Moderation of Prazosin’s Efficacy by Alcohol Withdrawal Symptoms
Publication: American Journal of Psychiatry
Abstract
Objective:
Alcohol use disorder (AUD) is a leading cause of global disease burden. Chronic, heavy use increases the likelihood of alcohol withdrawal symptoms and associated secondary outcomes of alcohol craving and mood, anxiety, and sleep disturbances, which are predictive of poor treatment outcomes. The authors examined whether alcohol withdrawal symptoms moderate the efficacy of prazosin in reducing alcohol intake and associated secondary outcomes.
Methods:
A 12-week, double-blind, randomized, controlled proof-of-concept trial of prazosin (16 mg/day, with a 2-week titration) was conducted in community-recruited adults with current alcohol dependence (N=100) with varying levels of alcohol withdrawal symptoms assessed at treatment entry. Primary outcomes were daily self-reported drinking days and heavy drinking days, and secondary outcomes were average drinks/day and mood, anxiety, craving, and sleep quality ratings.
Results:
Modified intent-to-treat analyses indicated a significant interaction of alcohol withdrawal symptom score by treatment by full-dose treatment period (weeks 3–12) for drinking days, heavy drinking days, and average drinks/day. By week 12, participants with high alcohol withdrawal symptoms on prazosin reported 7.07% heavy drinking days and 27.46% drinking days, while those on placebo had 35.58% heavy drinking days and 58.47% drinking days (heavy drinking days: odds ratio=0.14, 95% CI=0.058, 0.333; drinking days: odds ratio=0.265, 95% CI=0.146, 0.481). No such benefit of prazosin was observed in those reporting low or no alcohol withdrawal symptoms. Individuals with high alcohol withdrawal symptoms on prazosin compared with placebo also showed significantly improved anxiety, depression, and alcohol craving over the course of the trial.
Conclusions:
The findings indicate that alcohol withdrawal symptoms are a significant moderator of prazosin treatment response for alcohol use outcomes and for associated symptoms of alcohol craving, anxiety, and mood symptoms. These data support further evaluation of alcohol withdrawal symptoms as a prognostic indicator of prazosin’s efficacy in the treatment of AUD.
Alcohol use is a leading cause of global disease burden, and alcohol use disorder (AUD) is a chronic, relapsing illness associated with significant medical morbidity and mortality worldwide (1). Currently approved medications to treat AUD show modest therapeutic efficacy, partly because no specific alcohol–related pathophysiology has been identified as a clinical moderator of treatment response (2, 3). Cessation of chronic, heavy alcohol use frequently increases the likelihood of alcohol withdrawal symptoms. These symptoms may be accompanied by increases in anxiety, depressive symptoms, and sleep difficulties, and together they encompass an increased alcohol abstinence–related distress state that is associated with high alcohol craving and increased risk of alcohol relapse and poor treatment outcomes (4, 5). While treatment of alcohol withdrawal syndrome addresses acute alcohol-related delirium tremens, seizures, and mortality risk (6), alcohol withdrawal and abstinence symptoms occur without alcohol withdrawal syndrome and are not systematically assessed as a prognostic marker of risk of postdetoxification relapse and treatment failure, and there are no specific treatments available to address such abstinence-related pathophysiology to improve drinking outcomes in AUD.
Neuroscience and human laboratory research to understand brain and clinical effects of chronic heavy alcohol intake, abstinence symptoms, and history of alcohol detoxifications indicate disrupted functioning of the medial prefrontal cortex, which is involved in regulating stress biology, reward, behavioral choices, and decisions (4, 5, 7). Patients with AUD in early alcohol abstinence show parallel disruptions in peripheral stress physiology and in medial prefrontal cortex circuit functioning, which in turn are associated with higher stress and cue reactivity and increased risk of alcohol relapse and treatment failure (4, 8, 9). This growing body of evidence suggests that abstinence-related disruption of stress biology in AUD may need specific attention, both in systematic outpatient evaluation and with specific treatment development to address this additional clinical symptomatology in AUD.
Prazosin, an α1 adrenergic antagonist, reduces alcohol-related adrenergic hyperactivity and excessive drinking in laboratory animals (10, 11). Prazosin also improves working memory and prefrontal cortical functioning under high uncontrollable stress in nonhuman primates (12) and decreases stress-induced alcohol seeking in laboratory animals and in human alcohol-dependent patients (13–15). These findings suggest that prazosin’s effects in AUD may be specific to individuals who show acute alcohol abstinence–related distress, clinically manifested with at least some increases in alcohol withdrawal symptoms and associated craving, mood, and anxiety symptoms. Indeed, results of clinical trials of prazosin’s efficacy in AUD have been mixed, with some studies reporting improved drinking outcomes (16, 17) and others showing no significant benefit in drinking outcomes in overall analyses, but with benefit in subgroups with higher blood pressure (18, 19). Importantly, these clinical studies have varied significantly in participants’ recent alcohol use severity and pretreatment abstinence levels and have not reported assessments of alcohol withdrawal symptoms, and thus they have provided little information on whether alcohol withdrawal and abstinence symptoms may be a prognostic indicator of prazosin treatment in AUD (20, 21).
Despite the growing need to identify moderators of clinical response in the treatment of AUD (3, 20), systematic research on evaluating the relevance of prognostic clinical moderators of alcohol treatment response has lagged behind. As alcohol withdrawal symptoms are not observed in all patients with AUD entering treatment, and severity of the illness plays a significant role in its pathophysiology and chronic relapsing nature (2), there is an urgent need to test whether alcohol withdrawal symptoms and related abstinence symptoms are a relevant factor in moderating AUD treatment outcomes (3, 20). An ongoing problem in addressing this issue, however, is the lack of well-established thresholds for alcohol withdrawal and abstinence symptom assessments as they pertain to relapse risk, continued heavy drinking, and treatment failure. The Clinical Institute Withdrawal Assessment for Alcohol–Revised (CIWA-Ar) (22) is a well validated and established measure that is widely used in assessing alcohol withdrawal syndrome for medical detoxification, but it is rarely used postdetoxification to assess residual withdrawal and associated abstinence symptoms to identify those at risk of relapse and treatment failure in outpatient settings.
