Posts Tagged ‘NAS’

What’s a Doctor To Do?

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Above, you will see two documents which illustrate the problem.

The second is a letter sent to North Carolina opioid treatment program (OTP) physicians from the preeminent OB/GYN group at the University of Tennessee. The first is a letter sent last month to obstetrical providers and opioid use disorder treatment providers from the Center for Substance Abuse Treatment, an arm of SAMHSA (Substance Abuse and Mental Health Services Administration).

You will note they recommend polar opposite approaches to the management of opioid use disorder in pregnant women. The obstetricians at University of Tennessee recommend that pregnant women with “chronic narcotic use” be offered the option of taper from opioids, to avoid neonatal abstinence syndrome and to avoid microcephaly.

In contrast, the letter to providers from CSAT division of SAMHSA recommends, “Pregnant women with opioid use disorder should be advised that medically supervised withdrawal from opioids is associated with high rates of relapse and is not the recommended course of treatment during pregnancy.”

That mention of microcephaly in the U of T letter baffles me. The resources cited in their letter referred to one study of head circumference in babies with neonatal abstinence syndrome (NAS). There’s no mention whether the moms are on illicit opioids or MAT. The second study looked at head circumference in babies born to moms with polysubstance use. None of the studies looked at head circumference of infants born to moms on MAT and compared them with controls. Using microcephaly as an argument against MAT is a misuse of data.

Why on earth would Tennessee obstetricians send their letter to NC opioid treatment program providers? Because, as I have ranted about so often in the past, there are no opioid treatment programs in Eastern Tennessee. Because that portion of Tennessee still has no methadone programs, patients are forced to drive across the border to get the gold standard of treatment for opioid use disorder. True, there are some buprenorphine prescribers in that area, and that’s a great thing as far as it goes, but as we know, not all patients do well with buprenorphine, and we have around six decades worth of data about methadone in pregnancy.

So not only does Tennessee refuse to allow the most evidence-based treatment for opioid use disorder to exist in that part of their state, but their physicians seek to control the actions of opioid treatment physicians in North Carolina, and ask us to adopt treatment approaches discouraged by all other expert organizations.

The study touted by Dr. Towers in their above letter was published by Bell, Towers, et al. in September 2016 issue of the American Journal of Obstetrics and Gynecology: http://www.ajog.org/article/S0002-9378(16)00477-4/abstract

After reading this study in some detail, I’m surprised by the authors’ conclusions. I find their conclusions to be based on some very thin evidence.

This study was a retrospective analysis of four groups of pregnant women with opioid use disorder. The first group consisted of incarcerated women, allowed to go through opioid withdrawal without the standard of care, buprenorphine or methadone. How this is even legal is beyond me.

The study says that jail programs in east Tennessee have “no ability to provide opiates to prevent or perform an opiate-assisted withdrawal medical withdrawal.” It went on to say that the jail doctor can treat symptoms with anti-nausea meds, clonidine, and anti-diarrheal meds. They also lack the ability to perform fetal monitoring while incarcerated.

Of the 108 women in group 1, two suffered intrauterine fetal death, one at 34 weeks and one at 18 weeks. The authors don’t say what the expected rate of fetal death would be, and I don’t know either. Apparently the authors didn’t consider these two deaths to be outside the range of normal.

Group 2 consisted of 23 pregnant women with opioid use disorder who were sent to inpatient opioid detoxification followed by long-term follow-up behavioral health programs. These women did well, with only 17% relapsing while in treatment. This group had a 17% rate of neonatal abstinence syndrome in the newborns.

I guess that means all of the four women who relapsed had babies with NAS. That’s 100%, much higher than the 50% rate nationwide. That seems odd to me.

Group 3 did the worst. These 77 women had inpatient detoxification but then did not have the long-term treatment that group 2 were given. Of the infants born to these women, 22% needed admission to the neonatal intensive care unit. Of these 77 women, 74% relapsed, and NAS was present in 70% of those infants. Again, this gives a NAS rate of 95%, which is a great deal higher than most other studies of NAS in babies born to moms using opioids of any kind. Even with methadone, studies give estimates of 50% to 80% at the highest.

