SEARCH

SEARCH BY CITATION

Keywords:

  • alcoholism;
  • clinical trial;
  • compliance;
  • medication;
  • naltrexone

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Summary
  8. References

Objective:  The objective of this study was to demonstrate the utility of continuous monitoring and enhancement of medication compliance during a long-term clinical trial, predictors of compliance, and relationships to drinking outcomes.

Methods:  Alcohol-dependent patients enrolled in a multicenter VA cooperative study were randomly assigned to once-daily naltrexone (NTX) for 3 or 12 months (short-term or long-term NTX) or placebo for 12 months of treatment. All medications were dispensed in bottles with medication event monitoring (MEMS, AARDEX, Union City, CA) caps with a microprocessor that recorded openings as presumptive doses. Patients were trained to develop personal cues as dosing reminders. Monthly feedback sessions included review of compliance data and cues.

Results:  There were no significant differences among short-term NTX, long-term NTX, and placebo (209 each) groups in measures of compliance. Overall compliance rates were 71% ± 31% of doses for the first 13 weeks and 43% ± 33% of doses over 52 weeks. Some doses were taken during 83% ± 27% of the first 13 weeks. Higher medication compliance predicted fewer drinks per drinking day (P = .02) throughout follow-up and a lower percentage of drinking days (P = .002 during the first 13 weeks) with no significant effect for treatment group.

Conclusions:  The feedback and monitoring programs were important features to demonstrate that lack of treatment effect was not a result of poor compliance. Medication compliance data supported the internal validity of the trial by demonstrating that good compliers had better outcomes, irrespective of treatment with NTX or placebo. The MEMS feedback methodology is feasible for use in multicenter trials.


Introduction

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Summary
  8. References

One of the most important concerns for clinical trial designers is how well patients will comply with the protocol for the duration of follow-up. Inadequate or unequal compliance with the study medication regimen by patients in one or all randomized groups can affect the results of the trial. Some patients stop taking the study medication immediately after randomization, other continue to attend follow-up visits but discontinue the study medication, and others might take the medication erratically thereby receiving a lower dose than planned. All of these concerns were addressed during the planning of an 18-month trial to evaluate naltrexone (NTX ReVia, DuPont Pharmaceuticals, Wilmington, DE) as a treatment for alcohol dependence. The population to be enrolled was expected to be poor compliers with study medication, follow-up visits, and overall persistence in the study. Previous multicenter trials with alcohol-dependent patients revealed that medication compliance was a significant factor in drinking outcomes for medication and placebo groups, irrespective of the type of treatment [1–4]. In contrast, studies of NTX have shown that higher compliance was associated with improved outcomes only among the NTX-treated groups [5–7].

The main outcomes for this trial were 1) relapse to heavy drinking during the first 13 weeks; 2) drinks per drinking day; and 3) days drinking during 52 weeks of follow-up. The primary intention-to-treat analysis demonstrated that naltrexone was not superior to placebo treatment for any of the three end points [8]. Secondary analyses demonstrated that patients who were more compliant with medication had better outcomes whether they took naltrexone or placebo. Analyses of covariance, with one covariate taken at a time, showed that medication compliance, attendance at counseling sessions, and attendance at Alcoholics Anonymous meetings had strong effects on the drinks per drinking day and number of days drinking that were independent of naltrexone treatment [8].

Anticipating low medication compliance in this chronically alcohol-dependent population, we had used every feasible method to engage and maintain patients in the study to adequately evaluate the drug [8]. A program to promote compliance was included in the trial to avoid differences in compliance rates among groups and to reduce treatment dropouts so we could test the drug's effectiveness adequately [9,10]. Data describing medication compliance throughout the 52-week follow-up were available to explore predictors of medication compliance and the relationships between compliance and treatment outcomes. This report describes rates of compliance, patient characteristics predictive of compliance, and associations between compliance and alcohol use during the trial using the records of medication dosing throughout the 52-week trial.

