Naltrexone in the treatment of opioid‐dependent pregnant women: the case for a considered and measured approach to research

The present paper considers naltrexone to treat opioid dependence during pregnancy. The public health problem of opioid dependence and its treatment during pregnancy is reviewed first. Next, the naltrexone and opioid dependence treatment literature is summarized, with overviews of the pre‐clinical and clinical research on prenatal naltrexone exposure. Finally, considerations and recommendations for future medication research for the treatment of opioid dependence in pregnant women are provided. The efficacy of long‐acting injectable naltrexone relative to placebo, its blockade of opioid agonist euphoric effects, its lack of abuse and tolerance development and its modest adverse effect profile make it a potential medication for opioid‐dependent pregnant women. However, it is not without seriously concerning potential drawbacks, including the difficulty surrounding medication induction that may lead to vulnerability with regard to relapse, physical dependence re‐establishment, increased risk behaviors, treatment dropout and resulting opioid overdose. Before embarking on future research with this medication, the benefits and risks for the mother–embryo/fetus/child dyad should be weighed carefully. Should future research be conducted, a multi‐level commitment to proactive ethical research is needed to reach the ultimate goal of improving the lives of women and children affected by opioid dependence.     

Buprenorphine in pregnant opioid-dependent women: first results of a prospective study

Aim To report results on the prospective follow‐up of 34 pregnant women exposed to buprenorphine maintenance for opiate dependence. Design and setting Prospective multicentre study: all pregnant women receiving buprenorphine as maintenance therapy were included as early as possible during their pregnancy. Participants The pregnant women were recruited from opiate maintenance therapy centres, general practitioner‐networks involved in addiction, maternity hospitals and centres for drug information during pregnancy. Measurements Women: drugs and medications consumed, medical and obstetrical events; offspring: withdrawal syndrome, malformation, neonatal disease. Findings The buprenorphine‐exposed pregnancies resulted in 31 live births, one stillbirth, one spontaneous abortion and one voluntary termination. A neonatal withdrawal syndrome was observed in 13 cases (41.9%) and eight of these babies required opiate treatment. Two neonates had a malformation: a premature ductus arteriosus stricture and a tragus appendix. Conclusion Taken together with other prospective studies, no alarming results were observed concerning pregnancy outcomes. However, further data from the comparative prospective study are required to determine whether buprenorphine can be considered as a good alternative to methadone treatment in pregnant women.     

Cost‐effectiveness of extended buprenorphine–naloxone treatment for opioid‐dependent youth: data from a randomized trial

Aims The objective is to estimate cost, net social cost and cost‐effectiveness in a clinical trial of extended buprenorphine–naloxone (BUP) treatment versus brief detoxification treatment in opioid‐dependent youth. Design Economic evaluation of a clinical trial conducted at six community out‐patient treatment programs from July 2003 to December 2006, who were randomized to 12 weeks of BUP or a 14‐day taper (DETOX). BUP patients were prescribed up to 24 mg per day for 9 weeks and then tapered to zero at the end of week 12. DETOX patients were prescribed up to 14 mg per day and then tapered to zero on day 14. All were offered twice‐weekly drug counseling. Participants 152 patients aged 15–21 years. Measurements Data were collected prospectively during the 12‐week treatment and at follow‐up interviews at months 6, 9 and 12. Findings The 12‐week out‐patient study treatment cost was $1514 (P < 0.001) higher for BUP relative to DETOX. One‐year total direct medical cost was only $83 higher for BUP (P = 0.97). The cost‐effectiveness ratio of BUP relative to DETOX was $1376 in terms of 1‐year direct medical cost per quality‐adjusted life year (QALY) and $25 049 in terms of out‐patient treatment program cost per QALY. The acceptability curve suggests that the cost‐effectiveness ratio of BUP relative to DETOX has an 86% chance of being accepted as cost‐effective for a threshold of $100 000 per QALY. Conclusions Extended BUP treatment relative to brief detoxification is cost effective in the US health‐care system for the outpatient treatment of opioid‐dependent youth.     

Results of a pilot study using self‐collected mid‐turbinate nasal swabs for detection of influenza virus infection among pregnant women

Background

We evaluated the feasibility of asking pregnant women to self-collect and ship respiratory specimens.