Group 4 consisted of 93 women on buprenorphine prescribed by office-based physicians who agreed to taper the women’s doses during pregnancy. The rate of relapse in this group was noted to be 22%, and 17% of all the babies had NAS. Again, this gives a relatively higher NAS rate than has been found in other studies. In this Bell study, NAS occurred in 76% of the women who relapsed, up from 50% of women on buprenorphine in the MOTHER trial who were not tapered.

A little sentence in the articles table of demographics and outcomes gives the clue to why their NAS rates were so high. The way this study determined relapse was by drug screen at the time of admission to the hospital for delivery, or an admission by the pregnant woman, or positive meconium screen, or treatment of NAS in the newborn.

I think relapses could have gone undetected very easily, so that only the women with a relapse close enough to the time of delivery were detected to have used opioids.

Other problems with this study have been pointed out by much smarter people than me. Dr. Hendree Jones, author of the landmark MOTHER trial comparing methadone and buprenorphine during pregnancy, commented in the Journal of Addiction Medicine in the March/April 2017 issue: Her conclusions after a review of the Bell article plus a handful of other similar studies is: “Evidence of fetal safety to support the equivalence of medically assisted withdrawal to opioid agonist pharmacotherapy is insufficient.”

Of course, pregnant patients have one big concern: “What can I do to keep my baby from having withdrawal?” and that’s what they focus on. They are willing to do anything, including coming off methadone or buprenorphine or other opioids, if it will keep their baby from withdrawal. As Doctor Jones cogently points out in the above referenced article, there’s lack of data to show medically-supervised withdrawal from opioids results in less risk of NAS.

In other words, if prevention of NAS is our only goal, there’s not enough evidence to show that reducing opioids during pregnancy will achieve this. In part, that’s due to the high risk of relapse in the mother, and in part due to other factors.

This is the state of the situation right now. Things could change in the future. We do need new studies, done with closer attention to fetal monitoring and drug testing throughout pregnancy to help us determine the ideal treatment of pregnant women with opioid use disorder.

But for right now, maintenance on buprenorphine or methadone is still the treatment of choice.

It’s not only SAMHSA that’s recommending MAT as the treatment of choice for pregnant patients with opioid use disorder. Even the American College of Obstetrics & Gynecology (ACOG), the professional organization of OB/GYNs in the U.S., in a position statement from 2012, says:

  • “The current standard of care for pregnant women with opioid dependence is referral for opioid-assisted therapy with methadone, but emerging evidence suggests that buprenorphine also should be considered.”
  • “Medically supervised tapered doses of opioids during pregnancy often result in relapse to former use.”
  • “The rationale for opioid-assisted therapy during pregnancy is to prevent complications of illicit opioid use and narcotic withdrawal, encourage prenatal care and drug treatment, reduce criminal activity, and avoid risks to the patient of associating with a drug culture.”

The World Health Organization says, in its guidelines from 2014:

  • “Pregnant women dependent on opioids should be encouraged to use opioid maintenance treatment whenever available rather than to attempt opioid detoxification. Opioid maintenance treatment in this context refers to either methadone maintenance treatment or buprenorphine maintenance treatment.”

A new statement from the American Society of Addiction Medicine earlier this year, titled, “Substance Use, Misuse, and Use Disorders During and Following Pregnancy, with an Emphasis on Opioids” said:

  • “For pregnant women with opioid use disorder, opioid agonist pharmacotherapy is the standard of care; the ASAM National Practice Guideline for the Use of Medications in the Treatment of Addiction Involving Opioid Use recommends that pregnant women who are physically dependent on opioids receive treatment using methadone or buprenorphine monoproduct rather than withdrawal management to abstinence.

So the experts agree. Medication-assisted treatment is the gold standard for pregnant women with opioid use disorder.

Why are some OB/GYNs in Tennessee and other areas recommending the opposite, based on evidence that most of us consider preliminary at best, and flimsy at worst?

I don’t know for sure, but I think these physicians suffer from the same biases as other non-medical people. I would like for these physicians to base their actions on the best scientific data, but that’s not happening in some areas. I believe these doctors, with the best of intentions, have been swayed by the political climates of their areas. Rather than challenge long-held beliefs about medication-assisted therapies that have been based on ideology rather than fact, they have stayed inside the comfort zone of believing pregnant women shouldn’t be on methadone or buprenorphine.

