1. MAT and Pregnancy Deborah Acker RN, CFN Nurse Service Administrator
Division of Protection and Permanency
Department for Community Based Services
Cabinet for Health and Family Services

2. OBJECTIVES Discuss the medications available to treat opioid addiction
Understand the pros and cons associated with each medication
Understand the risks and benefits of utilizing these medications during pregnancy

3. Definitions
MAT – Medication Assisted Treatment MMT – Methadone Maintenance Program SAMHSA – Substance Abuse and Mental Health Services Administration FDA – U.S. Food and Drug Administration Half life – how long it takes for half of the drug to be eliminated from the bloodstream 42 CFR – federal law that governs confidentiality in substance abuse field
Schedule II
Schedule II drugs, substances, or chemicals are defined as drugs with a high potential for abuse, less abuse potential than Schedule I drugs, with use potentially leading to severe psychological or physical dependence. These drugs are also considered dangerous. Some examples of Schedule II drugs are:
cocaine, methamphetamine, methadone, hydromorphone (Dilaudid), meperidine (Demerol), oxycodone (OxyContin), fentanyl, Dexedrine, Adderall, and Ritalin

4. Definitions cont.
Schedule II drug – drugs with a high potential for abuse, but less abuse potential than Schedule I drugs. Examples: Percocet, Oxycontin, Adderall, Fentanyl, Methadone Schedule III drug – drugs with a moderate to low potential for physical and psychological dependence. Examples: Vicodin, Tylenol 3, Suboxone, Tussionex NAS – Neonatal Abstinence Syndrome MOTHER study - Maternal Opioid Treatment: Human Experimental Research
Schedule III
Schedule III drugs, substances, or chemicals are defined as drugs with a moderate to low potential for physical and psychological dependence. Schedule III drugs abuse potential is less than Schedule I and Schedule II drugs but more than Schedule IV. Some examples of Schedule III drugs are:
Combination products with less than 15 milligrams of hydrocodone per dosage unit (Vicodin), Products containing less than 90 milligrams of codeine per dosage unit (Tylenol with codeine), ketamine, anabolic steroids, testosterone

5. Medication Assisted Treatment
SAMHSA defines MAT as:
“The use of medications, in combination with counseling and behavioral therapies, to provide a whole-patient approach to the treatment of substance use disorders. Research shows that when treating substance-use disorders, a combination of medication and behavioral therapies is most successful.”

6. MEDICATION ASSISTED TREATMENT OPTIONS
Methadone
Buprenorphine- Suboxone and Subutex
Naltrexone- ReVia and Depade
The FDA has approved three medications for use in the treatment of opioid dependence: methadone, naltrexone, and buprenorphine.
Methadone and Buprenorphine trick the brain into thinking it is still getting the problem opiod. The person taking the medication feels normal, not high, and withdrawal does not occur. They also reduce craving,
Naltrexone is different. It blocks the effect of the opiod drug. This takes away the feeling of getting high if the problem drug is used again.
All three have the same positive effect: they reduce the problem addiction behavior.

7. Benefits of MAT in Pregnancy in a Clinical Setting
Assist women in remaining free of illicit drugs, by preventing opiate withdrawal and cravings.
Assist in eliminating criminal activity and other high risk behaviors that may be harmful.
Increase probability of access to prenatal care.
Allow for substance abuse education and therapy in a structured setting.

8. Benefits of MAT in Pregnancy in a Clinical Setting
Breastfeeding is possible and often preferable for most women on MAT (minimal amount of methadone found in breast milk).
Decrease risk to fetus of infection of HIV, Hepatitis and Sexually Transmitted Diseases.
Decrease the possibility of fetal death by stabilizing the intrauterine environment from fluctuations associated with abstinence syndrome.
According to the CDC - the median death rate of opiate-dependent individuals in MMT is 30 percent of the rate of those not in MMT

