Evidence on Buprenorphine Dose Limits: A Review.

OBJECTIVES: As overdose deaths from fentanyl continue to increase, optimizing use of medications for opioid use disorder has become increasingly important. Buprenorphine is a highly effective medication for reducing the risk of overdose death, but only if a patient remains in treatment. Shared decision making between prescribers and patients is important to establish a dose that meets each patient's treatment needs. However, patients frequently face a dose limit of 16 or 24 mg/d based on dosing guidelines on the Food and Drug Administration's package label. METHODS: This review discusses patient-centered goals and clinical criteria for determining dose adequacy, reviews the history of buprenorphine dose regulation in the United States, examines pharmacological and clinical research results with buprenorphine doses up to 32 mg/d, and evaluates whether diversion concerns justify maintaining a low buprenorphine dose limit. RESULTS: Pharmacological and clinical research results consistently demonstrate buprenorphine's dose-dependent benefits up to at least 32 mg/d, including reductions in withdrawal symptoms, craving, opioid reward, and illicit use while improving retention in care. Diverted buprenorphine is most often used to treat withdrawal symptoms and reduce illicit opioid use when legal access to it is limited. CONCLUSIONS: In light of established research and profound harms from fentanyl, the Food and Drug Administration's current recommendations on target dose and dose limit are outdated and causing harm. An update to the buprenorphine package label with recommended dosing up to 32 mg/d and elimination of the 16 mg/d target dose would improve treatment effectiveness and save lives.

Detection and quantitation of non-steroidal anti-inflammatory drug use close to the time of birth using umbilical cord tissue.

BACKGROUND: Nonsteroidal anti-inflammatory drugs are contraindicated in the third trimester of pregnancy due to negative effects including alteration of uteroplacental blood flow, premature ductus arteriosus closure, and adverse effects on the fetal kidney. However, many women are unaware of these risks, and commonly report their use in pregnancy. We aimed to determine if umbilical cord was a reliable matrix for detecting NSAID use, determine incidence of use close to labour, and uncover associations with obstetric/neonatal outcomes. METHODS: We developed a UHPLC-MS/MS method to simultaneously detect diclofenac, ibuprofen, indomethacin, naproxen, and salicylic acid in plasma and umbilical cord lysate. Using this method, we screened 380 lysates to determine the prevalence of NSAID use. Results were compared to the clinical outcomes in pregnancy using ICD9/10 chart codes (n = 21). RESULTS: The UHPLC-MS/MS method has excellent linearity, accuracy, and precision in solvent and plasma, but lower sensitivity in umbilical cord lysate. We report a 3 % rate of NSAID ingestion within days of labour - the pharmacokinetically-determined window for active ingestion. There were no significant differences observed for maternal, obstetric, or neonatal outcomes between the NSAID positive group (n = 11) and NSAID negative group (n = 369). CONCLUSIONS: Because NSAID use in third trimester is contraindicated, even a 3% usage rate is alarmingly high. Based on UHPLC-MS/MS performance of umbilical cord lysate, 3% is likely a conservative estimate. Recent adoption of NSAIDs under clinical supervision to support in vitro fertilisation and prevent pre-eclampsia indicates future work should focus on determining safe dosages of NSAIDs and the correct therapeutic window in pregnancy.

Umbilical cord as an analytical matrix - A technical note.

The umbilical cord (UC) connects the fetal blood supply to the placenta, so is exposed to all systemic endo- and xenobiotics. We have extensive experience using UC as an analytical matrix for detecting and/or quantitating drugs, chemicals and endogenous compounds. This technical note describes advantages (large amount available, ease of collection, small sample needed for use, rapid availability) and challenges (clinical relationships, processing difficulties, matrix effects on analytes and detection technologies) of UC as an analytical matrix in ELISA and LC/MS platforms, and provides guidance for successfully working with this tissue.

Integrating Reproductive Health Services Into Opioid Treatment Facilities: A Missed Opportunity to Prevent Opioid-exposed Pregnancies and Improve the Health of Women Who Use Drugs.

