Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03028883 |
| Other study ID # |
27675 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
January 16, 2017 |
| Last updated |
November 17, 2017 |
| Start date |
December 2, 2016 |
| Est. completion date |
December 22, 2016 |
Study information
| Verified date |
November 2017 |
| Source |
St. Louis University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
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
Description:
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.
