Psychopharmacologic Management of Opioid‐Dependent Women during Pregnancy

Illicit drug use during pregnancy presents complex clinical challenges, including reducing drug use and treating psychiatric disorders. Pharmacologic treatment of psychiatric disorders in a pregnant woman requires an evaluation of the balance between potential clinical benefit and the risk of potential neonatal consequences. This study describes psychiatric symptoms in 111 opioid‐dependent pregnant women and their prescribed psychotropic medications. Hypomania, generalized anxiety disorder and depression were the most common disorders for which psychiatric symptoms were endorsed. Over half of women studied were prescribed some form of psychoactive medication during pregnancy. Pharmacologic vs. non‐pharmacologic treatment approaches in this patient population are discussed.     

Treating pregnant women dependent on opioids is not the same as treating pregnancy and opioid dependence: a knowledge synthesis for better treatment for women and neonates

AIMS: Through a novel synthesis of the literature and our own clinical experience, we have derived a set of evidence-based recommendations for consideration as guidance in the management of opioid-dependent pregnant women and infants. METHODS: PubMed literature searches were carried out to identify recent key publications in the areas of pregnancy and opioid dependence, neonatal abstinence syndrome (NAS) prevention and treatment, multiple substance abuse and psychiatric comorbidity. RESULTS: Pregnant women dependent on opioids require careful treatment to minimize harm to the fetus and neonate and improve maternal health. Applying multi-disciplinary treatment as early as possible, allowing medication maintenance and regular monitoring, benefits mother and child both in the short and the long term. However, there is a need for randomized clinical trials with sufficient sample sizes. RECOMMENDATIONS: Opioid maintenance therapy is the recommended treatment approach during pregnancy. Treatment decisions must encompass the full clinical picture, with respect to frequent complications arising from psychiatric comorbidities and the concomitant consumption of other drugs. In addition to standardized approaches to pregnancy, equivalent attention must be given to the treatment of NAS, which occurs frequently after opioid medication. CONCLUSION: Methodological flaws and inconsistencies confound interpretation of today's literature. Based on this synthesis of available evidence and our clinical experience, we propose recommendations for further discussion.     

Acceptance of naltrexone by pregnant women enrolled in comprehensive drug addiction treatment: an initial survey

This paper reports the results of an initial survey regarding the potential interest in naltrexone treatment by pregnant women enrolled in comprehensive treatment for substance use disorders. Pregnant women (N = 112) were asked about their interest in taking either an oral or long-acting injectable medication that would stop heroin and/or alcohol use, leave them "clear-headed," and without neonatal withdrawal. Results indicate strong interest among pregnant women in antagonist treatment, in either form, with clear interest in learning more about naltrexone. Findings lend support for patients' acceptance of a clinical trial of antagonist treatment in this population.     

Gender Differences in Alcohol Treatment: An Analysis of Outcome From the COMBINE Study

Background: Relatively few studies have examined gender differences in the effectiveness of specific behavioral or pharmacologic treatment of alcohol dependence. The aim of this study is to assess whether there were gender differences in treatment outcomes for specific behavioral and medication treatments singly or in combination by conducting a secondary analysis of public access data from the national, multisite NIAAA‐sponsored COMBINE study. Methods: The COMBINE study investigated alcohol treatment among 8 groups of patients (378 women, 848 men) who received medical management (MM) with 16 weeks of placebo, naltrexone (100 mg/day), acamprosate (3 g/day), or their combination with or without a specialist‐delivered combined behavioral intervention. We examined efficacy measures separately for men and women, followed by an overall analysis that included gender and its interaction with treatment condition in the analyses. These analyses were performed to confirm whether the findings reported in the parent trial were also relevant to women, and to more closely examine secondary outcome variables that were not analyzed previously for gender effects. Results: Compared to men, women reported a later age of onset of alcohol dependence by approximately 3 years, were significantly less likely to have had previous alcohol treatment, and drank fewer drinks per drinking day. Otherwise, there were no baseline gender differences in drinking measures. Outcome analyses of 2 primary (percent days abstinent and time to first heavy drinking day) and 2 secondary (good clinical response and percent heavy drinking days) drinking measures yielded the same overall pattern in each gender as that observed in the parent COMBINE study report. That is, only the naltrexone by behavioral intervention interaction reached or approached significance in women as well as in men. There was a naltrexone main effect that was significant in both men and women in reduction in alcohol craving scores with naltrexone‐treated subjects reporting lower craving than placebo‐treated subjects. Conclusions: This gender‐focused analysis found that alcohol‐dependent women responded to naltrexone with COMBINE’s Medical Management, similar to the alcohol‐dependent men, on a wide range of outcome measures. These results suggest that clinicians can feel comfortable prescribing naltrexone for alcohol dependence in both men and women. In this study, it is also notable that fewer women than men reported receiving any alcohol treatment prior to entry into the COMBINE study. Of note, women tend to go to primary health care more frequently than to specialty substance abuse programs for treatment, and so the benefit we confirm for women of the naltrexone and MM combination has practical implications for treating alcohol‐dependent women.     