Methods

In a preliminary laboratory study, we compared the RT-PCR cycle threshold (CT) values of influenza A and B viruses incubated at 4 storage temperatures (from 4 to 35°C) for 6 time periods (8, 24, 48, 72, and 168 hours and 30 days), resulting in 24 conditions that were compared to an aliquot tested after standard freezing (−20°C) (baseline condition). In a subsequent pilot study, during January–February, 2014, we delivered respiratory specimen collection kits to 53 pregnant women with a medically attended acute respiratory illness using three delivery methods.

Results

CT values were stable after storage at temperatures <27°C for up to 72 hours for influenza A viruses and 48 hours for influenza B viruses. Of 53 women who received kits during the pilot, 89% collected and shipped nasal swabs as requested. However, 30% (14/47) of the women took over 2 days to collect and ship their specimen. The human control gene, ribonuclease P (RNase P), was detected in 100% of nasal swab specimens. However, the mean CT values for RNase P (26·5, 95% confidence interval [CI] = 26·0–27·1) and for the 8 influenza A virus positives in our pilot (32·2, 95% CI = 28·9–35·5) were significantly higher than the CTs observed in our 2010–2012 study using staff-collected nasal pharyngeal swabs (P-values < 0·01).

Discussion

Self-collection of respiratory specimens is a promising research method, but further research is needed to quantify the sensitivity and specificity of the approach.     

Abuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphine‐maintained intravenous heroin abusers

Background Sublingual buprenorphine is an effective maintenance treatment for opioid dependence, yet intravenous buprenorphine misuse occurs. A buprenorphine/naloxone formulation was developed to mitigate this misuse risk. This randomized, double‐blind, cross‐over study was conducted to assess the intravenous abuse potential of buprenorphine/naloxone compared with buprenorphine in buprenorphine‐maintained injection drug users (IDUs). Methods Intravenous heroin users (n = 12) lived in the hospital for 8–9 weeks and were maintained on each of three different sublingual buprenorphine doses (2 mg, 8 mg, 24 mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intravenous placebo, naloxone, heroin and low and high doses of buprenorphine and buprenorphine/naloxone were examined. Every participant received each test dose under the three buprenorphine maintenance dose conditions. Results Intravenous buprenorphine/naloxone was self‐administered less frequently than buprenorphine or heroin (P < 0.0005). Participants were most likely to self‐administer drug intravenously when maintained on the lowest sublingual buprenorphine dose. Subjective ratings of ‘drug liking’ and ‘desire to take the drug again’ were lower for buprenorphine/naloxone than for buprenorphine or heroin (P = 0.0001). Participants reported that they would pay significantly less money for buprenorphine/naloxone than for buprenorphine or heroin (P < 0.05). Seven adverse events were reported; most were mild and transient. Conclusions These data suggest that although the buprenorphine/naloxone combination has intravenous abuse potential, that potential is lower than it is for buprenorphine alone, particularly when participants received higher maintenance doses and lower buprenorphine/naloxone challenge doses. Buprenorphine/naloxone may be a reasonable option for managing the risk for buprenorphine misuse during opioid dependence treatment.     

Methadone versus buprenorphine in pregnant addicts: a double-blind, double-dummy comparison study

AIMS: To evaluate the efficacy and safety of methadone versus buprenorphine treatment in pregnant opioid-dependent women. DESIGN: Randomized, double-dummy, double-blind, flexible-dosing comparison study. SETTING: Addiction Clinic at the Medical University of Vienna, Austria. PARTICIPANTS: Eighteen women were assigned randomly to receive either methadone (n = 9) or buprenorphine (n = 9) during weeks 24-29 of pregnancy. After dropouts, data were available from 14 cases (six in the methadone and eight in the buprenorphine group). INTERVENTION: Sublingual buprenorphine tablets (8-24 mg/day) or oral methadone solution (40-100 mg/day), with matched placebos. MEASUREMENTS: Mothers: retention in treatment, urine toxicology and nicotine use. Neonates: Routine birth data, neonatal abstinence syndrome (NAS) in severity and duration. FINDINGS: There was somewhat greater retention in the buprenorphine group but significantly lowered use of additional opioids in the methadone group (P = 0.047).Neonates: There was earlier onset of NAS in neonates born to the methadone (mean 60 hours) than to the buprenorphine groups (mean 72 hours after last medication); 43% did not require NAS-treatment with short treatment duration in both groups (mean 5 days). CONCLUSION: This preliminary study had limited power to detect differences but the trends observed suggest this kind of research is practicable and that further studies are warranted.     