Methods

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Summary
  8. References

Protocol

Alcohol-dependent patients who signed consent forms were enrolled in a study of the efficacy of NTX versus placebo at 15 Department of Veterans Affairs Medical Centers (VA) hospitals over a 2-year period. Patients were randomly assigned to three groups of equal size. Institutional review boards at each center and an independent data safety monitoring board monitored the project.

The  double-blind  study  included  three  treat-ment groups: long-term, 50 mg of naltrexone for 12 months; short-term, 50 mg of naltrexone for 3 months followed by masked crossover to placebo for 9 months; or placebo for 12 months, all once daily. All patients were given individual counseling using a modified 12-step approach (Twelve Step Facilitation Treatment, TSFC) adapted for this clinical trial [11,12]. Evaluations were performed at baseline, monthly for 12 months, and quarterly through month 18. Monthly assessments included a review of drinking, medication usage, and compliance feedback, using MEMS data, and standardized counseling. The timeline follow-back system [13] was used to obtain drinking histories at every follow-up visit. Compensation was provided only for time to attend monthly visits to collect data, but not to take the medication or attend counseling sessions. Patients who discontinued study medication or counseling were asked to continue to participate in monthly assessments to provide drinking data.

The Obsessive-Compulsive Drinking Scale (OCDS) was completed at baseline for use as a covariate in analyses [14]. Fourteen questions cover obsessive and compulsive aspects of drinking (e.g., frequency of thoughts, ability to divert thoughts, ability to resist urges to drink). Higher scores, with a range of 0 to 82 indicate a more severe drinking disorder.

Eligibility Criteria

Subjects were diagnosed as alcohol dependent by DSM-IV criteria [15] with no comorbid Axis I diagnosis requiring psychotropic medication, nor a comorbid substance abuse/dependence diagnosis. They were veterans, 18 years or older with recent drinking to intoxication (heavy drinking two times in at least 1 week in the 30 days before screening). All subjects were outpatients and sober by examination for 5 days before randomization.

Compliance Enhancement

All patients participated in the Medication Usage Skills for Effectiveness Program (MUSE-P) [9,10]. The standardized program has been effective in enhancing medication compliance among patients with chronic schizophrenia and chronic mood disorders [10]. Medication was provided in bottles with microelectronic monitor caps (MEMS, purchased from APREX, division of AARDEX, Union City, CA) that recorded the date and time of each opening and showed the number of hours elapsed since the previous opening. The feedback system was a discussion between the site research coordinator and patient focused on development of personalized cues for self-reminders and maintenance of the once daily regimen. Data on the previous month's dosing were shown to the patient when the MEMS cap was downloaded to a computer at each monthly visit to demonstrate self-efficacy. MEMS data were accumulated for 12 months for each patient for use in efficacy analyses.

Analyses

Compliance with the once-daily study medication was defined as the number of days on which the bottle was opened divided by the number of days in that period. Intention-to-treat analyses used the protocol-defined denominators of 13 and 52 weeks. Additional analyses were based on the number of days until the patient discontinued the medication, no doses after that day. Medication compliance was assessed as overall rates of taking one dose daily or compliance rate. The window for 13 and 52 week follow-up was ±15 days.

Treatment efficacy variables were: percentage of days drinking, number of drinking days reported during that period divided by the number of days during that period for which data are available; drinks per drinking day, total number of drinks reported during the period divided by the number of days on which one or more drinks were reported; and time to relapse, number of days from randomization until relapse where relapse is defined as the first episode of a heavy drinking day with six or more drinks/drinking occasion for men and four or more for women.

The primary efficacy analysis was based on intention to treat. Secondary analyses were planned for an “as-treated” basis as well as analyses based on compliance with the treatment regimen. Analyzes of variance (ANOVA) and chi-square were performed. The PROC REG procedure from SAS with backward elimination of nonsignificant variables was used for multivariate analyzes. Multivariate analyses were based on summary variables for 13- and 52-week data.

Results

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Summary
  8. References

Baseline Characteristics

We randomly assigned 627 alcohol-dependent veterans into three equal groups of 209 subjects (placebo  and  short-term  and  long-term  naltrex-one). Table 1 lists demographic characteristics at baseline. There were no statistically significant differences among the groups in demographic characteristics or in measures of alcoholism severity [8].