We conducted a proof-of-concept randomized clinical trial of prazosin in AUD to specifically evaluate the role of alcohol withdrawal symptoms in treatment-entering individuals in moderating the efficacy of prazosin on the primary drinking outcomes of heavy drinking days and any drinking days and the secondary drinking outcome of average drinks/day and clinical outcomes of alcohol craving, anxiety symptoms, mood symptoms, and sleep disturbances. As there is no specific established CIWA-Ar cutoff score to identify those with risk for relapse and treatment failure, we used CIWA-Ar scores as a continuous measure to assess the moderating influence of alcohol withdrawal symptoms on prazosin treatment effects. The primary hypothesis was that prazosin’s efficacy will interact with alcohol withdrawal symptoms to influence primary heavy drinking days and drinking days as well as average drinks/day and other secondary outcomes, such that prazosin’s efficacy in primary and secondary outcomes will be specific to individuals with high alcohol withdrawal symptom severity, and with no treatment benefit in those with low alcohol withdrawal symptom severity or no withdrawal symptoms. Also, as some data suggest that sympathetic hyperactivity, with higher baseline systolic or diastolic blood pressure, may moderate prazosin’s treatment efficacy, we conducted post hoc secondary analyses to explore these as moderator variables.
Methods
Participants
Participants were community men and women over the age of 18 years who responded to direct advertising via newspapers, web sites, and social media for AUD treatment or were recruited via referrals from addiction treatment facilities in the Greater New Haven, Connecticut, region. Inclusion criteria were meeting DSM-IV-TR criteria for current alcohol dependence as determined by the Structured Clinical Interview for DSM-IV-TR (23), ability to give written informed consent, and ability to read and write in English to complete study evaluations. Exclusion criteria were meeting DSM-IV-TR criteria for current dependence on any other psychoactive substance other than nicotine and caffeine; current use of psychoactive medications, including anxiolytics, antidepressants (except SSRIs), naltrexone, and disulfiram; any psychotic disorder or current axis I disorder requiring specific medications or hospitalization; significant underlying medical conditions such as cerebral, renal, thyroid, hepatic, or cardiac pathology and pregnancy, that would interfere with or be of potential harm during the study; and hypotension, as indicated by a sitting blood pressure below 90/60 mmHg.
The study was approved by the Human Investigation Committee of the Yale University School of Medicine and was registered at ClinicalTrials.Gov (NCT00585780), and participants provided written informed consent before participating in the study.
Study Design, Moderator Assessment, and Medication Dosing
A total of 112 treatment-seeking AUD patients exhibiting varying levels of alcohol withdrawal symptoms at outpatient or inpatient treatment entry were assessed by trained clinical research staff, using the observer-rated Clinical Institute Withdrawal Assessment for Alcohol–Revised (CIWA-Ar) during the intake process (22). After assessments of additional eligibility criteria as determined by study physicians and staff, patients were enrolled in the study and underwent randomized assignment to receive either placebo or prazosin (16 mg/day), titrated over the course of 2 weeks as in previous research (16), followed by 9 weeks treatment at the target dosage, with a 5-day titration period in week 12 (for the titration schedule, see the Supplemental Methods section in the online supplement ). Patients were initiated on study medication upon presenting with a negative breath alcohol test; no minimum pretreatment alcohol abstinence period was required prior to medication initiation.
Randomization
Randomization to treatment group was conducted by the Yale Stress Center biostatistician, using an urn randomization procedure that balanced groups on gender, age, nicotine smoking status, years of education, and lifetime history of DSM-IV-TR anxiety disorders, including posttraumatic stress disorder. The randomization procedure also adjusted for randomized individuals who did not start the study protocol, to prevent any bias in balancing the treatment groups on the above factors. Randomized assignment of each patient was provided to the Yale Investigational Drug Service pharmacist, who formulated identical matched tablets of prazosin and placebo and provided dosing for each subject, in weekly blister packs labeled by day and time of dosing, to study staff for dispensing. All patients and study personnel, including investigators, physicians, and study staff, remained blind to medication group.
Procedures
After being deemed eligible for the study, participants were given the choice of participating in either a fully outpatient treatment or an initial inpatient period followed by a transition to outpatient treatment for the remainder of the study period. Individuals for whom further evaluation of their alcohol withdrawal symptoms was required for medical detoxification were recommended the inpatient option through the Clinical Neuroscience Research Unit, to undergo medical detoxification prior to study participation. Participants who opted for the inpatient-outpatient option were admitted to a clinical research unit for the 3- to 4-week admission and were initiated on study medication only after medical detoxification. After completing the inpatient phase, subjects participated in the remaining 8- to 9-week medication phase on an outpatient basis. At outpatient study visits, which occurred twice weekly over the 12-week period, vital signs, breath alcohol tests, and medication adherence were assessed, and recent alcohol intake and primary and secondary outcomes were assessed as specified below.
Behavioral support and counseling.
Weekly behavioral counseling was provided to all patients, using the empirically validated, standardized 12-Step Facilitation Therapy Manual, which included encouragement to attend self-help meetings and addressed triggers for relapse prevention (24). In addition, all participants received contingency management using the fishbowl method to reinforce weekly treatment attendance.
Medication adherence.
Medication adherence was ensured by medication reminders via an interactive voice response or smartphone application (MetricWire) at 8:00 a.m., 2:00 p.m., and 8:00 p.m. daily. Study medication included 25 mg of riboflavin, and patients’ urine samples were assessed for bright yellow discoloration (when medication is taken within 2–8 hours prior) under ultraviolet fluorescent light at each study visit (twice weekly). Blood levels of prazosin were assessed from samples obtained at week 4 (see the CONSORT chart in Figure 1).
Primary and secondary outcomes.
Participants completed a 4- to 5-minute survey via interactive voice response or smartphone nightly to track each day’s alcohol intake (alcohol type and amount consumed) throughout the trial. Alcohol intake was also assessed weekly using the 7-day substance use calendar, based on the timeline follow-back assessment (25), and, as in previous research (26), the substance use calendar was used if daily telephone data were missing on a particular day. The primary outcomes were daily alcohol intake during the 12-week treatment, as assessed for heavy drinking and for any drinking (both coded 1 for present and 0 for absent), and the secondary drinking outcome was average drinks per day. Heavy drinking days were defined using 4 and 5 drinks as the minimum thresholds for women and men, respectively. Ethyl glucuronide level was assessed weekly for biological verification of self-reported daily alcohol intake.