Inhibitory control in young adult women with fetal alcohol syndrome: Findings from a pilot functional magnetic resonance imaging study

Background

Executive dysfunction, especially impaired inhibitory control, is a common finding in individuals with fetal alcohol syndrome (FAS). Previous research has mostly focused on neural correlates of inhibitory deficits in children and adolescents. We investigated inhibitory functions and underlying cerebral activation patterns in young adult women with FAS.

Methods

Task performance and functional magnetic resonance imaging (fMRI) data were acquired during a Go/NoGo (GNG) inhibition task in 19 young adult women with FAS and 19 healthy female control subjects. Whole-brain activation and task performance analyses were supplemented by region of interest (ROI) analyses of fMRI data within a predefined cognitive control network (CCN).

Results

Task performance did not differ significantly between groups on errors of commission, associated with inhibitory control. Similarly, overall activation within the preselected ROIs did not differ significantly between groups for the main inhibitory contrast NoGo > Go. However, whole-brain analyses revealed activation differences in the FAS group when compared to controls under inhibitory conditions. This included hyperactivations in the left inferior frontal, superior temporal, and supramarginal gyri in the FAS group. Likewise, lateralization tendencies toward right-hemispheric ROIs were weaker in FAS subjects. In contrast to comparable inhibitory performance, attention-related errors of omission were significantly higher in the FAS group. Correspondingly, FAS subjects had lower activity in attention-related temporal and parietal areas.

Conclusions

The known alterations of inhibitory functions associated with prenatal alcohol exposure in children and adolescents were not seen in this adult sample. However, differential brain activity was observed, reflecting potential compensatory mechanisms. Secondary results suggest that there is impaired attentional control in young adult women with FAS.     

Outcomes of pregnancies in women with pre‐gestational diabetes mellitus and gestational diabetes mellitus; a population‐based study in New South Wales,Australia, 1998–2002

Aim To determine population‐based rates and outcomes of pre‐gestational diabetes mellitus (pre‐GDM) and gestational diabetes mellitus (GDM) in pregnancy. Methods This was a cross‐sectional study, using linked population databases, of all women, and their infants, discharged from hospital following birth in New South Wales (NSW) between 1 July 1998 and 31 December 2002. Women with, and infants exposed to pre‐GDM or GDM were compared with those without diabetes mellitus for pregnancy characteristics and outcomes. Results Women with a singleton pregnancy (n = 370 703) and their infants were included: 1248 women (0.3%) had pre‐GDM and 17 128 (4.5%) had GDM. Of those women with pre‐GDM, 57% had Type 1 diabetes, 20% had Type 2 diabetes and for 23% the type of diabetes was unknown. Major maternal morbidity or mortality was more common in women with pre‐GDM (7.9%) [odds ratio (OR) 3.2, 95% confidence interval (CI) 2.6, 3.9] and in women with GDM (3.1%) (OR 1.2, 95% CI 1.1, 1.4) when compared with women without diabetes (2.6%). Major infant morbidity or mortality occurred more frequently in infants exposed to pre‐GDM compared with no diabetes (13.6% vs. 3.1%) (OR 5.0, 95% CI 4.2, 5.8) and in infants exposed to GDM compared with no diabetes (3.2% vs. 2.3%) (OR 1.4, 95% CI 1.3, 1.5). Conclusions Pre‐GDM and GDM continue to be associated with an increased risk of adverse maternal and neonatal outcomes; however, women with GDM have adverse outcomes less frequently. Rates of GDM and pre‐GDM appear to be increasing over time. Clinicians should consider the potential for adverse outcomes, and arrange referral to appropriate services.     

Buprenorphine withdrawal syndrome in newborns: a report of 13 cases

Aims To assess neonatal abstinence syndrome (NAS) and neurodevelopmental outcome in infants born to addicted mothers under buprenorphine substitution therapy. Setting District general hospital, Angoulême, France. Methods Retrospective case records study of infants admitted to the neonatal intensive care unit (NICU) and/or special care baby unit (SCBU) from January 1994 to December 2000 for surveillance and/or treatment of buprenorphine NAS. Results Thirteen infants were born to addicted mothers under buprenorphine maintenance therapy during the study period. Eight were male and five were female; mean birth term and weight were 39 weeks gestation and 3000 g, respectively. Apgar scores were within normal limits; four infants were small for gestational age, none was dysmorphologic and none was extracted for fetal distress. NAS occurred in 11 cases (85%) and required treatment in 10 cases. Morphine chlorhydrate 0.5 mg/kg/day was administered in divided doses to seven children and gave better results than paregoric alone or in combination with diazepam. Upon follow‐up, seven children presented transient lower limbs hypertonia, jerky movements and jitteriness that lasted 3–9 months. The overall milestones acquisitions were within normal limits. Conclusion Buprenorphine substitution seems to be safe during pregnancy, and has had no teratogenic effects reported to date. It induces NAS of variable intensity that is less prolonged in comparison to methadone; the neurodevelopmental outcome of exposed children is normal in the majority of cases, although some presented with transient motor abnormalities that resolved completely in 85% of those recruited to our study.     