9. Methadone
Critics have cited the belief that methadone treatment merely substitutes one addiction for another and that achieving a drug-free state is the only valid treatment goal.
Misunderstandings about the nature of drug addiction (not seeing it as a biomedical condition) are part of the reason why MMT has sometimes been met with limited acceptance by communities, health care providers, and the public.
Critics opposed to expanding MMT programs also express concerns that they may be a magnet for crime and drug dealing and that patients will divert methadone (sell it to supplement their income or buy or sell it to help friends in withdrawal).
As a result, the use of methadone to treat addiction has been heavily regulated and strictly con-trolled in this country.
For example, until now, MMT has been delivered only through specially licensed clinics, called Opioid Treatment Programs.
IDUs come to MMT with a broad range of issues and problems in addition to their drug addiction. For example,
about 40 percent of patients entering methadone treatment use cocaine or crack as well as heroin; perhaps a quarter also abuse alcohol.
Studies have shown that 67-84% of MMT patients have been infected with hepatitis C.
About 10 million people in the U.S. have co-occurring substance abuse and mental disorders; more than 40 percent of those with addictive disorders also have mental disorders.
IDUs frequently have unstable living situations and may need multiple social services. Treatment programs tailored to the specific needs of patients can respond more effectively to these varied types of patients.

10. Methadone – a drug or a medication?
Methadone is both.
Methadone is a medication that if used illicitly may be thought of as a drug of abuse.
Methadone is a medication that if used correctly is a pain reliever and a part of drug addiction detoxification and maintenance programs.
Methadone is a opioid pain reliever, similar to morphine. An opioid is sometimes called a narcotic. It also reduces withdrawal symptoms in people addicted to heroin or other narcotic drugs without causing the "high" associated with the drug addiction.
Methadone is used as a pain reliever and as part of drug addiction detoxification and maintenance programs.
Methadone is a Schedule II controlled substance

11. Methadone Dolophine hydrochloride, Methadose Schedule II narcotic
Long acting opioid analgesic (6-12 hours)

12. Methadone
Long half-life (12-59 hours)- taken once daily or may be “split-dosed”
Administered orally- 5 and 10 mg tablets, 40 mg disket and liquid
40 mg tablets (disket) only available to treat opioid addiction (as of January 2008)
Take Methadone Diskets by mouth with or without food. Methadone Diskets is for oral use only and must not be injected.
Do not chew or swallow the tablet.
Place the correct dose in a glass and add about 4 oz (120 mL) of cold water, orange juice, or other acidic fruit beverage. Allow the medicine to dissolve completely, then drink all of the liquid. Rinse the container with an additional small amount of fluid and drink the contents to ensure the entire dose is taken.
Methadone Diskets must be administered under close medical supervision.
Do not suddenly stop taking Methadone Diskets. You may have an increased risk of withdrawal symptoms (eg, nausea, vomiting, diarrhea, anxiety, shivering). If you need to stop Methadone Diskets, your doctor will gradually lower your dose.
Methadone Diskets works best if it is taken at the same time(s) each day. Do not miss any doses.
If you miss a dose of Methadone Diskets, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once. Do not take more than your prescribed dose in 24 hours.

13. Stabilization Methadone is metabolized in the liver
It is then stored in the liver and bloodstream ……..
Unlike Heroin or other opiates, Methadone is time-released into the brain for up to a period of (2) days from one dose.
Methadone enables the person to remain stable or functional without the use of illicit drugs.

14. Methadone benefits
Right dose should not cause euphoric or tranquilizing effects.
Reduces/blocks effects of other opioids.
Tolerance is slow to develop.
Relieves cravings.
Allows the individual to feel “normal”.

15. Methadone benefits Improved employment and family relationships.
Decrease in criminal activities.
Decrease in high risk behaviors such as IVDU = decrease in HIV and Hep C.
Improved health and health care.

