1. 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
October 7, 2011

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

3. 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: 3 3

4. America Has Never Been Drug-free Most commonly used drugs in order of frequency:
1800 to 2000
21st Century:
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.

5. 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

6. Changes In Opioid Use
Percent of pregnant patients dependent on opioids referred to an Indiana Substance Use Program:
: 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.

7. 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

8. 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.

9. 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 mg to get high.
It sells for about $1 per milligram

10. PMP Restricts “Oxy” Abuse
47 states have a Prescription Monitoring Program (PMP)
Inspect:
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.

11. 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 year olds

12. 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!

13. 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.

14. 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?

15. 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 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.

16. 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:
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:

17. 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:
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 year old women in mid-Sweden; a population based study. J Clin Epidemiol ; 17

18. 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

19. 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”

20. 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)

21. 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):
Do you have a reference for the picture?

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

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

24. 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

25. 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.

26. 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.

27. 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

28. 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: /bjo

29. 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: days or more

30. 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 hours
Slow release into blood

31. 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.

32. 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

33. 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):

34. 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):

35. 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

36. Opioid Use in Pregnancy This is the Evidence
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

37. 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: 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%)

38. 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%)

39. 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%)

40. 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%)

41. 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%) NAS Treated 1 5 NS Mean Length of Stay Failed to return PP Returned PP “negative” 23 (74.2%) 25 (55.5%) NS

42. 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 days
NAS treated: 80 (86.9%)
Intrapartum Complications: 15
Nicotine: 51/90 (56.6%)

43. 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%)

44. Buprenorphine Patients
Subutex N = 12; Suboxone N = 34; Total N= 46
Preterm Delivery: 5 (10.9%)
Mean newborn weight: 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%)

45. 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%)

46. Methadone vs. Buprenorphine Major Pregnancy Outcomes
Bup. (46) Meth (90) p
Preterm Delivery 5 (10.9 %) 27 (30%) 0.001
Low Birth Weight (<2500g)
Mean Birth Weight g 2718g
Neonatal Abstinence (NAS)
NAS Treated
Mean Length of Stay
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.

47. 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

48. 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.

49. 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

50. 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.

51. 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.

52. 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

53. 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 pills a day
UDS positive for opiates; often find THC, Benzodiazepines, cocaine.

54. 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):

55. 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.

56. 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.

57. 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 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:
Philipp BL, Merewood A, O'Brien S. Methadone and breastfeeding: new horizons. Pediatrics 2003;111:

58. 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.

59. 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 mg h.s.
Gabapentin 300 mg TID
Physical Therapy – maintain mobility

60. 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

61. 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

62. 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.

63. 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

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

65. 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.

66. 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 % 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

67. 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.

68. 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

69. 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.

70. 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

71. 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.

72. 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:e

73. 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.

74. 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.

75. 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 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

76. 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 % 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

77. 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.

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

79. 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

80. 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:

81. 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.

82. 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:

83. 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.

84. 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.

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

86. 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.”

87. 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.