A 2022 meta-analysis sought to gauge the impact of extended-release injectable naltrexone, in comparison to a placebo, on alcohol consumption among patients dealing with alcohol use disorder (AUD). The analysis incorporated seven trials involving 1,500 adults with AUD who received monthly injections of either placebo or extended-release naltrexone at doses ranging from 150 to 400 mg for 2 to 6 months. These trials were conducted in outpatient clinic settings in the United States or Europe, including specialized alcohol/substance use clinics and HIV clinics. Generally, participants were treatment-seeking adult males or non-pregnant, non-lactating females with moderate to severe alcohol use, assessed through validated tools, and a minimum of one weekly episode of heavy drinking. The analysis measured the pooled weighted mean difference (WMD) in drinking days per month and heavy drinking days per month. [1]
The WMD favored extended-release naltrexone, showing -2.0 (95% confidence interval [CI] -3.4 to -0.6; p= 0.03) for drinking days per month and -1.2 (95% CI -0.2 to -2.1; p= 0.02) for heavy drinking days per month, reflecting that treatment resulted in two fewer drinking days per month and 1.2 fewer heavy drinking days per month compared to the placebo. Trials not mandating lead-in abstinence and those lasting over 3 months reported larger reductions in heavy drinking days per month, with WMDs of -2.0 (95% CI -3.52 to -0.48; p= 0.01) and -1.9 (95% CI -3.2 to -0.5; p= 0.01), respectively. [1]
Importantly, two trials (see Tables 1-2) comparing the clinical and cost-effectiveness of oral and injectable naltrexone were identified. Due to limited available data, a meta-analysis could not be performed. Nevertheless, these studies reported 3 to 6 monthly heavy drinking days with no significant differences between groups, suggesting equal efficacy between the two formulations. [1]
A recent randomized clinical trial (RCT) compared the effectiveness of oral naltrexone versus extended-release injectable naltrexone for hospitalized patients with AUD. A total of 248 participants were enrolled, with 125 receiving oral naltrexone and 123 receiving extended-release injectable naltrexone. The primary outcome, the change in percentage of heavy drinking days (HDDs) over the past 30 days, was assessed at a 3-month follow-up. At baseline, the oral naltrexone group had a median of 66.7% HDDs, and the extended-release injectable naltrexone group had a median of 70.7% HDDs. After 3 months, the oral naltrexone group reduced their HDDs to 27.4% (-38.4 percentage points), while the extended-release injectable naltrexone group reduced theirs to 23.8% (-46.4 percentage points). The difference between the groups was not statistically significant (p= 0.14). Regarding acute health care utilization, 59 out of 109 participants (54.1%) in the oral naltrexone group and 66 out of 108 participants (61.1%) in the extended-release injectable naltrexone group reported acute health care utilization in the previous 3 months. The odds ratio for health care utilization was 1.34 (95% CI 0.77 to 2.33), indicating no significant difference between groups. Overall, both treatments led to substantial reductions in heavy drinking, with no significant difference between the two, suggesting that the choice of treatment should depend on factors such as patient preference and insurance coverage. [2]
A 2019 protocol describes a phase 4, open-label RCT (NCT01893827) evaluating extended-release naltrexone (XR-NTX) versus oral naltrexone (O-NTX) for alcohol dependence treatment in a primary care setting. Notably, the trial was sponsored by NYU Langone Health and conducted at Bellevue Hospital Center in New York City. A total of 237 adults with alcohol dependence were recruited from the community and randomized to receive either XR-NTX 380 mg intramuscularly (IM) once monthly or oral naltrexone 50 mg daily for 24 weeks, with both groups receiving primary care–based Medical Management. The primary outcome was the percentage of participants achieving abstinence or moderate drinking, defined as ≤2 drinks per day for men, ≤1 drink per day for women, and ≤2 heavy drinking occasions per month, during the final 20 of 24 treatment weeks. According to data posted on ClinicalTrials.gov, 29% of XR-NTX participants (n= 117) and 23% of O-NTX participants (n= 120) met this outcome. Despite the availability of the protocol and trial results via ClinicalTrials.gov, no full peer-reviewed publication of the study’s findings has been identified to date. [3], [4]