Additional secondary outcomes were alcohol craving, as measured by the Obsessive Compulsive Drinking Scale (27) monthly; anxiety symptoms, as measured by the Hamilton Anxiety Rating Scale (28) weekly; depression symptoms, as measured by the Center for Epidemiologic Studies–Depression Scale (29) weekly; and sleep quality, as measured by the Pittsburgh Sleep Quality Index (30) monthly. Vital signs, including heart rate and blood pressure, and CIWA-Ar for alcohol withdrawal, were also assessed at each visit. Alcohol craving, depression, anxiety, sleep quality, and alcohol withdrawal symptoms assessed throughout the study were baseline-corrected to control for person-level basal differences in these measures. A modified version of the Systematic Assessment for Treatment Emergent Effects (31) was also used to assess adverse events (expected and unexpected side effects and serious adverse events) weekly (see also the Supplemental Methods section in the online supplement ).
Statistical Analysis
Power analysis.
Sample size and power analysis determinations were based on a previous randomized placebo-controlled pilot trial of prazosin (16), which yielded a large effect size (d) of 1.26 for mean weekly drinking days. This effect size was reduced to 0.60 to accommodate the hypothesized moderator interaction effect for the present study. At the more conservative effect size of 0.60 and with a power of 0.80, with p<0.05, sample size estimates indicated that 25 subjects per treatment arm were needed to detect treatment group main effects. This sample size was doubled to allow for assessment of interaction effects of treatment by alcohol withdrawal symptoms. Allowing for a 10%−20% dropout rate, we estimated enrollment of 120 participants with alcohol dependence, in order to enroll 100 participants to ensure adequate power for modified intent-to-treat analyses.
Data analysis.
All analyses were conducted in SAS, version 9.4, and RStudio, version 1.1456. Differences in demographic variables, baseline primary and secondary outcome variables, and medication adherence for the two treatment groups (prazosin, placebo) were assessed via t tests and chi-square analyses. Randomized patients who did not start the study (N=12) were not included in the analyses, and a modified intent-to-treat analytic approach was utilized to include only those who initiated the study on day 1 of the 12-week protocol. Also, as there are no established thresholds for the impact of alcohol withdrawal symptoms on drinking outcomes in outpatient treatment, baseline alcohol withdrawal symptom severity was included as a continuous measure in overall modified intent-to-treat analyses. The overall modified intent-to-treat analyses included baseline mean-centered continuous CIWA-Ar scores as a moderator of treatment (prazosin/placebo) and time assessed daily for the pre-full-dose weeks (weeks 1–2) and for the full-dose weeks (weeks 3–12) with linear or generalized linear mixed-effects piecewise growth models for continuous and binary primary and secondary outcomes. Piecewise growth models allow for separate assessment of the distinct dosing periods (pre-full-dose and full-dose) to account for any possible nonlinear effect of treatment dose on outcomes (see also the Supplemental Methods section in the online supplement ). Because of a positive skew, average drinks/day was log-transformed. Control variables that were modeled in all analyses were gender (0=male), inpatient (0=outpatient), and dropout (0=completed, 1=dropped out or withdrew prior to 4 weeks, 2=dropped out or withdrew after 4 weeks). Inpatient days were coded as 0.
Linear mixed models with random intercepts were used to assess the effect of baseline alcohol withdrawal symptoms, treatment, and week (weeks 1–12 for weekly assessments, or weeks 4, 8, and 12 for monthly assessment) on the secondary outcome variables. All control variables from the primary outcome analyses were included in secondary outcome analyses. If significant interactions with alcohol withdrawal symptoms were observed in overall primary or in secondary outcome analyses, simple-effects analyses to understand the source of the interactions were conducted using a median split of the alcohol withdrawal symptom continuous score to obtain low and high alcohol withdrawal symptom groups and to more easily represent the data graphically. Also, percent drinking days and heavy drinking days were computed by week for simple-effects analysis and for graphic depiction.
Results
Baseline Characteristics
Participants were enrolled between November 1, 2012, and May, 30, 2017. A CONSORT chart is presented in Figure 1, and the baseline characteristics of the modified intent-to-treat sample are summarized in Table 1. The two medication groups did not differ significantly in any of the demographic variables or in baseline alcohol use. All patients decreased alcohol use on entry into the study during week 0 (see Figure S2 in the online supplement ), as has been common in previous clinical studies. Thus, all outcome analyses were conducted for daily drinking starting with day 1 of week 1 without including week 0 drinking data.
| Characteristic | Placebo Group (N=45) | Prazosin Group (N=55) | ||
|---|---|---|---|---|
| N | % | N | % | |
| Male | 31 | 68.9 | 34 | 61.8 |
| Race | ||||
| Caucasian | 19 | 42.2 | 32 | 58.2 |
| African American | 25 | 55.9 | 23 | 41.8 |
| Other | 1 | 2.2 | 0 | 0.0 |
| Regular smoker | 29 | 64.4 | 30 | 54.5 |
| Stabilized on antidepressants | 1 | 2.2 | 5 | 9.1 |
| Inpatient-outpatient optionb | 4 | 8.9 | 8 | 14.5 |
| Lifetime depression | 11 | 24.4 | 15 | 27.3 |
| Lifetime anxiety (including PTSD) | 12 | 26.7 | 16 | 29.1 |
| Lifetime anxiety (excluding PTSD) | 6 | 13.3 | 10 | 18.2 |
| Mean | SD | Mean | SD | |
| Age (years) | 41.09 | 10.50 | 40.20 | 11.26 |
| Education (years) | 13.24 | 1.80 | 13.64 | 2.31 |
| Years of alcohol use | 17.80 | 11.04 | 16.18 | 9.24 |
| Past-30-day alcohol use | 20.56 | 8.07 | 19.84 | 9.07 |
| Average drinks per day | 5.78 | 6.93 | 6.04 | 4.91 |
| Percent drinking days | 63.47 | 32.03 | 71.13 | 30.41 |
| Percent heavy drinking days | 48.16 | 34.25 | 54.76 | 33.38 |
| Past-30-day tobacco use (N=61) | 26.51 | 6.84 | 23.80 | 10.70 |
| Past-30-day marijuana use (N=38) | 4.49 | 5.06 | 9.25 | 8.86 |
| Past-30-day cocaine use (N=12) | 8.00 | 5.33 | 6.33 | 5.28 |
| Anxiety rating (HAM-A) | 9.72 | 8.49 | 10.80 | 8.39 |
| Craving rating (OCDS) | 13.73 | 5.99 | 16.15 | 6.59 |
| Depression rating (CES-D) | 11.48 | 9.52 | 12.68 | 8.59 |
| Sleep quality rating (PSQI) | 11.83 | 4.41 | 12.76 | 4.48 |
| Systolic blood pressure (mmHg) | 132.51 | 17.73 | 134.67 | 19.33 |
| Diastolic blood pressure (mmHg) | 77.31 | 12.49 | 78.75 | 12.52 |
| Alcohol withdrawal symptom score (CIWA-Ar total score) | 3.76 | 4.27 | 4.26 | 5.74 |
a
No significant difference between groups on any variable. All participants met DSM-IV-TR criteria for current alcohol dependence, as determined by the Structured Clinical Interview for DSM-IV-TR. CES-D=Center for Epidemiologic Studies–Depression Scale; CIWA-Ar=Clinical Institute Withdrawal Assessment for Alcohol–Revised; OCDS=Obsessive Compulsive Drinking Scale; PSQI=Pittsburgh Sleep Quality Index; PTSD=posttraumatic stress disorder.
