Split Dosing of Methadone May Reduce NAS

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I just read a new article (McCarthy et al, Journal of Addiction Medicine, Vol. 9, (2), pp105-110, March/April 2015) on methadone dosing during pregnancy. This study’s data showed reduced incidence of withdrawal in babies born to moms on divided doses of methadone compared to once-daily dosing. This data also showed reduced incidence of withdrawal in these moms on higher total doses of methadone compared to what we have seen in the past with lower maternal doses.

Current practice is to adjust the maternal dose of methadone according to how she feels. If she has withdrawal signs and symptoms, we increase her dose. We assume that if the mother’s at an adequate dose, the fetus should be doing OK too. We know reduced dosing of methadone during pregnancy is not recommended due to higher relapse rates in the mom, and worse fetal and maternal outcomes. Additionally, past studies showed no clear relationship between the maternal methadone dose and the likelihood of neonatal abstinence syndrome (NAS). In other words, increased maternal dose doesn’t increase the incidence or severity of withdrawal in the newborn.

However, we also have past studies which showed a significant decrease in fetal heart rates and fetal movement during times of peak methadone levels (several hours after dosing), compared to fetal heart rates and movement during times of trough blood levels (end of the 24-hour dosing cycle). Those studies showed more normal fetal heart rates and movement after splitting the total dose into equal doses, which is called split dosing. Due to this data, many opioid treatment program doctors have been trying to split the mom’s total methadone dose into two halves, a morning and evening dose.

The authors of this new study decided to build on past data and look at more than once-daily dosing of methadone during pregnancy. They also increased the total dose of methadone to treat any maternal report of withdrawal.

The study is a bit complicated. It was a retrospective chart review done in an eight-hundred patient opioid addiction treatment program in California from June 2008 until January 2013. The study followed sixty-two pregnant patients who were 83% white, 13% Hispanic, 2% African American, and 2% Asian. Of these sixty-two patients, 71% used primarily prescription opioids and 29% used mainly heroin. Some of these patients were already pregnant when they enrolled in treatment and some (32%) became pregnant after starting treatment with methadone. Sixty-six percent of these patients were smokers.

All the patients were moved to twice-daily dosing within several weeks of entry into treatment. Subsequent increases and further dividing of maternal dose was determined by maternal report of opioid withdrawal, and on methadone trough blood levels. All efforts were made to maintain maternal blood level in the “therapeutic range.” Most women dosed three or four times per day by the last trimester, and the average maternal dose at delivery was 152mg per day.
The highest dose in this study was seen in a pregnant patient who was a fast metabolizer of methadone. She required a total dose of 415mg, which was split into six doses. Interestingly, her infant did not need treatment for NAS.

The outcomes of the study were unusual in several ways.

Of the fourteen hundred urine drug screens collected on these pregnant patients, 88.4% were negative for illicit drugs. The mean gestational age was 38 weeks, and only 18% of the babies were born before 37 weeks gestation.

But here is the most noteworthy finding: only 29% of the babies had neonatal abstinence syndrome (NAS) that was severe enough to need treatment. As in other studies, this study showed no correlation between maternal dose and the incidence of NAS.

In the past, the incidence of neonatal withdrawal syndrome has been estimated at 60-80%, though the MOTHER study of 2010 (Jones et. al) found 50% of infants born to both moms on methadone and moms on buprenorphine had withdrawal that was severe enough to need treatment. (That study also found infants born to moms on buprenorphine stayed in the hospital half as long as babies born to moms on methadone, and also had much less severe NAS.)

In this present study, the babies conceived during methadone treatment were not significantly more likely to have NAS than the babies born to moms who conceived prior to entering medication-assisted treatment with methadone.

Male infants were a little more likely to need treatment for NAS than the females.

The authors concluded that divided methadone dosing and adequate methadone dosing during pregnancy increased maternal recovery and resulted in less stress on developing fetuses. The authors postulate there was less sensitization to repeated episodes of intrauterine withdrawal, which ultimately resulted in much lower rates of neonatal abstinence syndrome.

The authors also identified some limitations of their study, and recommended further investigation.

Over the last few years, doctors in North Carolina have been trying to do split dosing on pregnant women when possible. To do this, the woman must be stable enough to manage the second half of the dose, given as a take home. If there’s an addicted male partner at home, that second dose may fall into the wrong hands, and the pregnant patient can get shorted part of her dose. That’s not a good thing during pregnancy, so it’s all about balancing risks with benefits.

This is an intriguing study, but it’s probably too soon to change what we are doing in OTPs. I know I’d like to hear how ASAM experts interpret this information.

The information in this study was gleaned from a retrospective review of patients, which may not be as good a study as a prospective double-blind study, if such could be conducted.

I’m impressed with the 66% smoking rate. I estimate that around 95% of pregnant patients at the OTPs where I work are addicted to nicotine. But I live in a tobacco state, and the study, done in California, has fewer smokers. I think that might be a significant difference, because we know NAS is more like to occur in smokers. Did that play a role in the lower NAS incidence found in this study?

Did the authors of this study take any extra measures to ensure their pregnant patients were living in a safe environment, conducive to recovery? Are the authors sure their pregnant patients were able to consume all of their take home doses? Were any doses diverted, willingly or unwillingly, to other people? Sometimes female patients live with partners who are also addicted, and the patients may be tempted or coerced into giving a dose to a partner in opioid withdrawal. If this happened it could change conclusions of this study.

I suspect the average maternal dose in this study was higher than at most opioid treatment programs in my area. As the authors concluded, this likely improved the mothers’ health and outcomes. This study had a very low rate of positive drug screens, so these patients appear to have been doing exceptionally well in treatment. So is it possible that there could be less withdrawal in babies born to moms on higher doses? That seems counterintuitive, but the authors do suggest that could be why they had low NAS incidence.

The pregnant women in this study got more counseling and support from their OTP than may be provided in other OTPs. The patients in this study had a weekly meeting with a pregnancy counselor, weekly group meeting for education and support facilitated by the clinic physician, psychiatric assessment, and monthly supportive psychotherapy. They got weekly urine drug screens, so there was close accountability. They also had methadone trough blood levels drawn when needed.

The study presents intriguing data. We need more information, more studies to see if higher and divided methadone doses will provide better outcomes with less NAS, as was seen in this study.

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3 responses to this post.

  1. In 2003 Sharon Dembinski a neonatal nurse practitioner had a hypothesis about this being true. She was one of the first Nurse and Methadone advocate and medical treatment provider that was always thinking on ways to improve outcomes for both neonates and their families. She is a true friend to people in recovery and those still struggling. She is a very special woman.

    Paul Bowman CMA
    Massachusetts NAMA recovery

    Reply

  2. I have already discovered the benefits (to the patient) of split dosing of buprenorphine. Even though methadone and burprenorphine are long-acting opioids, there are still adverse peak and trough effects. Unfortunately, while it is easy to carry out in an OBOT program, split dosing in an OTP almost impossible because of the hoops that programs are required negotiate.

    Reply

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