the milk to plasma ratio.

Methadone Long half life BUT, transfer to milk is minimal. Maternal dose of 80 mg. per day (typical) yields infant dose about 2.8% of maternal. Some studies indicate concentrations in breast milk unrelated to maternal methadone dose. Appears to have mitigating effect on NAS – shorter LOS of breast-fed infants. Phillip BL, Merewood A, O’Brien S. Methadone and breastfeeding; new horizons. Pediatrics 2003;111:1429-1430.

Buprenorphine Suboxone and Subutex Suboxone: buprenorphine and naloxone. Oral Rx for opiate dependent maintenance. Substantially reduced NAS. Minimal to no effect on breastfeeding. Most recent literature indicates using buprenorphine to treat NAS in newborn: improved efficacy and shortened LOS Kraft WK, et al. Sublingual buprenorphine for treatment of neonatal abstinence syndrome: a randomized trial. Pediatrics; published online August 11, 2008.

Opiate Dependent Chronic Pain Patients and Breastfeeding Hydrocodone, oxycodone and fentanyl. Usual doses for pain relief appear to have minimal to no effect on infant. However, many of these patients also use pain moderators which may depress infant: Benzodiazapines: Xanax; Klonopin Gabapentin: Neurontin Amytryptilene: Elavil (generally safe) Cyclobenzaprine: Flexoril High rate of tobacco use in these patients.

Methamphetamine Documented High dose in Breast Milk Resulted in infant death. Breast feeding contraindicated.

Recovery, Relapse and Breastfeeding Does breastfeeding enhance or detract from ongoing recovery in the postpartum patient? The most common cause of relapse is stress, and it doesn’t take much. If breastfeeding is not going well and the patient is experiencing significant stress, she is ripe for relapse. Plays into low self esteem - “I’m a failure” Baby always crying – “I need some peace and quiet.” Despair – using drugs to “numb out.”

Treating Addiction in Pregnancy What works - just about anything: Identifying the problem - 50% will abstain Motivating the patient - 85% will abstain What doesn’t - ignoring the problem.