16. Methadone limitations
Can only be dispensed/administered through an OTP.
Private can be expensive.
Heavily regulated, lots of rules, can be time consuming.
Heavily stigmatized

17. Methadone limitations
Abuse liability and diversion.
Increased risk when combined with other drugs.
Associated health complications.
Detoxification can be difficult.
*Torsade de pointes

18. Potential Methadone draw-backs
NAS
Not always available
Stigma
Daily visits (difficult with rural populations)
Treatment services often quite variable so outcomes can be quite variable

19. Methadone Maintenance - During Pregnancy
Since the late 1970’s methadone has been accepted to treat opioid addiction during pregnancy
(Kaltenback et al. 1998; Kandall et al. 1999)
In 1998 the National Institutes of Health consensus panel recommended MMT as the standard of care for pregnant women with opioid addiction.
(National Institutes of Health Consensus Development Panel 1998)
Methadone is currently the only opioid medication approved by the FDA for MAT for opioid addiction in pregnant patients.
A research-based guide on the principles of substance abuse treatment, released in 1999 by the National Institute on Drug Abuse (NIDA), notes that “For methadone maintenance, 12 months of treatment is the minimum, and some opiate-addicted individuals will continue to benefit from methadone maintenance treatment over a period of years.”
Despite this fact, the majority of MMT patients leave before 1 year, either because they drop out, the clinic encourages them to leave, or they are discharged for not complying with program regulations.

20. Methadone Maintenance - During Pregnancy
As the pregnancy progresses the woman may experience withdrawal symptoms and require an increase in her methadone dose due to greater plasma volume and increased renal blood flow.
Often “Split Dosing” will better stabilize the woman and avoid withdrawal without having to continue to increase the amount of methadone needed.
Medically supervised withdrawal is not recommended for pregnant women.
It appears that only patient endorsement of craving, withdrawal symptoms, or a return to heroin use—particularly just prior to the expected methadone dose—can accurately advise the clinician. Future research may offer better alternatives.
As a practical matter, it may be difficult to use split dosing for patients in methadone maintenance, particularly during the early stages of maintenance. Since federal regulations (42 CFR Part 8) require that take-home methadone be “limited to a single dose each week” during the first 90 days of treatment, twice-daily visits for split dosing would be impractical for most patients and nonviable because most clinics only offer morning dispensing. Federal regulations continue to limit take-home to “doses” rather than daily dosing for the first 9 months of treatment. These regulations can also be superseded by more restrictive state or program regulations. Although exemptions for split dosing can be requested, the study by Langleben et al. emphasizes the nontherapeutic rigidity of the federal guidelines. That being said, split dosing should not be taken lightly. Compliance typically drops sharply with twice-daily dosing, diversion worsens, and costs increase. An alternative approach, of course, is to switch these patients to the even longer acting partial agonist buprenorphine, although empirical (9) and anecdotal evidence suggests that this medication may also require split dosing in some patients.
Different reference specifically about pregnant women >>>>>>>>>>>>>>>>>>>
A prospective study was conducted to evaluate the effects of oral methadone on fetal activity (body movements, breathing, longest inactive period) for drug-dependent pregnant women on methadone maintenance. Seven consenting drug-dependent pregnant women between 26 and 37 weeks gestation were enrolled in the study. Pairs of ultrasound observation studies were conducted, before and after single-dose methadone (SDM) treatment and split-dose methadone treatment. There were significant decreases in both body movements (p less than 0.001) and breathing episodes (p less than 0.01), and a significant increase in the longest period of inactivity (p less than 0.001) following SDM. A similar but not significant trend was noted before and after split-dose methadone. The results of the single-dose studies differed significantly from normal controls. However, the results of the split-dose studies were similar to controls. It is recommended that women on methadone maintenance should be offered a split-dose treatment protocol.

21. Methadone Dosing during Pregnancy
Often methadone dose needs adjustment upwards
Greater plasma volume
Increased renal blood flow
Pond et al., 1985; Swift et al., 1989; Jarvis et al., 1999; Wolff et al., 2004) 80 70
Induction of CYP3A
This enzyme is involved in the metabolism of approximately half the drugs that are used today, including acetaminophen, codeine, ciclosporin (cyclosporin), diazepam, and erythromycin. The enzyme also metabolizes some steroids and carcinogens.[3] Most drugs undergo deactivation by CYP3A4, either directly or by facilitated excretion from the body. 65 60 50
Methadone (mg) 40