Serious adverse events in the Australian National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD)

Aims The study estimated serious adverse event (SAE) rates among entrants to pharmacotherapies for opioid dependence, during treatment and after leaving treatment. Design A longitudinal study based on data from 12 trials included in the Australian National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD). Participants and settings A total of 1244 heroin users and methadone patients treated in hospital, community and GP settings. Intervention Six trials included detoxification; all included treatment with methadone, buprenorphine, levo‐alpha‐acetyl‐methadol (LAAM) or naltrexone. Findings During 394 person‐years of observation, 79 SAEs of 28 types were recorded. Naltrexone participants experienced 39 overdoses per 100 person‐years after leaving treatment (44% occurred within 2 weeks after stopping naltrexone). This was eight times the rate recorded among participants who left agonist treatment. Rates of all other SAEs were similar during treatment versus out of treatment, for both naltrexone‐treated and agonist‐treated participants. Five deaths occurred, all among participants who had left treatment, at a rate of six per 100 person‐years. Total SAE rates during naltrexone and agonist treatments were similar (20, 14 per 100 person‐years, respectively). Total SAE and death rates observed among participants who had left treatment were three and 19 times the corresponding rates during treatment. Conclusions Individuals who leave pharmacotherapies for opioid dependence experience higher overdose and death rates compared with those in treatment. This may be due partly to a participant self‐selection effect rather than entirely to pharmacotherapy being protective. Clinicians should alert naltrexone treatment patients in particular about heroin overdose risks. Duty of care may extend beyond cessation of dosing.     

A Randomized Trial of Oral Naltrexone for Treating Opioid‐Dependent Offenders

Offenders with a history of opioid dependence are a particularly difficult group to treat. A large proportion of offenders typically relapse shortly after release from prison, commit drug‐related crimes, and then are arrested and eventually re‐incarcerated. Previous research demonstrated that oral naltrexone was effective in reducing opioid use and preventing recidivism among offenders under federal supervision. The 111 opioid‐dependent offenders in this study were under various levels of supervision that included county and federal probation/parole, a treatment court, an alternative disposition program, and an intermediate punishment program. Subjects were randomly assigned to receive 6 months of either 300 mg per week of oral naltrexone plus standard psychosocial treatment as usual (n = 56) or standard psychosocial treatment as usual (TAU) without naltrexone (n = 55). While the TAU subjects who remained in treatment used more opioids than the naltrexone subjects who remained, the high dropout rate for both groups made it difficult to assess the effectiveness of naltrexone. The study provides limited support for the use of oral naltrexone for offenders who are not closely monitored by the criminal justice system. (Am J Addict 2010;00:1–11)     

Clonidine and naltrexone in the outpatient treatment of heroin withdrawal

Clonidine hydrochloride (an alpha-2 adrenergic agonist) and naltrexone hydrochloride (an opioid antagonist), given in combination, provided a safe and effective treatment of abrupt opioid withdrawal over 5 days in an outpatient/day setting. Before starting the clonidine, a naloxone challenge test was used to verify and quantify opioid dependence, and the naloxone challenge test score was then used to determine initial medication doses. Initial naloxone challenge test scores predicted subsequent patient discomfort during the 5-day clonidine-naltrexone protocol. Twelve of 14 (86%) heroin users successfully withdrew from opioids and simultaneously initiated naltrexone maintenance.     