: Opioid treatment programs (OTPs) are federally mandated to provide certain medical services to patients, and are often the only place where people with substance use disorders (SUD) obtain medical care. Just as medication for addiction treatment (MAT) should be part of comprehensive addiction care, so should reproductive health care be a part of comprehensive medical care. The most significant barrier that must be overcome is that the majority of OTPs believe that it is outside their scope of service to provide reproductive health services. Reproductive health care is basic medical care. It is imperative for the long-term health of women with SUD, their children and the community that they receive this care. OTPs can and should do better for their female clients.

Dysregulation of inflammatory cytokines and inhibition of VEGFA in the human umbilical cord are associated with negative pregnancy outcomes.

INTRODUCTION: Cytokines and vascular endothelial growth factors (VEGF) are involved in all aspects of pregnancy: from placentation, through fetal development, parturition and neonatal well-being. Umbilical cord inflammatory cytokines and/or VEGF have not been well studied with respect to dysregulation associated with disorders of pregnancy or maternal/neonatal outcomes. METHODS: Here we have used multiplex ELISA to screen umbilical cord lysates (comprising cord blood, endothelia and Wharton's jelly, n = 380), for levels of IFN-γ, IL1-ß, IL-6, IL-8, IL-10, TNF-α and VEGFs A, C and D and associations with 46 ICD9/10 codes encompassing obstetric, maternal and neonatal variables. RESULTS: No significant differences were observed for IFNγ, VEGFC or VEGFD with any clinical outcomes. The cytokines IL1-ß, IL-6, IL-8, IL-10, and TNF-α showed varying levels of induction and suppression with primarily fetal-placental and neonatal complications. The largest number of significant differences between umbilical cytokines and clinical outcomes were observed for chorioamnionitis (IL1-ß, IL-6, IL-8, TNF-α), and meconium passage during birth (IL1-ß, IL-6, IL-8) where significant pro-inflammatory responses occurred and sex differences in IL-8 expression were noted. In contrast, gonococcal infection showed suppressed immune response significantly lowering IL1-ß, IL-6, IL-8, IL-10 and TNF-α. For 12/46 negative pregnancy outcomes, strong suppression of VEGFA occurred. DISCUSSION: Angiogenic and inflammatory changes in the umbilical cord could be detrimental by increasing vascular permeability in the umbilical artery or vein and/or altering vascular tone, either of which would alter blood flow affecting delivery and removal of compounds. Further elucidation of inflammatory responses in the umbilical cord may provide mechanistic understanding of adverse pregnancy outcomes.

Opioid prescribing trends in postpartum women: a multicenter study.

BACKGROUND: The postpartum period can be a particularly vulnerable time for exposure to opioid medications, and there are currently no consensus guidelines for physicians to follow regarding opioid prescribing during this period. OBJECTIVE: The purpose of this study was to evaluate inter- and intrahospital variability in opioid prescribing patterns in postpartum women and better understand the role of clinical variables in prescribing. STUDY DESIGN: Data were extracted from electronic medical records on 4248 patients who delivered at 6 hospitals across the United States from January 2016 through March 2016. The primary outcome of the study was postpartum opioid prescription at the time of hospital discharge. Age, parity, route of delivery, and hospital were analyzed individually and with multivariate analyses to minimize confounding factors. Statistical methods included χ2 to analyze frequency of opioid prescription by hospital, parity, tobacco use, delivery method, and laceration type. An analysis of variance was used to analyze morphine equivalent dose by hospital. RESULTS: The percentage of women prescribed postpartum opioids varied significantly by hospital, ranging from 27.6% to 70.9% (P <0.001). Oxycodone-acetaminophen was the most commonly prescribed medication (50.3%) with each hospital having its preferred opioid type. Median number of tablets prescribed ranged from 20 to 40 (P < .0001). Primiparous women were more likely to receive opioids than multiparous women when broken down by a parity of 1, 2, 3, 4, and ≥5 (52.8%, 48.0%, 47.6%, 40.1%, and 45.8%, respectively, P = .0005). Among women who had vaginal deliveries, opioid prescription rates were higher in women who experienced either a second-degree laceration (35.5%, P = .0002) or a third-/fourth-degree laceration (59.3%, P < .001). CONCLUSION: Postpartum opioid prescription rates vary widely among hospitals, but providers within the same hospital tend to follow similar prescribing trends. The variation in prescribing found in our study illustrates the need for clear consensus guidelines for postpartum pain management.