The impact of buprenorphine and methadone on mortality: a primary care cohort study in the United Kingdom

Aims

To estimate whether opioid substitution treatment (OST) with buprenorphine or methadone is associated with a greater reduction in the risk of all‐cause mortality (ACM) and opioid drug‐related poisoning (DRP) mortality.

Design

Cohort study with linkage between clinical records from Clinical Practice Research Datalink and mortality register.

Setting

UK primary care.

Participants

A total of 11 033 opioid‐dependent patients who received OST from 1998 to 2014, followed‐up for 30 410 person‐years.

Measurements

Exposure to methadone (17 373, 61%) OST episodes or buprenorphine (9173, 39%) OST episodes. ACM was available for all patients; information on cause of death and DRP was available for 5935 patients (54%) followed‐up for 16 363 person‐years. Poisson regression modelled mortality by treatment period with an interaction between OST type and treatment period (first 4 weeks on OST, rest of time off OST, first 4 weeks off OST, rest of time out of OST censored at 12 months) to test whether ACM or DRP differed between methadone and buprenorphine. Inverse probability weights were included to adjust for confounding and balance characteristics of patients prescribed methadone or buprenorphine.

Findings

ACM and DRP rates were 1.93 and 0.53 per 100 person‐years, respectively. DRP was elevated during the first 4 weeks of OST [incidence rate ratio (IRR) = 1.93 95% confidence interval (CI) = 0.97–3.82], the first 4 weeks off OST (IRR = 8.15, 95% CI = 5.45–12.19) and the rest of time out of OST (IRR = 2.13, 95% CI = 1.47–3.09) compared with mortality risk from 4 weeks to end of treatment. Patients on buprenorphine compared with methadone had lower ACM rates in each treatment period. After adjustment, there was evidence of a lower DRP risk for patients on buprenorphine compared with methadone at treatment initiation (IRR = 0.08, 95% CI = 0.01–0.48) and rest of time on treatment (IRR = 0.37, 95% CI = 0.17–0.79). Treatment duration (mean and median) was shorter on buprenorphine than methadone (173 and 40 versus 363 and 111, respectively). Model estimates suggest that there was a low probability that methadone or buprenorphine reduced the number of DRP in the population: 28 and 21%, respectively.

Conclusions

In UK general medical practice, opioid substitution treatment with buprenorphine is associated with a lower risk of all‐cause and drug‐related poisoning mortality than methadone. In the population, buprenorphine is unlikely to give greater overall protection because of the relatively shorter duration of treatment.     

Tiagabine increases cocaine-free urines in cocaine-dependent methadone-treated patients: results of a randomized pilot study

Aims We sought to evaluate the safety and efficacy of the GABAergic agent tiagabine in reducing cocaine use among methadone‐treated patients. Design Ten‐week randomized double‐blind placebo‐controlled trial. Setting Opiate Treatment Research Program, Veteran's Affairs Connecticut Healthcare System in West Haven, Connecticut, USA. Participants The participants were 45 cocaine‐dependent methadone‐treated patients who were predominately Caucasian (75.6%), male (77.8%) and never married (53%) with an average age of 38 years (SD = 6.5). Interventions Comparison groups received tiagabine 12 mg/day (n = 15), tiagabine 24 mg/day (n = 15) or placebo (n = 15). Measures Baseline assessments included the Structured Clinical Interview for DSM‐IV, the Addiction Severity Index, a urine drug test, self‐reported use and opiate withdrawal scales. Urine drug tests were performed thrice weekly. Findings Treatment retention was over 80% for all treatment groups. The sample mean (± SE) of cocaine‐free urines for the first week after study entry and before tiagabine was started was 1.16 (0.19) urines/week. During weeks 9 and 10 cocaine‐free urines increased significantly from baseline by 33% with high‐dose tiagabine (24 mg/day), by 14% with low‐dose tiagabine (12 mg/day) and decreased by 10% with placebo (hierarchical linear model, Z= 2.03; P < 0.05). Self‐reported cocaine use also decreased significantly more with active medications than with placebo. Conclusions Tiagabine at 24 mg/day was well tolerated among these methadone‐treated patients with only one reporting headache. Tiagabine appears to be a promising GABAergic medication that moderately improves cocaine‐free urines.     