Naltrexone and cognitive behavioral coping skills therapy for the treatment of alcohol drinking and eating disorder features in alcohol-dependent women: a randomized controlled trial

BACKGROUND: Despite important gender differences in drinking patterns, physiological effects of alcohol, and co-occurring psychiatric conditions, relatively little is known about the efficacy of naltrexone for the treatment of alcohol dependence in women. This study investigated the safety and efficacy of naltrexone in combination with Cognitive Behavioral Coping Skills Therapy (CBCST) in a sample of alcohol-dependent women, some with comorbid eating pathology. METHODS: One hundred three women meeting DSM-IV criteria for alcohol dependence (29 with comorbid eating disturbances) were randomized to receive either naltrexone 50 mg or placebo for 12 weeks in addition to weekly group CBCST. Subjects were enrolled between October 1995 and December 2000 at an outpatient research clinic. RESULTS: No significant differences were observed on the primary outcomes of time to first drinking day, time to first day of heavy drinking, or the percentage of participants who continued to meet the criteria for alcohol dependence. Secondary analyses revealed that naltrexone significantly delayed the time to the second (chi2=5.37, p=0.02) and third (chi2=4.35, p=0.04) drinking days among subjects who did not maintain abstinence from alcohol. Among those with eating disturbances, symptoms of eating pathology improved during treatment, but the effects did not differ according to medication condition. CONCLUSION: When used in conjunction with CBCST, naltrexone did not significantly improve drinking outcomes in the overall sample of alcohol-dependent women. However, naltrexone may be of benefit to women who are unable to maintain total abstinence from alcohol. For women with concurrent eating pathology, participation in treatment for alcoholism may be associated with improvements in eating pathology.     

The effect of naltrexone on alcohol's stimulant properties and self-administration behavior in social drinkers: influence of gender and genotype

Background: Few pharmacological treatments for alcohol dependence are available. Moreover, the best supported treatment, naltrexone hydrochloride, appears to work for only some. Methods: To investigate potential predictors of these differential responses, 40 social drinkers (20 women) were administered 6 days of treatment with naltrexone vs. placebo in a double‐blind, counterbalanced, crossover design. At the end of each treatment period, participants received a single dose of their preferred alcoholic beverage followed by the opportunity to work for additional alcohol units using a progressive ratio (PR) breakpoint paradigm. All subjects but one were genotyped for the A118G polymorphism of the mu opioid receptor gene (OPRM1). Results: Naltrexone decreased the ethanol‐induced ‘euphoria’ to a priming dose of alcohol in two subgroups: (i) in women, and (ii) in subjects with the A118G polymorphism of the mu opioid receptor gene (OPRM1). Naltrexone did not decrease motivation to work for additional alcoholic beverages on the PR task regardless of gender or genotype. Conclusions: The results add to the evidence that naltrexone decreases positive subjective effects of alcohol, with preferential effects in distinct subgroups. Similar effects in heavier drinkers might decrease alcohol use.     

Antagonists in the medical management of opioid use disorders: Historical and existing treatment strategies

Background and Objectives

Opioid use disorder (OUD) is a chronic condition with potentially severe health and social consequences. Many who develop moderate to severe OUD will repeatedly seek treatment or interact with medical care via emergency department visits or hospitalizations. Thus, there is an urgent need to develop feasible and effective approaches to help persons with OUD achieve and maintain abstinence from opioids. Treatment that includes one of the three FDA‐approved medications is an evidence‐based strategy to manage OUD. The purpose of this review is to address practices for managing persons with moderate to severe OUD with a focus on opioid withdrawal and naltrexone‐based relapse‐prevention treatment.

Methods

Literature available on PubMed was used to review the evolution of treatment strategies from the 1960s onward to manage opioid withdrawal and initiate treatment with naltrexone.

Results

Emerging practices for extended‐release naltrexone induction include the use of agonist tapers and adjuvant medications. Clinical challenges frequently encountered when initiating this therapy include managing withdrawal and ongoing opioid use during treatment. Clinical factors may inform decisions regarding patient selection and length of naltrexone treatment, such as recent opioid use and patient preferences.