Detection of opioids in umbilical cord lysates: an antibody-based rapid screening approach.

In pregnancy, opioids may be used medically and also misused. We hypothesized that the umbilical cord (UC) could be a good screening tool for determining opioid exposure and improving medical care. One hundred and one UC, each with 50 associated ICD9/ICD10 codes were used. Using predictive pharmacokinetic analysis we determined that opioids could be detected since last ingestion prior to birth. The UC were lysed and screened using ELISA detecting multiple opioids and their metabolites. Statistical comparisons to obstetric and neonatal outcomes were performed. Although the commercial ELISA was less sensitive in UC than blood or urine, there was perfect method selectivity as compared to a subset of cords designated positive or negative by clinical diagnostics, so our results are accurate and reliable. Absolute quantitation was not possible because the antibody cross reacts with multiple compounds, but 'low' or 'high' levels of exposure were assigned. Prevalence of opioids was 11%, which reduced to 7% when cesarean-section births were eliminated. For non-cesarean-section infants adjusted for preterm birth, advanced maternal age and smoking (independent risk factors), opioids were significantly associated with intra-uterine growth restriction (p = 0.017) and admission to neonatal intensive care (p = 0.002). UC can be collected noninvasively and rapidly providing a reliable tools for semi-quantitative opioid screening using ELISA. Moreover, as UC are usually discarded collection presents few technical or safety concerns for staff or patients. Further development of this methodology may provide a rapid, noninvasive clinical screening tool to identify NAS and/or opioid use in late pregnancy.

Screening Pregnant Women and Their Neonates for Illicit Drug Use: Consideration of the Integrated Technical, Medical, Ethical, Legal, and Social Issues.

North America is currently suffering from one of the worst epidemics of illicit drug use in recent history: the opioid crisis. Pregnant women are not immune to the ravages of substance misuse which affects themselves, their pregnancies, and the wider community. The prevalence of drug misuse in pregnancy is not well quantified due to the lack of good validated tests, cooperation between clinicians and scientists developing tests, and consensus as to who should be tested and how results should be used. A wide range of tissues can be tested for drug use, including maternal blood, urine, and hair; neonatal meconium, urine, and hair; and placenta and umbilical cord tissues. Testing methods range from simple spectrophotometry and clinical chemistry to sophisticated analytical HPLC or mass spectrometry techniques. The drive for ever greater accuracy and sensitivity must be balanced with the necessities of medical practice requiring minimally invasive sampling, rapid turnaround, and techniques that can be realistically utilized in a clinical laboratory. Better screening tests have great potential to improve neonatal and maternal medical outcomes by enhancing the speed and accuracy of diagnosis. They also have great promise for public health monitoring, policy development, and resource allocation. However, women can and have been arrested for positive drug screens with even preliminary results used to remove children from custody, before rigorous confirmatory testing is completed. Balancing the scientific, medical, public health, legal, and ethical aspects of screening tests for drugs in pregnancy is critical for helping to address this crisis at all levels.

Use of Kratom, an Opioid-like Traditional Herb, in Pregnancy.

BACKGROUND: Kratom (Mitragyna speciosa) is an herbal preparation with opioid-like effects made from a tree native to Southeast Asia and the Pacific Islands. Increasingly, kratom is used for self-treatment of opioid use disorder and recently has been associated with a multistate outbreak of salmonellosis. Few data are available on the clinical outcomes of kratom use in pregnancy. CASES: We present two cases of pregnant women presenting with kratom dependence. Both women presented with symptoms consistent with opioid withdrawal. Both women were initiated on opioid replacement, with successful treatment of symptoms. CONCLUSIONS: Kratom is an emerging self-treatment for opioid use disorder in the obstetric population. Obstetric care providers should be aware of kratom and consider opioid replacement for pregnant women with kratom dependence.

Opioid Detoxification During Pregnancy: A Systematic Review.

