Predictors of Daily Adherence to Naltrexone for Alcohol Use Disorder Treatment During a Mobile Health Intervention.
ABSTRACT: Background:Adherence to medications for treating alcohol use disorder (AUD) is poor. To identify predictors of daily naltrexone adherence over time, a secondary data analysis was conducted of a trial evaluating a mobile health intervention to improve adherence. Methods:Participants seeking treatment for AUD (n = 58; Mage = 38 years; 71% male) were prescribed naltrexone for 8 weeks. Adherence was tracked using the Medication Event Monitoring System (MEMS). In response to daily text messages, participants reported the previous day's alcohol use, craving, and naltrexone side effects. Using multilevel structural equation modeling (MSEM), we examined baseline dispositional factors and within-person, time-varying factors as predictors of daily adherence. Results:Naltrexone adherence decreased over time. Adherence was higher on days when individuals completed daily mobile assessments relative to days when they did not (odds ratio [OR] = 2.53, 95% confidence interval [CI] 1.61 to 3.98), irrespective of intervention condition. Days when individuals drank more than their typical amount were related to lower next-day adherence (OR = 0.93, 95% CI 0.88 to 0.99). A similar pattern was supported for craving (OR = 0.88, 95% CI 0.79 to 0.98). Weekend days were associated with lower adherence than weekdays (OR = 0.71, 95% CI 0.58 to 0.86); this effect was partly mediated by heavier daily drinking (indirect effect = -0.02, 95% CI -0.04 to -0.003) and stronger-than-usual craving (indirect effect = -0.01, 95% CI -0.02 to 0.00) on weekend days. Conclusions:The results further demonstrate the need to improve adherence to AUD pharmacotherapy. The present findings also support developing interventions that target daily-level risk factors for nonadherence. Mobile health interventions may be one means of developing tailored and adaptive adherence interventions.
Project description:<h4>Background</h4>Naltrexone is a front-line treatment for alcohol use disorders, but its efficacy is limited by poor medication adherence. This randomized controlled trial evaluated whether a mobile health intervention could improve naltrexone adherence.<h4>Methods</h4>Treatment-seeking participants with an alcohol use disorder (N = 76) were randomized to intervention and control conditions. All participants received naltrexone (50 mg/day) with a medication event monitoring system (MEMS) and a prepaid smartphone, and received a daily text message querying medication side effects, alcohol use, and craving. Those in the intervention arm received additional medication reminders and adherence assessment via text message.<h4>Results</h4>The primary outcome, proportion of participants with adequate adherence (defined as ?80% of prescribed doses taken through Week 8), did not differ between groups in intent-to-treat analyses (p = .34). Mean adherence at study midpoint (Week 4) was 83% in the intervention condition and 77% in the control condition (p = .35). Survival analysis found that the intervention group sustained adequate adherence significantly longer (M = 19 days [95% CI = 0.0-44.0]) than those in the control group (M = 3 days [95% CI = 0.0-8.1]) during the first month of treatment (p = .04). Medication adherence did not predict drinking outcomes.<h4>Conclusions</h4>These results suggest that in the context of daily monitoring and assessment via cell phone, additional text message reminders do not further improve medication adherence. Although this initial trial does not provide support for the efficacy of text messaging to improve adherence to pharmacotherapy for alcohol use disorders, additional trials with larger samples and alternate designs are warranted.<h4>Trial registration</h4>ClinicalTrials.gov: NCT01349985.
Project description:<h4>Background</h4>Initial evidence that OPRM1 genotype moderates the clinical response to naltrexone has not been replicated in prospective clinical trials. However, the use of traditional statistical analyses and clinical endpoints might limit sensitivity for studying pharmacogenetic associations, whereas the use of intensive daily assessments and person-centered analytic methods might increase sensitivity. This study leveraged person-centered analyses and daily measures of alcohol use, craving, and medication adherence to investigate OPRM1 as a moderator of changes in clinical outcomes during naltrexone treatment.<h4>Methods</h4>Treatment-seeking participants with alcohol use disorder (n = 58; M<sub>age</sub> = 38 years; 71% male) provided daily cell phone reports of craving and consumption while taking naltrexone as part of a mobile health trial. Daily medication adherence was measured remotely using electronic pill cap recordings. Multilevel modeling and multilevel structural equation modeling analyses evaluated the hypotheses that OPRM1 genotype would moderate prospective reductions in daily alcohol use and craving, and would also moderate within-person associations of daily adherence with same-day craving and consumption.<h4>Results</h4>OPRM1 genotype moderated the association of daily adherence with reduced same-day consumption (p = 0.007) and craving (p = 0.06), with these associations being stronger for participants with the 118G variant. OPRM1 genotype did not moderate changes in craving and consumption over time.<h4>Conclusions</h4>These findings suggest that high-density assessments and person-centered analytic approaches, including modeling within-person variation in medication adherence, could be advantageous for pharmacogenetic studies.