b
Participants were enrolled for study participation either when entering outpatient treatment for the entire 12-week period or via inpatient detoxification and treatment followed by outpatient treatment (inpatient-outpatient option) involving a 3- to 4-week inpatient admission for study initiation and study participation initiated after acute detoxification and followed by an outpatient phase through week 12.
Baseline alcohol withdrawal symptoms(continuous score).
Descriptive data on frequency of specific alcohol withdrawal symptom and cardiovascular measures at baseline for the sample are presented in Table 2, divided into high and low withdrawal symptom groups based on the sample median. Significant associations were observed between alcohol withdrawal symptoms and depression, anxiety, alcohol craving, sleep problems, and alcohol intake at baseline (see the Supplemental Results section and Figure S1 in the online supplement ). Baseline alcohol withdrawal symptom score was not significantly associated with baseline heart rate and blood pressure.
| Alcohol Withdrawal Symptom Score | ||||
|---|---|---|---|---|
| Symptom | Low (N=56) | High (N=44) | ||
| N | % | N | % | |
| Tremorb | 13 | 23.2 | 33 | 75.0 |
| Nervous/anxietyb | 11 | 19.6 | 30 | 68.2 |
| Agitationb | 0 | 0.0 | 20 | 45.5 |
| Sweatingb | 2 | 3.6 | 12 | 27.3 |
| Headacheb | 0 | 0.0 | 11 | 25.0 |
| Nauseab | 0 | 0.0 | 9 | 20.5 |
| Tactile disturbances | 2 | 3.6 | 6 | 13.6 |
| Visual disturbancesb | 0 | 0.0 | 7 | 15.9 |
| Auditory disturbances | 2 | 3.6 | 4 | 9.1 |
| Orientationb | 0 | 0.0 | 4 | 9.1 |
| Mean | SD | Mean | SD | |
| CIWA-Ar scoreb | 0.86 | 0.78 | 8.07 | 5.44 |
| Systolic blood pressure (mmHg)b | 128.59 | 14.70 | 138.75 | 21.47 |
| Diastolic blood pressure (mmHg) | 76.05 | 10.56 | 79.91 | 14.43 |
| Heart rate | 74.27 | 11.89 | 77.34 | 16.87 |
a
Alcohol withdrawal symptoms were assessed using the Clinical Institute Withdrawal Assessment for Alcohol Scale–Revised (CIWA-Ar), a 13-item observer-rated measure of current alcohol withdrawal signs and symptoms, administered by trained clinical research staff. The CIWA-Ar includes objective measures (e.g., pulse), participants’ responses to questions, such as orientation to time and space, and observations by the interviewer (evidence of tremor or paroxysmal sweats). Item responses range from 0, indicating no evidence of the symptom, to 4, indicating highest severity of symptoms. Possible total scores range from 0 to 67. A symptom was considered positive if a participant had a score of 1 or more on that item. In the table, participants with low alcohol withdrawal symptom scores are those who had a CIWA-Ar withdrawal score ≤2, and participants with high alcohol withdrawal symptom scores are those who had a CIWA-Ar withdrawal score ≥3.
b
Significant difference between groups, p<0.05.
Adherence with daily drinking outcome and medication.
The adherence rate among participants who completed daily drinking diaries using interactive voice response or smartphone was 73.7% (prazosin group, 73.5%; placebo group, 73.9%; t=0.08, df=96, p=0.94). Individuals who dropped out of the study had lower adherence with the daily drinking data submission than study completers (65.61% [SD=28.34] compared with 78.41% [SD=20.54]; t=−2.58, df=96, p=0.011). A positive weekly ethyl glucuronide urine test significantly predicted the previous day of drinking (B=0.33, p<0.001), indicating high concordance between daily self-report and objective assessment of alcohol intake. The two groups did not differ in medication adherence, including in the percentage of doses taken per week (prazosin group, 93.6%; placebo group, 96.1%; t=0.08, df=96, p=0.94), the number of individuals with more than 1 week of untraceable riboflavin (prazosin group, N=3 [5.7%]; placebo group, N=3 [7.1%]; χ2=0.067, N=98, p=0.80), and in medication adherence as assessed by plasma levels of study medication for presence or absence of prazosin in week 4 (prazosin group: 94% detected; placebo group: 97% absence of prazosin; χ2=0.48, N=68, p=0.49) (see the Supplemental Methods section in the online supplement for details).
Safety and Adverse Events
Prazosin was found to be safe and well tolerated, with no adverse events occurring at significantly greater frequency in the prazosin group compared with the placebo group (see Table S1 in the online supplement ). The most common adverse events in the sample were pain, dizzy/lightheadedness, headache, nausea/vomiting, and cold symptoms. Adverse events in less than 5% of patients included decreased appetite, forgetfulness, bloody nose, swollen ankle, weight gain, and diarrhea. There were two serious adverse events involving overnight hospital admission following emergency department visits, one involving acute alcohol intoxication for a patient with low alcohol withdrawal symptoms in the prazosin group and weakness and a fainting spell for a patient with low alcohol withdrawal symptoms in the placebo group.