This leaves addiction medicine physicians in the middle. We know what the standard of care is, but our patients are told we are wrong, and that they should taper off maintenance medication, or not start it in the first place.

I’ve tried, one OB at a time, to educate gently about what I see as the standard of care. I’ve sent studies and position papers and other data to the OBs with whom I share patients. I’ve blogged about the negative experiences I’ve had. In short, many of these obstetricians say something to the effect of: “Who are you to tell me how to care for this pregnant patient?” After all, I’m not an obstetrician. But I do read, and I do keep my fund of knowledge up to date in the field of addiction medicine, which overlaps with obstetrics at times.

I’m terribly frustrated by the situation, and I know my colleagues at other opioid treatment programs feel the same way. I’m fortunate that there is one group of OBs who are somewhat supportive of my pregnant patients on MAT, and I appreciate that. But often these pregnant ladies using opioids are already going to one of the anti-MAT OBs, and that creates real problems.

If it’s difficult for physicians, just think how the pregnant patients feel. They are given polar opposite recommendations by their OB and their physician at the OTP. They sought help in order to do the best thing for their babies, wanting to be good mothers. In most situations, they have tried desperately to quit opioid on their own, and couldn’t. Now the OB is telling them they must taper off their medication during pregnancy, and the OTP physician is recommending they stay on it, even recommending they increase their dose if needed.

At a difficult time in their lives, these mothers-to-be aren’t sure if they are doing the right thing by being in treatment with MAT or not. They second guess themselves, and their families also recommend, with the best of intentions, that they follow the OB’s directions.

I think this won’t change unless professional organizations like ACOG reach out more directly to obstetricians in the field. Perhaps SAMHSA can organize educational lectures, given by obstetricians who know the data and know the best practice recommendations. Perhaps state medical societies or state medical boards can contact these obstetricians with statements of best practices, if more are needed. With WHO, ACOG, SAMHSA, and ASAM all recommending MAT for opioid-dependent pregnant women, you wouldn’t think further statements of best practice would be needed…yet they are.

All I know is that I don’t seem to be making any headway at all. I need help, and my patients need help.

 

 

 

New Treatment for Neonatal Abstinence Syndrome

 

 

 

 

 

 

 

 

 

 

The June 15, 2017 issue of the New England Journal of Medicine contained an article of great interest. Written by Kraft et al., this article titled, “Buprenorphine for the Treatment of the Neonatal Abstinence Syndrome,” described a study comparing buprenorphine with morphine solution to treat opioid withdrawal in the newborn. This study showed significantly shorter duration of treatment and shorter median length of hospitalization for babies with neonatal abstinence syndrome when treated with sublingual buprenorphine compared to traditional treatment with morphine oral solution.

This study covers a hot topic. Many people are alarmed at the rising rate of NAS in our nation’s hospitals. The incidence of NAS has risen four-fold from 2003 to 2012, and cost $316 million in care for those babies just in 2012. [1] Any new treatment that can reduce the duration of withdrawal in newborns, and thus reduce treatment costs and parental anxiety, is an exciting new development.

The NEJM study described was done at Thomas Jefferson University in Philadelphia, Pennsylvania, with subjects enrolled from late 2011 until mid-2016. To qualify for the study, the babies had to be born full-term, defined as more than 37 weeks of gestation, and had to have been exposed to opioids during the pregnancy. The infants had to have signs and symptoms of neonatal abstinence syndrome (NAS), and parental consent to participate in the study.

The study, abbreviated BBORN, for “blinded buprenorphine or neonatal morphine solution,” excluded babies with low birth weight, exposure to benzodiazepines within 30 days of delivery, or serious other medical conditions. For the first part of patient enrollment, breast fed babies were excluded, but this restriction was lifted by 2013, with the national trend of that encouraged these mothers to breast feed. Nearly all of the mothers were on methadone maintenance, with doses ranging from 25 to 265 in the group assigned to buprenorphine treatment, and 30-260 in the group assigned to morphine oral solution, regarded as treatment as usual.

The design of this study was very strong, since it was doubly blinded, which means the providers caring for these infants didn’t know which were randomized to buprenorphine and which were randomized to morphine.

This double-blind approach is important in general, but especially important when dealing with the evaluation of babies in withdrawal. Sometimes nurses and other medical professionals who are evaluating withdrawal in babies have an emotional reactions. Some of these people can overestimate the degree of withdrawal, leading to longer hospitalization and over-medication.