Table 1.  Demographic characteristics at baseline
CharacteristicLong-term NTXShort-term NTXPlacebo
  1. Abbreviation: NTX, naltrexone.

Number of subjects209209209
Age (years)49.3 ± 1048.5 ± 1049.5 ± 10
Percent male 97.1 97.6 99.5
Education (years)13.2 ± 213.3 ± 213.2 ± 2
OCDS scores20.1 ± 1220.8 ± 1220.4 ± 12
No. drinks per drinking day in previous 90 days13.1 ± 814.1 ± 913.0 ± 7
Percentage of drinking days in previous 90 days65.9 ± 3068.3 ± 2965.6 ± 29

Compliance With Study Medication

Intention to treat.

Patients took study medication on 71% ± 31% of days during the first 13 weeks and 43% ± 33% of days during the entire 52-week trial. Patients took some medication, at least one dose weekly, for 51% ± 36% of weeks for the full year. Compliance rates were not significantly different among the NTX and placebo treatment groups (Table 2). Figure 1 depicts the patterns of treatment persistence. By the end of 52 weeks of follow-up, 48% of patients continued to take study medication.

Table 2.   Compliance (percentage of days taking study medication) for 13 and 52 weeks
 NTXLong-term NTXShort-term NTXPlaceboAll§§Weeks with some treatment
  • *

    Intention to treat: based on the expected duration of treatment (91 days for 13 weeks or 365 days for 52 weeks): N = 529 for 13-weeks’N = 560 for 52-weeks.

  • As treated: based on the number of days before discontinuation of medication (or completion of the study): N = 529 for 13 weeks’N = 560 for 52 weeks.

  • If treated: censoring patients who took study medication for 

  • ≤14 days: N = 513 for 13 weeks; N = 548 for 52 weeks.

  • §

    No significant differences across groups.

  • Abbreviation: NTX, naltrexone.

13 weeks
 N356 of 418  173 of 209529 of 627 
 No. of days in study89 ± 27  88 ± 2789 ± 27 
 Intention to treat (%)*72 ± 31  70 ± 3171 ± 3183 ± 27
 As treated (%)80 ± 25  79 ± 2580 ± 2593 ± 18
 If treated (%)    74 ± 2984 ± 26
52 weeks
 N 185 of 209190 of 209185 of 209560 of 627 
 No. of days in study 223 ± 134225 ± 136221 ± 132223 ± 134 
 Intention to treat (%)* 44 ± 3443 ± 3342 ± 3343 ± 3351 ± 36
 As treated (%) 72 ± 2972 ± 2972 ± 2972 ± 2985 ± 27
 If treated (%)    44 ± 3352 ± 36
image

Figure 1. Proportion of patients continuing to take study medication during 1 year of follow-up.

Download figure to PowerPoint

As treated: censoring postdiscontinuation data.

Limiting analyses to the period until patients either discontinued taking doses or completed the study provided a view of compliance patterns among patients while they were engaged in the treatment program. Mean duration of treatment was 44 ± 12 weeks before discontinuation. Patients took 72% ± 29% of medication during the year, while they wanted to participate (Table 2).

If treated: censoring nonparticipant data.

Another method for evaluating rates of compliance was to include only patients who took doses for a minimum of 14 days, thereby eliminating patients who clearly did not want to participate in the treatment program. The cohort included 87% (548 of 627) of the total randomized population. They took doses for mean 74% ± 29% during the first three months and 44% ± 33% of doses, taking at least one dose weekly for 52% of weeks over 12 months (Table 2).

Use of Compliance Techniques

Half of the patients (58%) reported that the digital displays on the MEMS cap were useful: number of hours since the bottle was last opened and number of openings today. Selection of a reminder cue was considered useful by 85% of patients (Table 3). Three-fourths of patients selected a morning time to take their once-daily tablet. Half of the doses (57%) were taken within the dose window, with a range of 1 hour before or after the selected dose time. These data did not change appreciably over weeks 13 to 52 (Table 4).