22. Breastfeeding on Methadone
Mothers maintained on methadone can breast-feed if they are not HIV positive, are not abusing substances, and do not have a disease or infection in which breast-feeding is contraindicated (Kaltenback et al. 1993).
American Academy of Pediatrics and the World Health Organization’s Working Group on Human Lactation approves breastfeeding among women on methadone.
Studies have found minimal transmission of methadone in breast milk regardless of maternal dose (Geraghty et al. 1997; Wojnar-Horton et al. 1997)

23. Buprenorphine

24. Another Option - Buprenorphine
Development of Subutex®/Suboxone®
Suboxone (buprenorphine/naloxone)
Suboxone contains four parts buprenorphine and one part naloxone.
Naloxone was added to in an effort to dissuade patients from injecting the tablets.
Subutex (buprenorphine)
Subutex contains only buprenorphine.
U.S. FDA approved Subutex® and Suboxone® sublingual strips for opioid addiction treatment on October 8, 2002.
Product launched in U.S. in March 2003
Interim rule changes to federal regulation (42 CFR Part 8) on May 22, 2003 enabled Opioid Treatment Programs (specialist clinics) to offer buprenorphine.
Need information on films vs. tablets.

25. Buprenorphine Long half-life (24-60 hours)
Administered as sublingual tablet* or film
Subutex- 2 mg or 8 mg buprenorphine
Suboxone- 2 mg buprenorphine + .5 mg naloxone
8 mg buprenorphine + 2 mg naloxone
*Reckitt announced in September 2012 they will cease production of the tablets

26. Subutex Administered as sublingual film
Initially used as an analgesic (but not in sublingual form)
Has been used in France for over a decade for opioid addiction
Use buprenorphine without naloxone in pregnancy
Schedule III pain medication (Buprenex)
Approved in 2002 for outpatient treatment of opiate addiction
Partial opiate agonist (sublingual tablet)
Only approved M.D.’s can prescribe Subutex/Suboxone.
Most have no affiliation with, or background
in treating addiction.
Administered as sublingual film
Subutex- 2 mg or 8 mg buprenorphine
Check on strip vs tablet

27. Suboxone Administered as sublingual film
Naloxone added as means to decrease misuse.
Poor bioavailability sublingually, but if dissolved and injected, will precipitate withdrawal.
Reduced abuse potential.
Film meant to provide added means to combat diversion.
Administered as sublingual film
Suboxone- 2 mg buprenorphine + .5 mg naloxone
8 mg buprenorphine + 2 mg naloxone

28. Buprenorphine benefits
Virtually no euphoric or tranquilizing effects unless opiate naive.
Blocks effects of other opiates.
Relieves cravings to use other opiates.
Allows “normal function”.
Lower abuse liability and diversion potential than Methadone.
Increased anonymity and less intrusive, vs. attending a MAT clinic daily.

29. Buprenorphine benefits
Increased treatment options/access to treatment.
Decrease in high-risk behaviors.
Good “step down” option for those tapering from Methadone.
Provides option for those that cannot tolerate methadone.
Is currently covered by Medicaid.

30. Buprenorphine limitations
Can be expensive when self pay.
Currently still no generic for Suboxone.
Should not take if opiates still in system.
Counseling may not be available or affordable in the same area as doctor.

31. Buprenorphine limitations
Not enough certified doctors or doctors willing to treat.
No regulations for office based opiate treatment, only “practice guidelines”.
Potential for overdose of other opiates due to ceiling effect.
Abuse and diversion potential still exists.

32. Buprenorphine breastfeeding
Does get into breast milk
Poor oral bioavailability
No reports of NAS when women acutely stop taking buprenorphine while breastfeeding
So – assess baby’s adequate growth, mothers nutritional status/milk production
Poor oral bioavailability - Because of the low levels of buprenorphine in breastmilk, its poor oral bioavailability in infants, and the low drug concentrations found in the serum and urine of breastfed infants, its use is acceptable in nursing mothers*.
*US Department of Health and Human Services. Clinical guidelines for the use of buprenorphine in the treatment of opioid addiction. A treatment improvement protocol: TIP ;70.
ACOG Committee Opinion No. 524: Opioid abuse, dependence, and addiction in pregnancy. Obstet Gynecol. 2012;119: PMID: 32