Primary Outcomes
Significant interactions of alcohol withdrawal symptoms by treatment by full-dose weeks were observed for the primary outcomes of drinking days (χ2=9.43, p=0.002) and heavy drinking days (χ2=6.02, p=0.01) (Figure 2A–B) and the secondary outcome of average drinks/day (F=5.00, p=0.028) (see Figure S2, and complete modified intent-to-treat model results in Table S2, in the online supplement ).
FIGURE 2. Interactions of alcohol withdrawal symptoms by treatment group in a study of prazosin’s efficacy in relation to alcohol withdrawal symptomsa
a The graphs show significant interactions of the continuous score for alcohol withdrawal symptoms with treatment (prazosin or placebo) during the full-dose period (weeks 3–12) for percent drinking days (p<0.002) (panel A) and percent heavy drinking days (p<0.01) (panel B). For the placebo group, the higher the alcohol withdrawal symptom scores, the greater the number of drinking days (p<0.0002) and heavy drinking days (p<0.003), but for the prazosin group, number of drinking days (p<0.86) and heavy drinking days (p<0.77) did not increase with alcohol withdrawal symptom score (also shown for week 12, at end of treatment, for comparison). No differences were observed between the prazosin and placebo groups for participants with low alcohol withdrawal symptom scores. A median split of alcohol withdrawal symptom continuous score to assess the high alcohol withdrawal symptom group by treatment indicates (panel C) that in individuals with high alcohol withdrawal symptom scores, for average drinking across the full-dose period (weeks 3–12), the percentage of drinking days was 41.2% for the placebo group and 26.9% for the prazosin group (z=2.24, p<0.01; odds ratio=0.50, 95% CI=0.28, 0.92), and the percentage of heavy drinking days was 27.11% for the placebo group and 8.83% for the prazosin group (z=3.36, p<0.0004; odds ratio=0.23, 95% CI=0.1, 0.55). As shown in panel D, by week 12, individuals with high alcohol withdrawal symptom scores showed the greatest treatment effect, with percentage of drinking days at 58.47% in the placebo group and 27.46% in the prazosin group (z=4.36, p<0.00006; odds ratio=0.265, 95% CI=0.146, 0.481), and percentage of heavy drinking days at 35.58% for the placebo group and 7.07% for the prazosin group (z=4.45, p<0.00005; odds ratio=0.14, 95% CI=0.058, 0.333). Drinking days and heavy drinking days are binary outcomes assessed daily for the overall analyses. For depiction purposes and simple-effects analyses, the percentages of drinking days and heavy drinking days were calculated for each participant in each week and then averaged across time periods. Error bars indicate standard error of the mean. (See also Figure S2 in the online supplement .)
**p<0.01. ***p<0.001. ****p<0.0001.
To understand the source of the interaction effect of alcohol withdrawal symptom score with treatment, we first assessed alcohol withdrawal symptom effects within each treatment group for the full-dose period (weeks 3–12). We found that with placebo, the higher the alcohol withdrawal symptom severity, the greater the number of drinking days (z=3.76, p<0.0002), number of heavy drinking days (z=2.98, p<0.003), and average drinks/day (t=3.2, p<0.002), whereas prazosin reversed these alcohol withdrawal symptom–related increases in all three measures (heavy drinking days, p<0.77; drinking days, p<0.86; average drinks/day, p<0.57) (Figure 2A–B). To further assess the significant alcohol withdrawal symptom moderation of the treatment effects, alcohol withdrawal symptom continuous scores were median split to determine high and low alcohol withdrawal symptom groups, and percent drinking days and percent heavy drinking days were computed for each week. We found that only for individuals with high alcohol withdrawal symptom levels, prazosin treatment relative to placebo led to significantly lower percent drinking days (z=2.24, p<0.01) and percent heavy drinking days (z=3.36, p<0.0004), with the likelihood of occurrence of a drinking day or a heavy drinking day in the full-dose period being 50% and 76% lower, respectively (see Figure 2C). By week 12, the prazosin group had a 73.5% and 86% lower likelihood of having an occurrence of a drinking day or heavy drinking day, respectively, than the placebo group (see Figure 2D). In contrast, no significant medication effect was observed among those with no or low alcohol withdrawal symptoms, with participants in the no or low alcohol withdrawal symptom groups showing no benefit of prazosin relative to placebo treatment (heavy drinking days, p<0.32; drinking days, p<0.30; average drinks/day, p<0.23) (see Figure S2 in the online supplement ).
Post Hoc Exploratory Effects of Baseline Cardiovascular Measures on Prazosin Efficacy
Baseline continuous measures of heart rate and blood pressure assessed at intake were also explored as treatment moderators. The findings indicate that diastolic blood pressure moderated prazosin treatment benefit only for heavy drinking days (treatment by diastolic blood pressure by full-dose weeks, χ2=5.65, p<0.02), such that individuals with higher diastolic blood pressure showed significantly lower heavy drinking days in weeks 3–12, while those on placebo showed increases in heavy drinking days. Baseline heart rate also moderated treatment effects in the full-dose period for drinking days (treatment by heart rate by full-dose weeks, χ2=2.48, p<0.01) and for average drinks/day (treatment by heart rate by full-dose weeks: F=7.17, p<0.007) but not for heavy drinking days. The findings indicated that the higher the heart rate, the greater the reduction in drinking days and average drinks/day with prazosin treatment, while participants on placebo showed increased drinking days only but not increased average drinks/day, over the course of the trial (see the Supplemental Results section and Table S3 in the online supplement ).
Secondary Outcomes
Depression and anxiety symptoms.
A significant interaction of alcohol withdrawal symptom continuous score by treatment by week was observed for depression symptoms (F=2.79, df=3, 96, p<0.002) and for anxiety symptoms (F=2.38, df=3, 96, p=0.006) (see Table S4 in the online supplement ). Individuals with high alcohol withdrawal symptoms in the placebo group showed increases in depression levels, while those in the prazosin group showed decreased depression, with symptom ratings lower than baseline levels during the latter part of the trial (p values <0.05) (Figure 3A). Individuals with higher alcohol withdrawal symptoms in the prazosin group had reduced levels of anxiety relative to baseline, that were maintained during the latter part of the trial and relative to those on placebo (p values <0.05) (Figure 3B).