Project description:Naltrexone (NTX) has been widely studied for the treatment of alcohol use disorder with overall support for its efficacy. The mechanisms of action of naltrexone are thought to involve attenuation of the hedonic effects of alcohol and potentiation of its aversive effects. In order to provide a quantitative estimate of the effects of naltrexone on subjective response to alcohol, the aims of this meta-analytic review are to examine the effects of naltrexone across four domains of subjective response. Meta-analyses of naltrexone effects on alcohol craving (k = 16, N = 686), stimulation (k = 15, N = 675), sedation (k = 18, N = 777), and negative mood (k = 9, N = 281) suggested that under laboratory conditions and compared with placebo, naltrexone reduces craving (Hedges g = -0.252; SE = 0.054; 95% CI, -0.375 to -0.130; P < 0.01), reduces stimulation (g = -0.223; SE = 0.067; 95% CI, -0.372 to -0.074; P < 0.01), increases sedation (g = 0.251; SE = 0.064; 95% CI, 0.112-0.389; P < 0.01), and increases negative mood (g = 0.227; SE = 0.047; 95% CI, 0.100-0.354; P < 0.01). Results were robust when drinks per month and alcohol dose were added to the models as covariates. The effects of naltrexone varied by severity of alcohol use with medication effects on craving and stimulation being observed in sample of both heavy drinkers and AUD individuals. These results are consistent with the hypothesized mechanisms of action of NTX, although the effects are of small magnitude. This meta-analysis aggregates across multiple human laboratory studies of NTX's effects on subjective response to alcohol, providing a comprehensive summary of a key mechanism of NTX efficacy, namely, alteration of the subjective experience of alcohol.
Project description:Obese individuals vary in their experience of food cravings and tendency to engage in reward-driven eating, both of which can be modulated by the neural reward system rather than physiological hunger. We examined two predictions in a sample of obese women: (1) whether opioidergic blockade reduced food-craving intensity, and (2) whether opioidergic blockade reduced an association between food-craving intensity and reward-driven eating, which is a trait-like index of three factors (lack of control over eating, lack of satiation, preoccupation with food).Forty-four obese, pre-menopausal women completed the Reward-Based Eating Drive (RED) scale at study start and daily food-craving intensity on 5 days on which they ingested either a pill-placebo (2 days), a 25 mg naltrexone dose (1 day), or a standard 50mg naltrexone dose (2 days).Craving intensity was similar under naltrexone and placebo doses. The association between food-craving intensity and reward-driven eating significantly differed between placebo and 50mg naltrexone doses. Reward-driven eating and craving intensity were significantly positively associated under both placebo doses. As predicted, opioidergic blockade (for both doses 25mg and 50mg naltrexone) reduced the positive association between reward-driven eating and craving intensity to non-significance.Opioidergic blockade did not reduce craving intensity; however, blockade reduced an association between trait-like reward-driven eating and daily food-craving intensity, and may help identify an important endophenotype within obesity.