If you are wondering “How do they get the babies to keep the medication under their tongue?” I wondered the same thing. The study explained that after getting a buprenorphine dose (or placebo, if their active drug was morphine solution), the babies were given a pacifier to extend the time the medication is in contact with the sublingual mucosa.

How clever. When my cat Yoshi was prescribed buprenorphine for urethritis, I had to dose him with buprenorphine, but there’s no way he kept it under his tongue. I thought some had to have gotten absorbed just from the oral mucosa. He definitely had a response to the medication, being opioid-naïve…he fell asleep, which gave him respite from frantic over-grooming of his urethra…

But I digress.

Anyway, this study showed buprenorphine significant decreased the duration of treatment for NAS, by an average of thirteen days, with no increase in adverse events, as compared to treatment as usual with morphine oral solution. The study authors postulate that the long half-life of buprenorphine levels the peaks and troughs seen with the shorter-acting morphine solution.

The study was limited by its small sample size. The authors wanted to get at least 40 subjects in each treatment arm, but had a hard time recruiting parents willing to enter their newborn into a treatment trial. They ended up with 30 patients in the buprenorphine treatment arm, and 28 in the morphine treatment as usual arm.

I can only imagine how hard it was to convince nervous mothers-to-be to enter their babies in this study. They were likely already worried about NAS in their infants, and perhaps feeling guilty about being pregnant while having the disease of opioid use disorder. Asking a mom – or dad – to then enroll in a study using a new medication (new for this use, at least) would be a hard sell.

Thankfully even with fewer test subjects than desired, the data still reached statistical significance. If future studies can replicate these outcomes, we will have a new medication with which to treat NAS, which will reduce the length of stay in the hospital for babies, reduce medical costs, and get these babies home sooner.

  1. Corr et al., “The Economic Burden of Neonatal Abstinence Syndrome in the United States,” Addiction, 6/13/17 http://onlinelibrary.wiley.com/doi/10.1111/add.13842/abstract

The “Protect Our Infants Act”

Rate of neonatal abstinence syndrome per 1,000 live births, by mother's county of residence

Rate of neonatal abstinence syndrome per 1,000 live births, by mother’s county of residence

(This map can be seen at:http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6405a4.htm )

I just read an interesting news piece about new legislature named “Protecting Our Infants Act.” This bill was sponsored last year by Rep. Katherine Clark of Massachusetts, but died during the session. Then she got support from other congressmen, including Rep. Steve Stivers from Ohio (who happens to represent the area of the country where I was raised, in Southeastern Ohio), and Sen. Bob Casey of Pennsylvania. When Majority leader Senator McConnell got onboard as a sponsor of the bill this year, it gained momentum, and is now in a congressional committee, waiting to be sent to the house or Senate.

When I first heard about this new bill, and that Senator McConnell was backing it, I worried it might be something weird and unscientific that would send us backward in time. But after reading the bill online for myself, I’m in favor of it: https://www.congress.gov/bill/113th-congress/senate-bill/2722/text

This bill asks the Secretary of Health and Human Services to collect and evaluate all of the best evidence-based information available about how to prevent and treat babies born dependent on opioids. The bill’s actual wording is that the secretary of HHS “shall conduct a study and develop recommendations for preventing and treating prenatal opioid abuse and neonatal abstinence syndrome, soliciting input from nongovernmental entities, including organizations representing patients, health care providers, hospitals, other treatment facilities and other entities, as appropriate.”

The bill asks for Health and Human Services to identify and also report on any gaps in our knowledge, where more research is needed. The bill also requests an evaluation of medical use of opioids during pregnancy, and an assessment regarding access to treatment for opioid-addicted pregnant women and post-partum women. The bill asks for an evaluation of the risk factors for opioid addiction, and the barriers to treatment.

According to the bill, the Secretary of Health and Human Services will collect all this information and post it on a website, available healthcare providers in the U.S., in no less than one year after the bill (hopefully) passes.