FIGURE 3. Treatment effects on baseline-corrected anxiety, depression, and craving ratings during the 12-week triala
a Panel A illustrates a three-way interaction of treatment (prazosin or placebo) with alcohol withdrawal symptom continuous score and week for baseline-corrected weekly depression ratings (Center for Epidemiologic Studies–Depression Scale) (p=0.007). Panel B illustrates a three-way interaction of treatment, alcohol withdrawal symptom continuous score, and week for baseline-corrected weekly anxiety ratings (Hamilton Anxiety Rating Scale) (p=0.002). Panel C illustrates a two-way interaction of treatment and alcohol withdrawal symptom continuous score on alcohol craving, measured at weeks 4, 8, and 12 (Obsessive Compulsive Drinking Scale) (p=0.003). Alcohol withdrawal symptom continuous scores are shown here in a median split for low symptom levels (Clinical Institute Withdrawal Assessment for Alcohol–Revised [CIWA-Ar] score ≤2; placebo group, N=22; prazosin group, N=34]) and high symptom levels (CIWA-Ar score ≥3; placebo group, N=23; prazosin group, N=21]) for illustration of simple effects. Error bars indicate standard error of the mean.
*p<0.05.
Alcohol craving.
A significant interaction of alcohol withdrawal symptom continuous score by treatment was seen for baseline-corrected craving (F=9.6, df=2, 97, p=0.003) (see Table S4 in the online supplement ). Individuals with higher alcohol withdrawal symptoms in the prazosin group showed greater decreases in craving relative to those in the placebo group (p<0.017) (see Figure 3C). On the other hand, among individuals with no or low alcohol withdrawal symptoms, the placebo group showed greater craving reductions than the prazosin group (p<0.038) (see Figure 3C).
Weekly CIWA-Ar, sleep quality, and cardiovascular measures.
There was no influence of alcohol withdrawal symptom continuous score moderation or treatment group on weekly CIWA-Ar scores, sleep quality, or blood pressure during the trial (see Table S4 in the online supplement ). There was a significant prazosin treatment-by-week effect on weekly heart rate (treatment by week: F=1.93, df=11, 725, p=0.033), such that individuals in the prazosin group showed higher heart rate on average compared with the placebo group (see Table S4).
Discussion
Our findings identify alcohol withdrawal symptoms as a significant moderator of prazosin’s treatment efficacy for primary and secondary alcohol use outcomes and for additional secondary outcomes of anxiety, depressed mood, and alcohol craving over the course of the trial. The findings indicate that the greater the baseline alcohol withdrawal symptom score, the higher the drinking outcomes in the placebo group, but this effect was reversed in the prazosin group. In direct comparison among individuals with high alcohol withdrawal symptoms (CIWA-Ar scores ≥3), there was a greater benefit of prazosin relative to placebo in reduction of heavy drinking, any drinking days, and average drinks/day over the course of the trial. In parallel, we found that the higher the alcohol withdrawal symptom severity, the greater the benefit of prazosin in reducing anxiety, depressed mood, and alcohol craving over the course of the trial. While higher baseline alcohol withdrawal symptom severity significantly influenced reduction in withdrawal symptoms during the study, these responses were not influenced by treatment assignment. Notably, those with no or low alcohol withdrawal symptom scores (two symptoms or fewer) showed no benefit from prazosin treatment. Together, the findings suggest that the presence of high alcohol withdrawal symptom severity at treatment entry may serve as a prognostic indicator of the potential benefit of prazosin treatment for alcohol use and related secondary outcomes.
Significant moderation of prazosin’s efficacy in reducing alcohol use outcomes by baseline alcohol withdrawal symptom severity may serve to explain, at least partially, the mixed findings from previous prazosin clinical trials for AUD (16–19). These studies enrolled individuals with significant variation in current alcohol use severity and in pretreatment abstinence and did not account for baseline alcohol withdrawal symptom severity, thereby including a heterogeneous group of individuals possibly varying in extent of alcohol withdrawal symptoms and other mood, anxiety, and craving symptoms indicative of greater AUD-related distress. In contrast, in the present study, we had no pretreatment abstinence requirement for enrollment. Thus, patients could have been in acute abstinence, with an increased likelihood of exhibiting alcohol withdrawal symptoms.
Notably, the sensitivity of these factors in affecting AUD treatment efficacy has been documented previously. For example, number of pretreatment abstinence days was found to be a significant factor affecting efficacy of injectable naltrexone in the treatment of AUD (32), with greater number of days of pretreatment abstinence associated with better efficacy of naltrexone. Similarly, high alcohol withdrawal symptom severity was found to significantly affect the efficacy of gabapentin in the treatment of AUD (33), and may also explain mixed results with gabapentin for alcohol use outcomes (34, 35). Diastolic blood pressure has also previously been found to moderate prazosin’s efficacy in drinking outcomes (19), a finding that was replicated here for the heavy drinking days outcome in our secondary exploratory analyses. These findings underscore the need to systematically evaluate alcohol withdrawal symptoms, blood pressure, and associated abstinence symptoms at treatment entry for their role as prognostic indicators of alcohol use outcomes.
Consistent with the well-documented heterogeneity in clinical features of AUD, we found that placebo-treated individuals with no or low alcohol withdrawal symptoms successfully reduced their drinking after entering treatment and showed low levels of alcohol consumption throughout the trial. All participants received fishbowl contingency management as well as manualized, empirically validated 12-step counseling as behavioral support to promote treatment retention and recovery from AUD. Thus, it is not surprising that those with low alcohol withdrawal symptom scores and with less severe AUD were able to reduce and maintain lower drinking levels. Although the individuals with low or no alcohol withdrawal symptoms in the prazosin group were drinking more than those in the placebo group during the trial, the drinking outcomes during the full-dose period, after titration of prazosin, did not differ from each other. These findings underscore the importance of assessing alcohol withdrawal symptoms as a prognostic indicator of withdrawal and stress-related abstinence symptoms at treatment entry, which could potentially identify those individuals who may be responsive to behavioral treatments, while others with higher alcohol withdrawal and abstinence symptoms might require additional pharmacotherapy treatment options.