Project description:<h4>Importance</h4>Persons with opioid use disorder (OUD) and co-occurring alcohol use disorder (AUD) are understudied and undertreated. It is unknown whether the use of medications to treat OUD is associated with reduced risk of alcohol-related morbidity.<h4>Objective</h4>To determine whether the use of OUD medications is associated with decreased risk for alcohol-related falls, injuries, and poisonings in persons with OUD with and without co-occurring AUD.<h4>Design, setting, and participants</h4>This recurrent-event, case-control, cohort study used prescription claims from IBM MarketScan insurance databases from January 1, 2006, to December 31, 2016. The sample included persons aged 12 to 64 years in the US with an OUD diagnosis and taking OUD medication who had at least 1 alcohol-related admission. The unit of observation was person-day. Data analysis was performed from June 26 through September 28, 2020.<h4>Exposures</h4>Days of active OUD medication prescriptions, with either agonist (ie, buprenorphine or methadone) or antagonist (ie, oral or extended-release naltrexone) treatments compared with days without OUD prescriptions.<h4>Main outcomes and measures</h4>The primary outcome was admission for any acute alcohol-related event defined by International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes. Conditional logistic regression was used to compare OUD medication use between days with and without an alcohol-related event. Stratified analyses were conducted between patients with OUD with and without a recent AUD diagnostic code.<h4>Results</h4>There were 8?424?214 person-days of observation time among 13?335 participants who received OUD medications and experienced an alcohol-related admission (mean [SD] age, 33.1 [13.1] years; 5884 female participants [44.1%]). Agonist treatments (buprenorphine and methadone) were associated with reductions in the odds of any alcohol-related acute event compared with nontreatment days, with a 43% reduction for buprenorphine (odds ratio [OR],?0.57; 95% CI, 0.52-0.61) and a 66% reduction for methadone (OR, 0.34; 95% CI, 0.26-0.45). The antagonist treatment naltrexone was associated with reductions in alcohol-related acute events compared with nonmedication days, with a 37% reduction for extended-release naltrexone (OR, 0.63; 95% CI, 0.52-0.76) and a 16% reduction for oral naltrexone (OR, 0.84; 95% CI, 0.76-0.93). Naltrexone use was more prevalent among patients with OUD with recent AUD claims than their peers without AUD claims.<h4>Conclusions and relevance</h4>These findings suggest that OUD medication is associated with fewer admissions for alcohol-related acute events in patients with OUD with co-occurring AUD.
Project description:<h4>Importance</h4>The US Food and Drug Administration recognizes total abstinence and no heavy drinking days as outcomes for pivotal pharmacotherapy trials for alcohol use disorder (AUD). Many patients have difficulty achieving these outcomes, which can discourage seeking treatment and has slowed the development of medications that affect alcohol use.<h4>Objective</h4>To compare 2 drinking-reduction outcomes with total abstinence and no heavy drinking outcomes.<h4>Design, setting, and participants</h4>Data were obtained from 3 multisite, randomized, placebo-controlled clinical trials of medications for treating alcohol dependence (naltrexone, varenicline, and topiramate) in adults with DSM-IV-categorized alcohol dependence.<h4>Main outcomes and measures</h4>Within each trial, the percentage of participants in active and placebo conditions who met responder definitions of abstinence, no heavy drinking days, a WHO 1-level reduction, and a WHO 2-level reduction was computed by month with corresponding effect sizes (Cohen h).<h4>Results</h4>Across the 3 trials (N = 1169; mean [SD] age, 45  years; 824 [70.5%] men), the percentage of participants classified as responders during the last 4 weeks of treatment was lowest for abstinence (naltrexone, 34.7% [100 of 288]; varenicline, 7.3% [7 of 96]; topiramate, 11.7% [21 of 179]) followed by no heavy drinking days (naltrexone, 51.0% [147 of 288]; varenicline, 24.0% [23 of 96]; topiramate, 20.7% [37 of 179]), WHO 2-level reduction (naltrexone, 75.0% [216 of 288]; varenicline, 55.2% [53 of 96]; topiramate, 44.7% [80 of 179]), and WHO 1-level reduction (naltrexone, 83.3% [240 of 288]; varenicline, 69.8 [67 of 96]; topiramate, 54.7% [98 of 179]) outcomes. Standardized treatment effects observed for the WHO 2-level reduction outcomes (naltrexone, Cohen h = 0.214 [95% CI, 0.053 -0.375]; varenicline, 0.273 [95% CI, -0.006 to 0.553]; topiramate, 0.230 [95% CI, 0.024-0.435]) and WHO 1-level reduction (naltrexone, Cohen h = 0.116 [95% CI, -0.046 to 0.277]; varenicline, 0.338 [95% CI, 0.058-0.617]; topiramate, 0.014 [95% CI, -0.192 to 0.219]) were comparable with those obtained using abstinence (naltrexone, Cohen h = 0.142 [95% CI, -0.020 to 0.303]; varenicline, 0.146 [95% CI, -0.133 to 0.426]; topiramate, 0.369 [95% CI, 0.163-0.574]) and no heavy drinking days (naltrexone, Cohen h = 0.140 [95% CI, -0.021 to 0.302]; varenicline, 0.232 [95% CI, -0.048 to 0.511]; topiramate, 0.207 [95% CI, 0.002-0.413]).<h4>Conclusions and relevance</h4>WHO drinking risk level reductions appear to be worthwhile indicators of treatment outcome in AUD pharmacotherapy trials. These outcomes may align with drinking reduction goals of many patients and capture clinically meaningful improvements experienced by more patients than either abstinence or no heavy drinking days.<h4>Trial registration</h4>ClinicalTrials.gov identifiers: NCT00006206; NCT01146613; NCT00210925.
