Buprenorphine Dose Adjustments and Gestational Age
Buprenorphine Dose Adjustments and Gestational Age
In this retrospective cohort study, we plan to examine the relationship between buprenorphine
 dose adjustments, gestational age, urine buprenorphine levels and the rate of neonatal
 abstinence syndrome in opioid-maintained pregnant women
The prevalence of opioid use disorder in pregnancy was four per 1000 deliveries in 2011 and
 has increased to 5.4% in 2013. Repeated, acute withdrawal during pregnancy is not recommended
 as it is may be associated with intrauterine growth restriction (IUGR) and preterm labor and
 delivery. The American College of Obstetricians and Gynecologists (ACOG) recommends methadone
 as the first line treatments for opioid use during pregnancy and buprenorphine as an
 alternative. Methadone therapy has been used since the 1970's for the treatment of heroin
 addiction during pregnancy and efficacy is well documented. Prescribing methadone has
 barriers, such as significant drug interactions and enrollment in a registered substance
 abuse treatment program. Emerging evidence supports the use of buprenorphine for opioid use
 disorder in pregnancy. Buprenorphine has some distinct advantages over methadone which
 include a lower risk of overdose, fewer drug interactions, and no need for registration into
 a methadone treatment program. However, buprenorphine has a lower rate of retention in
 treatment than methadone.

 Opioid use disorder increases the risk of adverse pregnancy outcomes compared to women who do
 not use opioids.One such outcome is neonatal abstinence syndrome (NAS) which affects
 approximately 55% to 94% of neonates exposed to addictive medications during pregnancy. A
 2016 review of five trials involving buprenorphine and methadone in pregnant patients found
 that buprenorphine significantly improved or had similar outcomes to methadone for neonatal
 outcomes. Buprenorphine exposed infants required less treatment for NAS (20%-47% vs
 45.5%-57%, respectively) and experienced a shorter duration of NAS (4.1-5.6 vs 5.3-9.9 days,
 respectively) compared to methadone exposed infants. Buprenorphine is associated with fewer
 preterm deliveries and adverse fetal outcomes including the rate of NAS, medication
 assistance for NAS, and total dose of morphine used to treat NAS. There are currently no
 studies evaluating the level of buprenorphine doses on the rate of NAS.

 Several pharmacokinetic changes occur during pregnancy which impact medications and increase
 the risk for subtherapeutic levels. Subtherapeutic buprenorphine levels may increase the risk
 for withdrawal symptoms and cravings, which may increase the risk for relapse. The volume of
 distribution increases for both hydrophilic and lipophilic medications throughout pregnancy
 due to increased body fluid, increased adipose tissue, and decreased protein binding.
 Buprenorphine is metabolized through cytochrome P450 (CYP450) 3A4, UGT1A1, 1A3, and 2B7.
 Pregnancy increases hepatic metabolism of the CYP450 3A4 and UGT2B7. Buprenorphine is
 eliminated 70% through the feces and 30% through the urine. Pregnancy increases hepatic and
 renal elimination. Elimination is increased partly due to increased cardiac output secondary
 to increased plasma volume. Cardiac output reaches its maximum at approximately 32 weeks,
 whereas peak renal elimination occurs at 36 weeks. These pharmacokinetic changes typically
 require doses to be increased as pregnancy progresses.

 A limitation of methadone therapy is the unpredictable pharmacokinetics during pregnancy.
 Methadone is a lipophilic and highly protein-bound medication, making the medication less
 available during pregnancy. It is metabolized mainly by CYP3A4, which leads to decreased
 concentrations of methadone in the plasma during pregnancy. One study performed by Pond and
 colleagues examined methadone serum concentrations during the second and third trimesters and
 at two separate time points post-partum. They found plasma trough methadone concentrations
 were lower and methadone renal clearance was higher in the second and third trimesters than
 in the post-partum time period, supporting the finding that methadone requires dose increases
 as pregnancy progresses. A literature review explored studies related to dosing and
 monitoring of methadone in pregnancy. This review included a a study that found a methadone
 plasma trough level of 0.78 µmol/L was required to prevent withdrawal. The authors of the
 review found evidence to support that methadone pharmacokinetics appear to be altered in
 pregnancy but that there is a lack of evidence to support routine serum monitoring. Although
 based on the Drozdick study they do endorse monitoring trough levels when withdrawal symptoms
 are apparent.