An important aspect of our results is that prazosin’s efficacy in individuals with high alcohol withdrawal symptoms was observed after participants achieved the full dosage of medication and progressively over the course of the trial, and not during the early weeks. These findings suggest that prazosin’s efficacy may not be due to its effects on the sympathetic hyperarousal associated with locus coeruleus hyperactivity during acute alcohol withdrawal, as noted in some previous work (10, 11). In fact, we found that the prazosin group showed higher heart rate and (nonsignificantly) lower systolic blood pressure overall during the trial relative to the placebo group, but prazosin treatment did not have an impact on alcohol withdrawal symptoms and sleep problems during the trial. These data suggest a divergence of prazosin’s effects on sympathetic hyperarousal relating to acute withdrawal and its effects on anxiety, mood, craving, and alcohol use outcomes, with the former relating to prazosin’s effects on locus coeruleus pathways and the latter likely being associated with its effects in reducing adrenergic hyperactivity in forebrain cortico-striatal circuits that regulate stress, reward, and behavioral choices (4, 9, 12, 14).
Higher alcohol withdrawal symptom severity has previously been associated with heavier drinking (6, 36), as seen in the present sample at baseline and in the placebo group over the 12-week treatment period, which was reversed by prazosin in this study. As expected, we also found that higher alcohol withdrawal symptom scores were associated with greater stress-related symptoms of anxiety, depression, alcohol craving, and alcohol intake at treatment entry. These clinical symptoms pose a significant challenge to AUD treatment success, and there is growing acknowledgment of the need to address alcohol withdrawal symptoms and related abstinence symptoms that jeopardize alcohol recovery and increase relapse risk (3, 4). Notably, we found significant effects of prazosin relative to placebo in reducing alcohol craving, anxiety, and mood symptoms over the course of the trial. Because chronic alcohol use exacerbates these symptoms, it is possible that prazosin’s effect of significantly reducing drinking outcome measures in individuals with higher alcohol withdrawal symptoms led to concomitant reductions in these secondary symptoms. However, previous work indicates that stress and negative mood increase alcohol craving, which in turn increases lapses and relapse risk (26, 37, 38), and that prazosin treatment reduces such stress-induced alcohol craving, negative emotions, and anxiety (13, 39). These findings support the speculation that prazosin’s benefits may be mediated by its effects on the high craving, negative mood, and anxiety that are clinically observed in those with greater alcohol withdrawal symptom severity. Further research is needed to understand prazosin’s effects on these abstinence symptoms as they relate to alcohol use outcomes.
This study had some limitations. First, while women were included, they made up only one-third of the sample, and although gender was controlled for in the analyses, there was not adequate power to assess gender differences in treatment response. Second, no objective biological measure of alcohol intake was used as a primary outcome measure. Third, while medication adherence documented by urine and plasma levels was good and was comparable across treatment groups, plasma levels were assessed only once, at weeks 4–5, and no blood levels were available at later points in the trial. Finally, although the between-group difference was not significant, more individuals in the prazosin group were withdrawn because of side effects (N=6) than in the placebo group (N=2), and this effect will need further attention in future studies.
Despite these limitations, the present findings address an important clinical problem in AUD treatment, namely, heterogeneity of treatment responses and modest efficacy of currently available treatments. Our findings support the need to systematically assess alcohol withdrawal symptoms and related abstinence symptoms at treatment entry as a prognostic indicator of disease severity, while also suggesting the utility of alcohol withdrawal symptom severity as a key moderator of treatment response for a widely available, safe, and well-tested therapeutic agent such as prazosin. Although this is a proof-of-concept study and thus requires specific replication in those with high alcohol withdrawal and abstinence symptoms, the results shed new light on the widely implementable clinical diagnostic measure of alcohol withdrawal and abstinence symptoms, which may be used as a prognostic indicator and precision-medicine tool to address potential treatment failure and the need for pharmacotherapies like prazosin to improve alcohol treatment outcomes.
Acknowledgments
The authors thank the staff at the Yale Stress Center, the Clinical Neuroscience Research Unit of the Connecticut Mental Health Center, the Yale New Haven Health Investigational Drug Service, and the staff at the Yale Stress Center, including Rachel Hart, Zubaida Dabre, and Mary Kurjanowicz.
Footnote
ClinicalTrials.gov identifier: NCT00585780.
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References
1.
Collaborators GA ; GBD 2016 Alcohol Collaborators : Alcohol use and burden for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 2018 ; 392 : 1015 – 1035
2.
Garbutt JC : The state of pharmacotherapy for the treatment of alcohol dependence. J Subst Abuse Treat 2009 ; 36 : S15 – S23
3.
Litten RZ, Ryan ML, Falk DE, et al : Heterogeneity of alcohol use disorder: understanding mechanisms to advance personalized treatment. Alcohol Clin Exp Res 2015 ; 39 : 579 – 584
4.
Milivojevic V, Sinha R : Central and peripheral biomarkers of stress response for addiction risk and relapse vulnerability. Trends Mol Med 2018 ; 24 : 173 – 186
5.
Koob GF, Volkow ND : Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry 2016 ; 3 : 760 – 773
6.
Schuckit MA : Recognition and management of withdrawal delirium (delirium tremens). N Engl J Med 2014 ; 371 : 2109 – 2113
7.
Duka T, Trick L, Nikolaou K, et al : Unique brain areas associated with abstinence control are damaged in multiply detoxified alcoholics. Biol Psychiatry 2011 ; 70 : 545 – 552
8.
Sinha R : New findings on biological factors predicting addiction relapse vulnerability. Curr Psychiatry Rep 2011 ; 13 : 398 – 405
9.
Seo D, Lacadie CM, Tuit K, et al : Disrupted ventromedial prefrontal function, alcohol craving, and subsequent relapse risk. JAMA Psychiatry 2013 ; 70 : 727 – 739
10.
Rasmussen DD, Alexander LL, Raskind MA, et al : The α1-adrenergic receptor antagonist, prazosin, reduces alcohol drinking in alcohol-preferring (P) rats. Alcohol Clin Exp Res 2009 ; 33 : 264 – 272
11.
Walker BM, Rasmussen DD, Raskind MA, et al : α1-Noradrenergic receptor antagonism blocks dependence-induced increases in responding for ethanol. Alcohol 2008 ; 42 : 91 – 97
12.
Arnsten AFT : Stress weakens prefrontal networks: molecular insults to higher cognition. Nat Neurosci 2015 ; 18 : 1376 – 1385
13.