Project description:OBJECTIVE:To evaluate factors associated naturalistically with adherence to a mobile headache diary. BACKGROUND:Self-monitoring (keeping a headache diary) is commonly used in headache to enhance diagnostic accuracy and evaluate the effectiveness of headache therapies. Mobile applications are increasingly used to facilitate keeping a headache diary. Little is known about the factors associated with adherence to mobile headache diaries. METHODS:In this naturalistic longitudinal cohort study, people with headache (n = 1561) registered to use Curelator Headache® (now called N1-Headache®), an application that includes a mobile headache diary, through their physician (coupon), or directly through the website or app store using either a paid or free version of the application. Participants completed baseline questionnaires and were asked to complete daily recordings of headache symptoms and other factors for at least 90 days. Baseline questionnaires included headache characteristics and migraine disability. Daily recordings included headache symptoms and anxiety ratings. Adherence to keeping the headache diary was conceptualized as completion (kept the headache diary for 90 days), adherence rate (proportion of diary days completed 90 days after registration), and completion delay (the number of days past 90 days after registration required to complete 90 days of headache diary). RESULTS:The majority of participants reported migraine as the most common headache type (90.0%), and reported an average of 30.8 headache days/90 days (SD = 24.2). One-third of participants completed 90 days of headache diary (32.4%). Endorsing higher daily anxiety scores (8/10 OR = 0.97 [95% CI = 0.96, 0.99]; 10/10 OR = 0.96 [95% CI = 0.91, 0.99]) was associated with lower odds of completion, whereas higher age (OR = 1.04 [95% CI = 1.03, 1.05]), and downloading the app paid vs free (OR = 4.27 [95% CI = 2.62, 7.06]), paid vs coupon (OR = 2.43, 95% CI = 1.41, 4.26]), or through a physician coupon vs free (OR = 1.75 [95% CI = 1.27, 2.42]) were associated with higher odds of completion. The median adherence rate at 90 days was 0.34 (IQR = 0.10-0.88), indicating that half of participants kept 34 or fewer days 90 diary days after registration. Endorsing high daily anxiety scores (5/10 OR = 0.98 [95% CI = 0.97, 1.00]; 8/10 OR = 0.96 [95% CI = 0.94, 0.98]; 10/10 OR = 0.96 [9% CI = 0.92, 0.98]) and higher age (OR = 1.05 [95% CI = 1.04, 1.07]) were associated with lower odds of adhering at 90 days, whereas downloading the app paid vs free (OR = 9.63 [95% CI = 4.61, 25.51]), paid vs coupon (OR = 2.39, 95% CI = 1.27, 5.10]), or through a physician coupon vs free (OR = 4.01 [95% CI = 2.54, 7.26]) were associated with higher odds of adhering at 90 days. Among completers, the median completion delay was 6.0 days (IQR = 2.0-15.0). Among completers, endorsing high daily anxiety scores (9/10 OR = 1/06 [95% CI = 1.01, 1.12]) and younger age (OR = 0.98 [95% CI = 0.97, 1.00]) was associated with completion delay; downloading the app through physician coupon vs free (OR = 0.40 [95% CI = 0.22, 0.71]) or paid vs free (OR = 0.38 [95% CI = 0.20, 0.72]) was associated with lower odds of completing 90 diary days in 90 calendar days. CONCLUSION:This naturalistic observational study confirmed evidence from clinical observation and research: adherence to mobile headache diaries is a challenge for a significant proportion of people with headache. Endorsing higher levels of daily anxiety, younger age, and downloading the app for free (vs either paying for the self-monitoring app or receiving a physician referral coupon) were associated with poorer adherence to keeping a mobile headache diary.