OBJECTIVE: To systematically review maternal and neonatal outcomes associated with opioid detoxification during pregnancy. DATA SOURCES: PubMed, PsycINFO, EMBASE, Cochrane, and ClinicalTrials.gov databases were searched from January 1, 1966, to September 1, 2016. METHODS OF STUDY SELECTION: English-language studies that reported outcomes associated with opioid detoxification among pregnant women with opioid use disorder were included. Nonoriginal research articles (case reports, editorials, reviews) and studies that failed to report outcomes for detoxification participants were excluded. Bias was assessed using the Cochrane Collaboration's tool for assessing risk of bias and quality was assessed using the U.S. Preventive Service Task Force Quality of Evidence scale. TABULATION, INTEGRATION, AND RESULTS: Of 1,315 unique abstracts identified, 15 met criteria for inclusion and included 1,997 participants, of whom 1,126 underwent detoxification. Study quality ranged from fair to poor as a result of the lack of a randomized control or comparison arm and high risk of bias across all studies. Only nine studies had a comparison arm. Detoxification completion (9-100%) and illicit drug relapse (0-100%) rates varied widely across studies depending on whether data from participants who did not complete detoxification or who were lost to follow-up were included in analyses. The reported rate of fetal loss was similar among women who did (14 [1.2%]) and did not undergo detoxification (17 [2.0%]). CONCLUSIONS: Evidence does not support detoxification as a recommended treatment intervention as a result of low detoxification completion rates, high rates of relapse, and limited data regarding the effect of detoxification on maternal and neonatal outcomes beyond delivery.

Screening, brief intervention, and referral to treatment for opioid and other substance use during infertility treatment.

Opioid use and misuse have reached epidemic proportions in the United States, especially in women of childbearing age, some of whom seek infertility treatments. Substance use is much more common than many of the conditions routinely screened for during the preconception period, and it can have devastating consequences for the woman and her family. Substance use can worsen infertility, complicate pregnancy, increase medical problems, and lead to psychosocial difficulties for the woman and her family. The reproductive endocrinologist thus has an ethical and medical duty to screen for substance use, provide initial counseling, and refer to specialized treatment as needed. This article provides an overview of screening, brief intervention, and referral to treatment (SBIRT), a public health approach shown to be effective in ameliorating the harms of substance use.

Insights in Public Health: Substance Use in Pregnant Women in Hawai'i: Extending Our Capacity and Compassion.

Substance use can have serious consequences for the health and well-being of individuals. The problem is of particular concern when it involves pregnant women due to health risks for the mother and the fetus. In utero exposure to either legal (eg, alcohol, cigarettes, and certain prescription drugs) or illicit (eg, amphetamines, cocaine, and opioids) substances can result in potentially serious and long-lasting health problems for infants. Available data from Hawai'i indicate that substance use among pregnant women is higher than national targets, which reflect the fact that there is essentially no acceptable rate of use of these substances. Developing an effective system to support virtual elimination of substance use in pregnancy requires broad-based strategies. Progress is being made in Hawai'i to better identify and address substance use in pregnancy. These efforts are being guided by a variety of stakeholders who are dedicated to improving the healthcare and health outcomes for this population. However, significant challenges to the system remain, including provider shortages, lack of local investment, and limited capacity of appropriate, individualized treatment.

The role of screening, brief intervention, and referral to treatment in the perinatal period.

Substance use during pregnancy is at least as common as many of the medical conditions screened for and managed during pregnancy. While harmful and costly, it is often ignored or managed poorly. Screening, brief intervention, and referral to treatment is an evidence-based approach to manage substance use. In September 2012, the US Centers for Disease Control and Prevention convened an Expert Meeting on Perinatal Illicit Drug Abuse to help address key issues around drug use in pregnancy in the United States. This article reflects the formal conclusions of the expert panel that discussed the use of screening, brief intervention, and referral to treatment during pregnancy. Screening for substance use during pregnancy should be universal. It allows stratification of women into zones of risk given their pattern of use. Low-risk women should receive brief advice, those classified as moderate risk should receive a brief intervention, whereas those who are high risk need referral to specialty care. A brief intervention is a patient-centered form of counseling using the principles of motivational interviewing. Screening, brief intervention, and referral to treatment has the potential to reduce the burden of substance use in pregnancy and should be integrated into prenatal care.