Our present Secretary of Health and Human services is Sylvia Mathews Burwell, who replaced Kathleen Sibelius last summer. I didn’t know much about her, so I went to the website for HHS, and found a blog post of hers, addressing our epidemic of opioid addiction: http://www.hhs.gov/blog/2015/03/26/its-time-act-reduce-opioid-related-injuries-deaths.html

I really like what I read. In her blog post, she emphasizes three areas which need attention: wider distribution of naloxone to prevent opioid overdose deaths, better prescribing practices by doctors, and…“using medication-assisted treatment to slowly move people out of opioid addiction.”

What a relief. She supports MAT. I mean, one would hope and expect such support for evidence-based treatments, but as my readers know, sometimes politicians take strong positions on matters about which they know little (oh yes I’m talking about Tennessee).

If the Secretary does a good job, this is a golden opportunity to promote evidence-based treatment of opioid addiction in pregnancy: MAT.

I also think some politicians could learn things they didn’t expect.

Is it possible that with such a prominent seal of approval, both methadone and buprenorphine treatment of opioid addiction will move out of the dark ages? Perhaps politicians will say, “Oh I now see I don’t know what I’m talking about when I limit access to treatment at methadone and buprenorphine programs! How foolish of me!”

Is it possible that someday in the future I’m going to call a certain obstetrician in my area about the methadone dose of a patient we both treat, and he will say, as he’s said before, “It’s wrong to treat pregnant patients with methadone. You need to get them off that stuff!”

And I will say…please go to the Health and Human Services website, to read what the experts say, since you won’t believe me. And he will read. And he will change his mind. He will begin to encourage all his opioid-addicted patients to seek effective, evidence-based treatment… And the health of the whole community will improve as we come to agree on evidence-based solutions to medical problems.

So my first train of thought was a happy engine, chugging along with optimism and relief. Then came the caboose of negativity.

Why do doctors need to have the Secretary of Health and Human Services research this issue for them? For prevention, yes, that’s a public health issue and more research would be valuable. But to find out how to treat a medical issue?? If doctors have a question about how to deal with a medical issue, we have sources that summarize and review best data to date. We go to a reliable source, to the experts in the field. For the topic of opioid addiction in pregnancy, one would ask obstetricians and addiction medicine doctors.

Oh wait. The American College of Obstetrics and Gynecology, along with the American Society of Addiction Medicine, already have published a position paper of best practices in this area. It is titled, “Opioid Abuse, Dependence, and Addiction in Pregnancy.” They didn’t hide their report in a dark cave. They published it. They posted it on the internet:

In fact, if you Google “pregnancy and opioid addiction,” one of the first options is ACOG’s paper: http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Health-Care-for-Underserved-Women/Opioid-Abuse-Dependence-and-Addiction-in-Pregnancy
And for those people who are deeply puzzled by how to treat opioid addiction in pregnancy, this is the summary sentence of the report, published in 2012: “The current standard of care for pregnant women with opioid dependence is referral for opioid-assisted therapy with methadone, but emerging evidence suggests that buprenorphine also should be considered.”

That wasn’t so hard, was it?

Then I Googled “american academy of pediatrics and neonatal abstinence syndrome,” because I figure who knows kids better than pediatricians, and my first choice was a state of the art review article from 2014 describing NAS and its treatment in detail.

After considering the “Protecting our Infants Act,” I have several observations. First, it’s not terribly hard to find state of the art information about the treatment of opioid addiction in pregnancy, and the treatment of neonatal abstinence syndrome, if the healthcare worker really wants to find it. But if the healthcare worker can’t or won’t accept these answers due to ideology, a report from the Secretary of HHS may carry more weight than the science that’s already available.

I also believe we have a whole lot more to learn in this field. This new Act’s best feature is the mandate to assess areas where we need more research, and to investigate barriers to treatment, because there are many. For example, Eastern Tennessee has one of the highest rates of NAS in all the country, yet that state denied a certificate of need for a methadone clinic to be established to serve that area. I do believe that history will judge those politicians harshly.

I hope the bill passes. It would be interesting to see what the Act’s current sponsor, Senator Mitch McConnell, would think about the DHH report.