33. MAT and Pregnancy

34. Substance Abuse lifestyle Concern for mother - fetus - and - neonate
High rates of smoking, other drug use, depression, anxiety, PTSD among mothers
High rates of dysfunctional families, abusive partners
Lack of social supports
Often financially struggling
Poor coping and parenting skills
Legal problems
Unemployment, lack of job skills

35. What happens to Mom happens to baby…

36. MAT and pregnancy standards
Federal standards
Prenatal care
Gender-specific services
Additional state standards
Medically able to participate
Collaborate with OB-GYN
Post-partum care
Nutrition, parenting, and weekly drug test

37. MAT and pregnancy
“Cold turkey” detox may trigger miscarriage, pre-term labor.
Methadone has most research and is still preferred.
Subutex has shown very positive results – MOTHER Study.
Several reports of using Suboxone with positive results.
Well metabolized and well tolerated.
Maternal Opioid Treatment: Human Experimental Research

38. MAT and pregnancy Individualized approach, informed choice
Decreases/ceases cycles of intoxication and withdrawal
Decrease in high risk behaviors
Opportunity to address other factors-mental health, social supports, basic needs

39. Potential medical complications for the pregnant opioid using females and the fetus
HIV, Hepatitis C, STDs, seizures
Gestational diabetes, preeclampsia and eclampsia
Spontaneous abortion
Intrauterine Growth Retardation
Placental abruption
Premature rupture of membranes and labor
Placental insufficiency
Postpartum hemorrhage

40. Methadone and pregnancy
Methadone has been used to treat pregnant opiate addicts for nearly 40 years.
While relatively safe, not completely without risk.
Minimizing risk includes:
comprehensive assessment
education with family and patient regarding risks/benefits
providing medical supervision to decrease/eliminate illicit drugs of abuse.

41. Potential Risks
Neonatal Methadone Abstinence Syndrome. Similar to that of heroin, often longer lasting
In-utero exposure to methadone may lead to low birth weight. (Many patients also smoke—uncertain which causes the low weight)
Onset of withdraw can be delayed for several hours to two weeks.
The maternal dose vs. NAS severity is the subject of some debate.
Seizures can be seen in a minority of babies. Although some MDs attribute this to the use of benzodiazepines during pregnancy.

42. Potential Neonatal complications
Premature birth
Low birth weight and small for gestational age
Microcephaly
Meconium aspiration syndrome
Neonatal abstinence syndrome
SIDS
HIV infection

43. Post Delivery Issues Neonatal Abstinence (Finnegan Scale)
“Look what you’ve done to your baby” attitude by hospital staff and family members
Pain management issues
Dose adjustment/regulation
Confidentiality in the hospital: Drs. and nurses must not discuss methadone in the presence of anyone other than the patient
Support Network: often limited - needs to attend 12-step meetings, church, self-help groups, etc.
Increased risk of relapse
Post-Partum depression
Now what? - work on parenting issues, relationship with baby’s father, family of origin, friendships, life issues…

44. NEONATAL ABSTINENCE SYNDROME
NAS is defined as:
Neonatal abstinence syndrome (NAS) is a group of problems that occur in a newborn who was exposed to addictive illegal or prescription drugs while in the mother’s womb. Babies of mothers who drink during pregnancy may have a similar condition.

45. NAS Predictability
Can happen with any opioid (heroin, oxycontin, methadone, etc.)
Not clearly related to methadone dose in mother
May occur less often with buprenorphine
Contribution of genetics, other drugs
Smoking and vagal tone have been associated with NAS
Vagal tone – impulses from the vagus nerve producing inhibition of heartbeat. 45

46. Neonatal Abstinence Syndrome (NAS)
CNS excitability such as hyperactivity, irritability, sleep disturbance
Autonomic Nervous System such as fever, sweating, nasal stuffiness
Gastrointestinal dysfunction such as uncoordinated sucking/swallowing, vomiting, loose stools
Respiratory Distress such as increased respiratory rate, bluish color around the mouth, nasal flaring