 Few studies evaluated the effect of pregnancy on the pharmacokinetics of buprenorphine. Based
 on the characteristics of the medication it would be expected that pharmacokinetic changes in
 pregnancy would be similar to those of methadone. One difference is that buprenorphine has an
 active metabolite which may make buprenorphine dosing more predictable. the pharmacokinetics
 of buprenorphine in plasma, oral fluid, and sweat of pregnant women (n=9). At 28-29 and 34
 weeks gestation and 2 months postpartum, plasma, oral fluid and sweat levels were collected
 over 24 hours. The maximum concentration and total amount of buprenorphine and
 norbuprenorphine in plasma were lower during pregnancy compared with postpartum levels
 (buprenorphine Cmax 0.2ng/mL/mg vs 1ng/mL/mg and Tmax 1.5h*ng/mL/mg vs 7h*ng/mL/mg,
 norbuprenorphine Cmax 3ng/mL/mg vs 13ng/mL/mg and Tmax no change). Therefore, these
 significant metabolic changes during pregnancy and immediately postpartum could indicate the
 need for dose adjustment of buprenorphine. Another small trial of nine pregnant women on
 buprenorphine maintenance therapy assessed the urinary excretion of buprenorphine and its
 metabolites every 12 days from the second trimester through 6 weeks postpartum. The mean
 ratio of urine buprenorphine to norbuprenorphine was significantly higher in the second
 trimester compared to the third trimester in all patients. Additionally, the mean dose of
 buprenorphine increased from the second to the third trimester in seven of the nine women. In
 a subset of 3 patients, 24-hour buprenorphine and metabolite excretion was collected.
 Buprenorphine levels were higher during pregnancy than postpartum in all three (0.8 mg, 5.0
 mg, 2.0 mg vs 0.55 mg, 4.0 mg, 0.8 mg, respectively). The uncorrected buprenorphine urine
 concentrations ranged from 5.5 to 12.1 µg/L [mean 7.0 (2.8) µg/L], although they did not
 evaluate if withdrawal symptoms occurred below a certain threshold. The buprenorphine dose in
 this study was flexible, with increases or decreases made through clinical decisions based on
 compliance in taking medication, participant requests, urine toxicology, and participant
 self-reports of opioid withdrawal symptoms or craving. Buprenorphine dose was positively
 correlated to creatinine-corrected norbuprenorphine (P < 0.001, R = 0.197),
 buprenorphine-glucuronide (P < 0.002, R = 0.143), and norbuprenorphine-glucuronide (P <
 0.001, R = 0.182) concentrations across the study. However low correlation coefficients
 indicate that prediction of metabolite concentrations in urine based on buprenorphine dose,
 or vice versa, would be unreliable. These studies support the need for increased doses of
 buprenorphine throughout pregnancy, but may have been too small to determine whether a
 relationship between buprenorphine urine levels and dose adjustments exists. Currently, no
 studies examined the relationship between gestational age and buprenorphine dose adjustments
 after having achieved maintenance dosing.

 This information could assist providers in optimizing monitoring of pregnant women and
 informing providers regarding dose adjustments. Preventing subtherapeutic levels may decrease
 the risk for withdrawal symptoms, craving, and risk of relapse.

 No data are available to evaluate whether a particular gestational age requires dose
 adjustments due to pregnancy-related pharmacokinetic changes. The program obtains
 quantitative and qualitative buprenorphine and norbuprenorphine urine levels at each visit.
 These data are used to confirm that she is taking her buprenorphine prescription. No data are
 available to determine if there is a lower threshold in urine buprenorphine and metabolite
 that levels correlate with symptoms that require dose increases. Additionally, no data are
 available evaluating if rates of NAS, treatment for NAS, or total dose of morphine for NAS
 correlates as a function of maternal dose.
Inclusion Criteria:

 -  Pregnant

 -  opioid-dependent

 -  being treated at same location

 Exclusion Criteria:

 -  Not pregnant

 -  not opioid-dependent