Fox HC, Anderson GM, Tuit K, et al : Prazosin effects on stress- and cue-induced craving and stress response in alcohol-dependent individuals: preliminary findings. Alcohol Clin Exp Res 2012 ; 36 : 351 – 360
14.
Mantsch JR, Baker DA, Funk D, et al : Stress-induced reinstatement of drug seeking: 20 years of progress. Neuropsychopharmacology 2016 ; 41 : 335 – 356
15.
Lê AD, Funk D, Juzytsch W, et al : Effect of prazosin and guanfacine on stress-induced reinstatement of alcohol and food seeking in rats. Psychopharmacology (Berl) 2011 ; 218 : 89 – 99
16.
Simpson TL, Saxon AJ, Meredith CW, et al : A pilot trial of the alpha-1 adrenergic antagonist, prazosin, for alcohol dependence. Alcohol Clin Exp Res 2009 ; 33 : 255 – 263
17.
Simpson TL, Saxon AJ, Stappenbeck C, et al : Double-blind randomized clinical trial of prazosin for alcohol use disorder. Am J Psychiatry 2018 ; 175 : 1216 – 1224
18.
Petrakis IL, Desai N, Gueorguieva R, et al : Prazosin for veterans with posttraumatic stress disorder and comorbid alcohol dependence: a clinical trial. Alcohol Clin Exp Res 2016 ; 40 : 178 – 186
19.
Wilcox CE, Tonigan JS, Bogenschutz MP, et al : A randomized, placebo-controlled, clinical trial of prazosin for the treatment of alcohol use disorder. J Addict Med 2018 ; 12 : 339 – 345
20.
Sinha R : Prazosin for the treatment of alcohol use disorders. Am J Psychiatry 2018 ; 175 : 1159 – 1160
21.
Kleinman RA, Ostacher MJ : Prazosin and alcohol use disorder. Am J Psychiatry 2019 ; 176 : 165
22.
Sullivan JT, Sykora K, Schneiderman J, et al : Assessment of alcohol withdrawal: the revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar). Br J Addict 1989 ; 84 : 1353 – 1357
23.
First MB, Williams JBW, Gibbon M, et al : Structured Clinical Interview for DSM-IV-TR. Washington, DC, American Psychiatric Association, 2001
24.
Nowinski J, Baker S, Carroll K : Twelve-Step Facilitation Therapy Manual: A Clinical Research Guide for Therapists Treating Individuals With Alcohol Abuse and Dependence ( Project MATCH Monograph Series ). Rockville, Md, National Institute on Alcohol Abuse and Alcoholism, 1992
25.
Sobell LC, Sobell MB : Timeline follow-back: a technique for assessing self-reported alcohol consumption, in Measuring Alcohol Consumption: Psychosocial and Biochemical Methods. Edited by Litten RZ, Allen JP. Totowa, Canada, Humana Press, 1992, pp 41 – 72
26.
Wemm SE, Larkin C, Hermes G, et al : A day-by-day prospective analysis of stress, craving and risk of next day alcohol intake during alcohol use disorder treatment. Drug Alcohol Depend 2019 ; 204 : 107569
27.
Anton RF, Moak DH, Latham PK : The Obsessive Compulsive Drinking Scale: a new method of assessing outcome in alcoholism treatment studies. Arch Gen Psychiatry 1996 ; 53 : 225 – 231
28.
Maier W, Buller R, Philipp M, et al : The Hamilton Anxiety Scale: reliability, validity, and sensitivity to change in anxiety and depressive disorders. J Affect Disord 1988 ; 14 : 61 – 68
29.
Randloff LS : The CES-D scale: a self-report depression scale for research in the general population. Appl Psychol Meas 1977 ; 1 : 385 – 401
30.
Buysse DJ, Reynolds CF 3rd, Monk TH, et al : The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989 ; 28 : 193 – 213
31.
Levine J, Schooler NR : SAFTEE: a technique for the systematic assessment of side effects in clinical trials. Psychopharmacol Bull 1986 ; 22 : 343 – 381
32.
Garbutt JC, Kranzler HR, O’Malley SS, et al : Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial. JAMA 2005 ; 293 : 1617 – 1625
33.
Anton RF, Latham P, Voronin K, et al : Efficacy of gabapentin for the treatment of alcohol use disorder in patients with alcohol withdrawal symptoms: a randomized clinical trial. JAMA Intern Med 2020 ; 180 : 728 – 736
34.
Mason BJ, Quello S, Goodell V, et al : Gabapentin treatment for alcohol dependence: a randomized clinical trial. JAMA Intern Med 2014 ; 174 : 70 – 77
35.
Falk DE, Ryan ML, Fertig JB, et al : Gabapentin enacarbil extended-release for alcohol use disorder: a randomized, double-blind, placebo-controlled, multisite trial assessing efficacy and safety. Alcohol Clin Exp Res 2019 ; 43 : 158 – 169
36.
Malcolm R, Roberts JS, Wang W, et al : Multiple previous detoxifications are associated with less responsive treatment and heavier drinking during an index outpatient detoxification. Alcohol 2000 ; 22 : 159 – 164
37.
Sinha R, Lacadie CM, Constable RT, et al : Dynamic neural activity during stress signals resilient coping. Proc Natl Acad Sci USA 2016 ; 113 : 8837 – 8842
38.
Witkiewitz K, Bowen S, Donovan DM : Moderating effects of a craving intervention on the relation between negative mood and heavy drinking following treatment for alcohol dependence. J Consult Clin Psychol 2011 ; 79 : 54 – 63
39.
Milivojevic V, Angarita GA, Hermes G, et al : Effects of prazosin on provoked alcohol craving and autonomic and neuroendocrine response to stress in alcohol use disorder. (Online ahead of print, May 25, 2020) Alcohol Clin Exp Res 2020
Information & Authors
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History
Received: 7 May 2020
Revision received: 27 July 2020
Revision received: 25 August 2020
Revision received: 9 September 2020
Accepted: 14 September 2020
Published online: 19 November 2020
Published in print: May 01, 2021
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Competing Interests
The authors report no financial relationships with commercial interests.
Funding Information
Supported by National Institute of Alcohol Abuse and Alcoholism grant R01-AA020504 and by the Connecticut State Department of Mental Health and Addiction Services.
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