Glycaemic control during early pregnancy and fetal malformations in women with Type I diabetes mellitus

Aims/hypothesis. To assess the relation between glycaemic control in early pregnancy and the risk of congenital malformations in offspring of mothers with Type I (insulin-dependent) diabetes mellitus.¶Methods. From 1988–1997, we prospectively collected data from 691 pregnancies and 709 offspring of 488 women with Type I diabetes in a specific geographic area in Southern Finland. Glycated haemoglobin A_{1 c} at less than 14 weeks of gestation was used as the indicator of glycaemic control. The malformations were diagnosed either by ultrasonography in pregnancy or during the neonatal period. We also studied 729 non-selected control pregnancies in women without diabetes.¶Results. The numbers of major fetal malformations were 30 (4.2 %) in patients with Type I diabetes and 10 (1.2 %) in the control subjects (relative risk 3.1; 95 % confidence interval: 1.6 to 6.2). Even women whose HbA_{1 c} was only slightly raised (5.6 to 6.8 %, ie 2.0 to 5.9 standard deviation units) showed a relative risk of 3.0 (95 % confidence interval: 1.2 to 7.5). Haemoglobin A_{1 c} retained its statistically significant association with the occurrence of malformations after adjusting for White's class, age at onset of diabetes, duration of diabetes, parity, smoking and participation in pre-pregnancy counselling.¶Conclusions/interpretation. Even a slightly raised HbA_{1 c} during early pregnancy in women with Type I diabetes carries an increased risk for fetal malformations. Therefore normoglycaemia should be strived for during early pregnancy. [Diabetologia (2000) 43: 79–82]     

Detectability of colorectal neoplastic lesions using a narrow‐band imaging system: A pilot study

Background and Aim: Flat and depressed colorectal neoplastic lesions can be difficult to identify using conventional colonoscopy techniques. Narrow‐band imaging (NBI) provides unique views especially of mucosal vascular network and helps in visualization of neoplasia by improving contrast. The aim of this study was to assess the feasibility of using NBI for colorectal neoplasia screening. Methods: Forty‐seven consecutive patients, who underwent high definition colonoscopy (HDC) screening examinations revealing neoplastic lesions, were enrolled in our prospective study. No biopsies or resections were performed during the initial HDC, but patients in whom lesions were detected underwent further colonoscopies using NBI, with the results of the first examination blinded from the colonoscopist. They then received appropriate treatment. We compared diagnostic detection rates of neoplastic lesions for HDC and NBI procedures using total number of all identified neoplastic lesions as reference standard. Results: Altogether, 153 lesions were detected and analyzed in 43 patients. Mean diagnostic extubation times were not significantly different (P = 0.18), but the total number of lesions detected by NBI was higher (134 vs 116; P = 0.02). Based on macroscopic type, flat lesions were identified more often by NBI (P = 0.04). As for lesion size, only flat lesions < 5 mm were detected more frequently (P = 0.046). Lesions in the right colon were identified more often by NBI (P = 0.02), but NBI missed two flat lesions ≥ 10 mm located there. Conclusions: Narrow band imaging colonoscopy may represent a significant improvement in the detection of flat and diminutive lesions, but a future multi‐center controlled trial should be conducted to fully evaluate efficacy for screening colonoscopies.     

Fetal Intra‐pericardial Morgagni Hernia with effusion affecting one member of a twin gestation

Congenital diaphragmatic hernia (CDH) is a rare type of developmental defect of the diaphragm, occurring in 1 per 2000 pregnancies. Morgagni hernia, in particular, which results from an anterior defect of the diaphragm, is the least common type of CDH (5%). Herniation of the liver into the pericardial space, presenting as a thoracic mass with pericardial effusion, is an extremely rare form of Morgagni hernia. Such reported cases are few and occurred only in singleton pregnancies. To the best of our knowledge, we report the first case of fetal echocardiography and fetal MRI following referral due to large pericardial effusion.