48. NAS Treatment
Pharmacotherapies used to reduce withdrawal symptoms include:
Phenobarbital
Morphine
Methadone
Non-pharmacologic supportive care
Decrease sensory inputs
Stabilize environment
Help parents have realistic expectations (babies are not addicted)

49. Remember… Opiate addiction is a disease, an epidemic.
There is no cure, but we do have options and we need to take advantage of all of them.
Treatment is not “one size fits all.”
Just as addiction is lifelong, so is the recovery process.
Chances of maintained recovery significantly increase when combined with counseling, drug tests, medication call backs, etc.

50. Remember… No “perfect” medication that is one size fits all.
Medication is a tool, not a “cure”.
MAT may be appropriate for pregnant women but must be closely monitored and have informed consent.
MAT is a legal, valid, and widely researched evidence-based treatment for addiction.
Individuals receiving MAT are in recovery!

51. Then what?

52. Infant/child development
Difficult to determine the effects of methadone vs. other drugs of abuse/genetic problems, etc.
Head circumference normalizes by preschool (Lifshitz, 1985)
Neurological development assessed by Bayley Scales of Infant Development within normal limits (Patso, 1989)
Poorer performance in fine and gross motor coordination, attention, language vs. controls (for review see: Chapt. 20 of Strain and Stitzer, The Treatment of Opioid Dependence, 2006 and Helmbrecht 2008)

53. Factors influencing long-term outcomes of methadone exposed children
Effects of poverty
Effects of other drugs of abuse (including nicotine and alcohol)
Effects of environments (supports, opportunities)
Caregiver capacity
Infant, child, young adult resilience

54. OPOID ADDICTION PROGRAM’S TREATMENT PROTOCOL
Pregnant woman contacts the clinic.
She is assessed for appropriateness on the phone and then comes in for a face to face assessment.
Once deemed appropriate, “patient” is then admitted to hospital for prenatal assessment and induction to methadone.
She will stay in the hospital for 5-7 days and is typically discharged on 30 to 40mg of methadone.
Upon discharge from hospital, patient will come to MAT clinic and have a psychiatric assessment by the physician.
This is the Lexington protocol but all are similar.
Best practices for licensed clinics.
Pregnant women are a priority population!!!!!
She is pregnant
She is addicted to opiates
She is wanting treatment

55. OPIOD ADDICTION PROGRAM’S TREATMENT PROTOCOL
Patient will then go for up to 30 days of residential substance abuse treatment—she will get her methadone dose there.
Upon completion of residential substance abuse treatment, patient will begin daily dosing in the clinic, meet with her therapist once a week, and submit to random drug testing.
Referral to other services (group counseling, self-help, parenting classes, vocational rehab, etc.) may be required as is prenatal care.
It is recommended, when appropriate, the patient continue residential long-term treatment.
Other supportive services are available such as nutritional counseling, parenting classes, prenatal appointments, etc.

56. Vincent Dole:
“Some people became overly converted. They felt, without reading our reports carefully, that all they had to do was give methadone and then there was no more problem with the addict…I urged physicians should see that the problem was one of rehabilitating people with a very complicated problem and that they ought to tailor their programs to the kinds of problems they were dealing with. . .The stupidity of thinking that just giving methadone will solve a complicated social problem seems to me beyond comprehension (Courtwright, 1989, p 338)”
I really like this slide – I ‘d like to repeat it with buprenorphine, too.
Dr. Vincent P. Dole, who along with a young researcher who later became his wife did the studies proving that the synthetic drug methadone blocks the cravings of heroin addicts

57. Remember…
The substance abusing lifestyle brings concerns for mother, fetus and neonate.
Although there are risks, Medication Assisted Treatment (MAT) provides benefits to the opiate addicted pregnant woman.
Methadone maintenance is still the treatment of choice and standard of care in the US.
Buprenorphine (Subutex) treatment is possible, evidence still lacking.
Detoxification is contraindicated unless done in hospital with monitoring.

58. And one more thing:
She’s in RECOVERY!