A 2017 randomized pilot proof-of-concept study investigated the impact of pre-discharge administration of injectable versus oral naltrexone on post-hospitalization treatment engagement among veterans with AUD. This single-center trial randomized 54 hospitalized veterans diagnosed with DSM-IV alcohol dependence to receive either a one-time 380 mg IM naltrexone injection or a 50 mg oral dose along with a 30-day prescription prior to discharge. Participants were recruited from general medical, psychiatric, surgical, and residential treatment units and followed for 45 days post-discharge. Inclusion criteria required absence of opioid use or dependence, clinically stable hepatic function, and capacity for informed consent. Baseline assessments included alcohol consumption via Timeline Follow-back, depression and anxiety screening (PHQ-9 and GAD-7), and psychiatric comorbidities assessment using the MINI. Medication adherence was defined as receiving the second injection in the injectable group or taking ≥80% of oral doses in the other group. Among the 45 participants who received study medication, follow-up rates reached 77.8% for both 14- and 45-day assessments. Median alcohol consumption dropped significantly from 128 drinks in the 14 days prior to hospitalization to zero drinks at both follow-up points (p<0.001). Medication adherence was comparable between groups (62% oral vs. 61% injection). Although not powered to detect statistical significance, post-discharge specialty addiction treatment engagement was high, with 86.4% of injectable and 78.3% of oral naltrexone recipients attending at least one visit within 14 days. Retention in treatment over three months was numerically greater in the injectable group (40.9% vs. 21.7%). No significant differences were observed between groups in alcohol consumption, treatment engagement metrics, or hospital readmission rates. The data affirm feasibility of initiating either formulation of naltrexone in the inpatient setting, and suggest potential for enhanced care continuity post-discharge when pharmacologic treatment is integrated into the hospitalization process. [5]
Regarding opioid use disorder (OUD), a 2019 randomized, open-label, single-center trial compared the clinical outcomes of extended-release naltrexone (XR-naltrexone) and daily oral naltrexone, both administered in conjunction with a comprehensive behavioral therapy regimen, in a cohort of 60 adults diagnosed with DSM-IV-defined opioid dependence. Following inpatient detoxification and successful naltrexone induction, participants were stratified by baseline opioid use severity and then randomized in a 1:1 fashion to receive either monthly IM injections of XR-naltrexone (380 mg) or daily oral naltrexone (50 mg), with all patients concurrently enrolled in behavioral naltrexone therapy. Participants were scheduled for outpatient clinic visits two to three times per week over the 24-week treatment period, with urine toxicology monitoring at each encounter. Kaplan-Meier analysis demonstrated significantly improved 24-week treatment retention among participants receiving XR-naltrexone compared with those on oral naltrexone (57.1% vs. 28.1%, respectively; p= 0.03. Multivariable Cox regression adjusting for demographic and clinical covariates revealed a hazard ratio (HR) for dropout of 2.18 (95% CI 1.07 to 4.43) favoring XR-naltrexone. Rates of opioid use, assessed via onsite urine drug screening, did not significantly differ between groups (median proportion of opioid-positive specimens: 2.4% in XR-naltrexone vs. 8.8% in oral naltrexone; p= 0.57). The XR-naltrexone group attended more behavioral sessions on average (mean 17.0 vs. 12.3) and earned a higher mean value in voucher incentives ($371.37 vs. $197.68). Although both groups experienced common adverse effects consistent with protracted opioid withdrawal, XR-naltrexone was generally well tolerated, with only one serious adverse event (pruritic hives) directly attributed to the study drug. These findings underscore the superiority of XR-naltrexone in sustaining treatment adherence over oral formulations despite the use of intensive psychosocial support in both arms. [6]
Lastly, a 2010 quasi-experimental analysis compared early treatment outcomes between long-acting injectable naltrexone and oral naltrexone maintenance therapy, each combined with psychosocial intervention, for individuals with heroin dependence. The study included patients enrolled in two concurrently conducted randomized trials, 69 received oral naltrexone between 1999 and 2002, and 42 received long-acting injectable naltrexone between 2000 and 2003. During the first 8 weeks following detoxification, patients treated with injectable naltrexone had significantly greater retention in treatment (p= 0.012) and improved opiate use outcomes on one of several measures (p= 0.024), favoring the injectable group. Subgroup analysis revealed that individuals with less severe baseline heroin use responded better to injectable naltrexone, whereas those with more severe use had better retention when treated with oral naltrexone combined with intensive psychotherapy. These findings suggest that while injectable naltrexone may offer advantages overall, the severity of heroin use and intensity of accompanying psychosocial support play critical roles in treatment outcomes. The authors note that results are exploratory due to the study’s quasi-experimental design. [7]