Opioid Addiction in Pregnancy: More Information about the Use of Methadone Versus Buprenorphine

aaaaaaaaaaababy

The MOTHER (Maternal Opioid Treatment: Human Experimental Research) trial of 2012 (Jones et al) gave us much-needed information about how buprenorphine compares to methadone when used to treat opioid-addicted pregnant women. This landmark study showed us buprenorphine can be just as effective as methadone. Babies born to moms on buprenorphine had the same incidence of opioid withdrawal (called neonatal abstinence syndrome, or NAS) at 50%, but the withdrawal was significantly less severe, the babies required about half the medication as the babies born to moms on methadone. Also, buprenorphine-exposed babies spent significantly less time in the hospital – about half as long as methadone-exposed infants.

Some doctors point out that more women on buprenorphine dropped out of that study than women on methadone, and say that proves buprenorphine is less effective. However, the majority of those women didn’t leave treatment; they just left the buprenorphine arm of the study.

This week I read another study, by Meyer et al, soon to be published in the Journal of Addiction Medicine. This study also looked at pregnant patients being treated for opioid addiction.

The authors of this new study pointed out that the MOTHER trial was a placebo- controlled, double- blind study comparing buprenorphine with methadone, but in real life, the decision to start an opioid-addicted pregnant woman on buprenorphine versus methadone is more complex, and determined by other factors. So the study by Meyer et al did a retrospective analysis. They looked at cases where the choice of buprenorphine versus methadone was made by the patient and physician, as happens in real life, then studied the outcomes. The authors of the new study believed findings will be more pertinent to what happens in everyday clinical practice.

In this retrospective cohort study, 609 pregnant patients were started on either buprenorphine (361) or methadone (248). This study took place over the years from 2000 to 2012 at a single site, University of Vermont.

The study collected various data about the newborns: their sex, estimate gestational age at delivery, birth weight, head circumference, length of stay in the hospital, whether the baby received breast milk, and if the child was sent home with the mother. The study also looked at if the newborn has NAS and if the baby needed medication, and length NAS treatment.

In the results, first-time mothers were significantly more likely to start buprenorphine than methadone. Mothers positive for Hepatitis C were more likely to be started on methadone. In both groups, more than 80% of the moms were smokers. About 30% of both groups had to have a C-section at delivery.

Both groups had similar prenatal care; more than 65% of the mother in both groups initiated care within the first trimester. However, women in the buprenorphine group were significantly more likely to get what the authors defined as “adequate” prenatal care. Women on buprenorphine were also more likely to already be in treatment when they became pregnant, compared to the women in the methadone group.

Nineteen women switched from buprenorphine to methadone, out of the three-hundred and sixty-one women who started on buprenorphine. Only five of those patients switched because buprenorphine was not strong enough for them, or other medication side effects. Most were switched to methadone because they needed more intensive monitoring at an opioid treatment program due to continued positive urine drug screens. Only three women out of the three-hundred and sixty-one started on buprenorphine dropped out and were lost from treatment.

No women were switched from methadone to buprenorphine, as one would expect. That’s because in order to switch from a full opioid, methadone, to a partial opioid, buprenorphine, the pregnant opioid addict would have to go into at least mild withdrawal, thus putting her at risk for adverse events. That’s not a risk most doctors are willing to consider.

Babies born to moms on buprenorphine, as compared to methadone, were significantly more likely to have longer gestational age. This is a good thing, because it means there were significantly fewer preterm deliveries on buprenorphine compared to methadone. The babies born to moms on buprenorphine were significantly more likely to have higher birth weights and bigger head circumference.

Just like what we saw in the MOTHER trial, this study also showed that the infants born to moms on buprenorphine required significantly less medication to treat neonatal abstinence syndrome. The buprenorphine-exposed babies required medication for a significantly shorter time than methadone-exposed newborns.

More than 95% of the infants were sent home in the care of the mother or family, which makes me think this study was done on women with fairly good stability at the time of delivery.

The authors of the study concluded that this evidence suggests that buprenorphine gives outcomes that are at least as good as with methadone.

I’d take that conclusion one step farther and say we now have several studies that show less neonatal withdrawal in babies exposed prenatally to buprenorphine compared to methadone. I have to ask myself: knowing what I do from these studies, which medication would I want to take during pregnancy? I’d prefer buprenorphine, and if it didn’t work for any reason, I’d switch to methadone.

I explain all of this to pregnant patients with opioid addiction upon admission, though I’m careful to also point out that methadone is still officially the gold standard in many places.

I think that will change soon. We are getting more information that shows outcomes equal to methadone with less severe neonatal withdrawal.