Project description:BACKGROUND:Stress has been known to increase craving in individuals with Alcohol Use Disorders (AUD) and predict future alcohol relapse risk, but whether stress on a particular day affects craving on that day to impact prospective alcohol intake in the real world, particularly during early treatment and recovery, has not been studied thus far. METHOD:The first study included 85 AUD individuals who reported their daily stress, craving, and alcohol intake in the first two weeks of early treatment. A second validation study included 28 AUD patients monitored daily during eight weeks of outpatient 12-Step based behavioral counseling treatment for AUD. Data were collected from telephone-based daily diaries for 903 days in Study 1 and 1488 in Study 2. Multilevel latent models tested if daily and person-averaged craving mediated the link between stressful events and next day drinking during treatment. RESULTS:In both Study 1 and 2, exposure to a stressful event on a particular day predicted increased craving on that day (p's?.002); and such increases in craving predicted the likelihood of drinking the next day (p's?.014) and the drinking amount (p's<?=?008). Individuals who experienced more stressful events reported higher craving (p's?.012), and higher cravers reported greater next day drinking (p's<.001). CONCLUSIONS:The results across two studies with separate samples are the first to establish that craving directly mediates the association between stress and next day alcohol intake in individuals with AUD. Findings suggest a need for novel treatment approaches to address stress-induced craving to improve alcohol use outcomes.
Project description:BACKGROUND:Alcohol use disorder (AUD) is a highly prevalent, chronic relapsing disorder with a high disease burden in the USA. Pharmacotherapy is a promising treatment method for AUD; however, the few FDA-approved medications are only modestly effective. Medications development for AUD is a high priority research area, but the cumbersome drug development process hinders many potential compounds from reaching approval. One area with major opportunities for improvement is the process of screening novel compounds for initial efficacy, also known as early phase 2 trials. Early phase 2 trials incorporate human laboratory paradigms to assess relevant clinical constructs, such as craving and subjective responses to alcohol. However, these controlled paradigms often lack the ecological validity of clinical trials. Therefore, early phase 2 trials can be more efficient and clinically meaningful if they combine the internal validity of experimental laboratory testing with the external validity of clinical trials. To that end, the current study aims to develop and validate a novel early efficacy paradigm, informed by smoking cessation literature, to screen novel medications for AUD. As an established AUD medication, naltrexone will serve as an active control to test both the practice quit attempt model and the efficacy of a promising AUD pharmacotherapy, varenicline. METHODS:Individuals with current AUD reporting intrinsic motivation to change their drinking will complete a week-long "practice quit attempt" while on study medication. Participants are randomized and blinded to either naltrexone, varenicline, or placebo. During the practice quit attempt, participants will complete daily visits over the phone and fill out online questionnaires regarding their drinking, alcohol craving, and mood. Additionally, participants will undergo two alcohol cue-reactivity sessions. DISCUSSION:The successful completion of this study will advance medications development by proposing and validating a novel early efficacy model for screening AUD pharmacotherapies, which in turn can serve as an efficient strategy for making go/no-go decisions as to whether to proceed with clinical trials. TRIAL REGISTRATION:ClinicalTrials.gov NCT04249882 . Registered on 31 January 2020.
Project description:To test the feasibility and effectiveness of brief counseling intervention (BCI) and naltrexone integrated into tuberculosis (TB) care in Tomsk, Russia.Using a factorial randomized controlled trial design, patients were randomized into: naltrexone (NTX), brief behavioral compliance enhancement therapy (BBCET), treatment as usual (TAU) and BCI.In the Tomsk Oblast, hospitalized TB patients diagnosed with alcohol use disorders (AUDs) by the DSM-IV were referred at the start of TB treatment. Of the 196 participants, the mean age was 41 years and 82% were male. Severe TB (84.7% had cavitary disease) and smoking (92.9%) were common. The majority had a diagnosis of an AUD (63.0%); 27.6% reported nearly daily drinking and consumed a median of 16 standard drinks per day.Primary outcomes were 'favorable' TB outcome (cured, completed treatment) and change in mean number of abstinent days in the last month of study compared with baseline. Change in mean number of heavy drinking days, defined as four drinks per day and five drinks per day for women and men, respectively, and TB adherence, measured as percentage of doses taken as prescribed under direct observation, were secondary outcomes. Analysis based on 'intention-to-treat' was performed for multivariable analysis.Primary TB and alcohol end-points between naltrexone and no-naltrexone or BCI and no-BCI groups did not differ significantly. TB treatment adherence and change in number of heavy drinking days also did not differ significantly among treatment arms. Among individuals with a prior quitting attempt (n?=?111), naltrexone use was associated with an increased likelihood of favorable TB outcomes (92.3% versus 75.9%, P?=?0.02).In Tomsk Oblast, Russia, tuberculosis patients with severe alcohol use disorders who were not seeking alcohol treatment did not respond to naltrexone or behavioral counselling integrated into tuberculosis care; however, those patients with past attempts to quit drinking had improved tuberculosis outcomes.