ATP-binding cassette proteins BCRP, MRP1 and P-gp expression and localization in the human umbilical cord.

1. The umbilical cord is a direct conduit to the fetus hence transporters could have roles in partitioning substances between the maternal-placental-fetal units. Here we determined the expression and localization of the ATP-Binding Cassette (ABC) transporters BCRP (ABCG2), P-gp (ABCB1) and MRP1 (ABCC1) in human umbilical cords. 2. The mRNA for BCRP and MRP1 was detected in 25/25 samples, but P-gp was detected in only 5/25. ABC transporter mRNA expression relative to 18S was 25.6 ± 0.3, 26.5 ± 0.6 and 22.2 ± 0.2 cycles for BCRP, MRP1 and P-gp respectively. 3. Using a subset of 10 umbilical cords, BCRP protein was present in all samples (immunoblot) with positive correlation between mRNA and proteins (p = 0.07, r = 0.62) and between immunoblotting and immunohistochemistry (IHC) (p = 0.03, r = 0.67). P-gp protein was observed in 4/10 samples by both immunoblot and IHC, with no correlation between mRNA and protein (p = 0.45, r = 0.55) or immunoblotting and IHC (p = 0.2, r = 0.72), likely due to small sample size. MRP1 protein was not observed. 4. Localization of BCRP and P-gp proteins was to Wharton's jelly with no specific staining in arterial or venous endothelia. 5. Understanding ABC transporter expression in the umbilical cord may be useful for determining fetal exposures to xenobiotics if functional properties can be defined.

Biochemical Screening for in utero Drug Exposure.

Licit and illicit drug use is a common complication of pregnancy. Accurate information on drug use is difficult to obtain for many reasons as women fear self-disclosure or consenting for drug testing due to stigma, guilt, and fear of social and legal harm. As information about drug use is clinically very important, biochemical testing is an important adjunct to careful maternal history. In addition, research studies depend on accurate measures of exposure when reporting risks of a substance. This paper delineates available matrices for and methods of biochemical drug testing in pregnant women and neonates.

Methamphetamines and pregnancy outcomes.

INTRODUCTION: Methamphetamine (MA) is one of the most commonly used illicit drugs in pregnancy, yet studies on MA-exposed pregnancy outcomes have been limited because of retrospective measures of drug use; lack of control for confounding factors; other drug use, including tobacco; poverty; poor diet; and lack of prenatal care. This study presents prospective collected data on MA use and birth outcomes, controlling for most confounders. MATERIALS AND METHODS: This is a retrospective cohort study of women obtaining prenatal care from a clinic treating women with substance use disorders, on whom there are prospectively obtained data on MA and other drug use, including tobacco. Methamphetamine-exposed pregnancies were compared with non-MA exposed pregnancies and non-drug-exposed pregnancies, using univariate and multivariate analysis to control for confounders. RESULTS: One hundred forty-four infants were exposed to MA during pregnancy, 50 had first trimester exposure only, 45 had continuous use until the second trimester, 29 had continuous use until the third trimester, but were negative at delivery, and 20 had positive toxicology at delivery. There were 107 non-MA-exposed infants and 59 infants with no drug exposure. Mean birth weights were the same for MA-exposed and nonexposed infants (3159 g vs 3168 g; P = 0.9), although smaller than those without any drug exposure (3159 vs 3321; P = 0.04), infants with positive toxicology at birth (meconium or urine) were smaller than infants with first trimester exposure only (2932 g vs 3300 g; P = 0.01). Gestation was significantly shorter among the MA-exposed infants than that among nonexposed infants (38.5 vs 39.1 weeks; P = 0.045), and those with no drug exposure (38.5 vs 39.5; P = 0.0011), the infants with positive toxicology at birth had a clinically relevant shortening of gestation (37.3 weeks vs 39.1; P = 0.0002). CONCLUSIONS: Methamphetamine use during pregnancy is associated with shorter gestational ages and lower birth weight, especially if used continuously during pregnancy. Stopping MA use at any time during pregnancy improves birth outcomes, thus resources should be directed toward providing treatment and prenatal care.