Conclusions and Scientific Significance

Treatment strategies to manage opioid withdrawal have evolved, but many patients with OUD do not receive medication for the prevention of relapse. Clinical strategies for induction onto extended‐release naltrexone are now available and can be safely and effectively implemented in specialty and select primary care settings. (© 2018 The Authors. The American Journal on Addictions Published by Wiley Periodicals, Inc. on behalf of The American Academy of Addiction Psychiatry (AAAP);27:177–187)     

Naltrexone Maintenance

Naltrexone has been tested in numerous clinical trials for both safety and efficacy in the treatment of relapse to opioid dependence. In the doses used for this purpose, it has been found to be safe and pharmacologically effective. Recently it has been found that chronic treatment with naloxone or naltrexone produces supersensitivity to opioid agonists in rodents. Seven normal human volunteers were tested for opiate sensitivity, using morphine 8 mg iv before and after 2 weeks of naltrexone treatment at 50 mg po qd. There were no significant differences in morphine-induced respiratory depression before or after naltrexone treatment. These results indicate that at the dose of morphine used in this study, it is unlikely that naltrexone maintenance would increase the risk of opiate toxicity.     

Hepatitis E and pregnancy: understanding the pathogenesis

Hepatitis E virus (HEV) is a single‐stranded RNA virus that causes large‐scale epidemics of acute viral hepatitis, particularly in developing countries. In men and non‐pregnant women, the disease is usually self‐limited and has a case‐fatality rate of less than <0.1%. However, in pregnant women, particularly from certain geographical areas in India, HEV infection is more severe, often leading to fulminant hepatic failure and death in a significant proportion of patients. In contrast, reports from Egypt, Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in non‐pregnant women. The reasons for this geographical difference are not clear. The high mortality rate in pregnancy has been thought to be secondary to the associated hormonal (oestrogen and progesterone) changes during pregnancy and consequent immunological changes. These immunological changes include downregulation of the p65 component of nuclear factor (NF‐κB) with a predominant T‐helper type 2 (Th2) bias in the T‐cell response along with host susceptibility factors, mediated by human leucocyte antigen expression. Thus far, researchers were unable to explain the high HEV morbidity in pregnancy, why it is different from other hepatitis viruses such as hepatitis A with similar epidemiological features and the reason behind the difference in HEV morbidity in pregnant women in different geographical regions. The recent developments in understanding the immune response to HEV have encouraged us to review the possible mechanisms for these differences. Further research in the immunology of HEV and pregnancy is required to conquer this disease in the near future.     

Comparison of Characteristics of Opioid-Using Pregnant Women in Rural and Urban Settings

Historically, research on opioid use during pregnancy has occurred in urban settings and it is unclear how urban and rural populations compare. We examined socio-demographic and other variables in opioid-using pregnant women seeking treatment and screened for participation in a multi-site randomized controlled trial. Women screened in rural Burlington, Vermont (n = 54), were compared to those screened in urban Baltimore, Maryland (n = 305). Rural opioid-using pregnant women appear to have some characteristics associated with better treatment outcomes (e.g., less severe drug use, greater employment). However, they may face additional barriers in accessing treatment (e.g., greater distance from treatment clinic).     

Comparison of characteristics of opioid-using pregnant women in rural and urban settings

Historically, research on opioid use during pregnancy has occurred in urban settings and it is unclear how urban and rural populations compare. We examined socio-demographic and other variables in opioid-using pregnant women seeking treatment and screened for participation in a multi-site randomized controlled trial. Women screened in rural Burlington, Vermont (n = 54), were compared to those screened in urban Baltimore, Maryland (n = 305). Rural opioid-using pregnant women appear to have some characteristics associated with better treatment outcomes (e.g., less severe drug use, greater employment). However, they may face additional barriers in accessing treatment (e.g., greater distance from treatment clinic).     

Gender Differences in Predictors of Treatment Attrition with High Dose Naltrexone in Cocaine and Alcohol Dependence

Recently, we reported that naltrexone at 150 mg/day significantly decreased cocaine and alcohol use for men but not women with co‐occurring cocaine and alcohol dependence. The present study is an exploratory investigation of predictors that explain the different gender responses to naltrexone, with a particular focus on differential predictors of treatment attrition. No significant predictors were associated with treatment discontinuation in men. Women, however, were more likely to discontinue treatment when reporting severe pre‐treatment psychiatric problems or nausea while in treatment. Further research on the impact of pre‐treatment and in‐treatment gender differences with naltrexone is warranted.