Table 3.  Usefulness (%) of medication compliance reminders
 13 weeks52 weeks
MEMS (frequency selected)
 Cap is a reminder5958
 Cue is a reminder8585
Cue usefulness (frequency of use)
 Clock time6768
 Meal time 9 7
 Daily activity1816
 Other 6 9
Table 4.  Compliance rates by schedule
Compliance with selected dose time13 weeks52 weeks
% Choosing windowDoses taken as planned* (within dose window)% Choosing windowDoses taken as planned* (within dose window)
N%N%
  • *

    Dose window was 1 hour before to 1 hour after the dose time selected by the patient. Determination of morning, afternoon, evening, or bedtime dosing was based on the time selected for the dose allowing windows to overlap two periods.

Morning dose (3 am to <12 pm) 7516,04061 7639,13457
Afternoon dose (12 pm to <5 pm) 7 1,22052 6 2,91151
Evening dose (5 pm to <8 pm) 6  87047 6 1,80143
Bedtime dose (8 pm to <3 am) 12 2,15259 12 5,80455
All dose times10020,2825910049,65056

Predictors of Medication Compliance

Examining the correlations between patient characteristics and compliance rates, multivariate analyses of the intention-to-treat population showed that higher 52-week compliance rates were found among patients who had low OCDS scores (P = .005) and a low percentage of drinking days (P = .009) before enrollment. Patients who had a family member willing to be interviewed and those who took medication for other medical disorders were better compliers than those without those attributes. Compliance was 50% when there was family member support, and 39% if not (P = .0001). Compliance was 47% if patient took other medication, and 38% if not (P = .003). The coefficients indicate that for an increase of 10 points in OCDS, medication compliance drops 3.4%. An increase in percentage of drinking days of 10% leads to a drop in compliance of 1.3%. These were small in magnitude. Only OCDS and family support were significantly related to outcomes at 13 weeks.

Predictors of  Treatment Outcomes

Higher medication compliance predicted fewer drinks per drinking day (P = .02) throughout follow-up and a lower percentage of drinking days (P = .002 during the first 13 weeks), whereas naltrexone treatment had no effect. Higher baseline OCDS also predicted more drinking days (P = .03). An increase of 10% in medications compliance would be associated with a decrease of 0.3 drinks per drinking day during 52-week follow-up. The same increase in compliance is related to a decrease of one percentage point in percentage of drinking days. Using medication compliance both as a continuous variable and as a categorical variable (≥50, ≥70, and ≥ 90% compliance) as a covariate with treatment, no relationships were found for any of the outcomes at 13 or 52 weeks.

Discussion

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Summary
  8. References

These data demonstrated that alcohol-dependent patients who volunteered to participate in this 52-week medication treatment program adequately complied with the once-daily regimen. Compliance with the study medication was significantly correlated with improved outcome, but unrelated to naltrexone treatment. The primary and secondary outcomes have been reported previously, as the basis for this report on additional analyses undertaken to better understand the study results. Continuous electronic compliance measurement provided data throughout follow-up for analyses by rate or by follow-up interval. Without these data, critics could have charged that compliance rates differed among treatment groups, that NTX adverse effects had caused patients to discontinue treatment, or that inadequate amounts of NTX were taken to assess outcomes. We used the continuous compliance records for these analyses to generate hypotheses that could be evaluated in future studies.

Internal Validity of the Clinical Trial

Continuous electronic compliance-monitoring methodology has been demonstrated to be superior to counting returned tablets because patients could appear to be better compliers by not returning unused tablets [16,17]. MEMS data could be reviewed to determine that the patient opened the bottle at the planned time to remove a dose. Previous experience has shown that patients do not open the MEMS cap at the appropriate time day after day simply to appear to have taken a dose [10]. As demonstrated again in this trial, patients simply stop taking the medication when they decide not to continue. MEMS data revealed that few subjects stopped and restarted medication or took tablets sporadically. Most subjects who discontinued treatment simply stopped taking the tablets, at which point we considered them discontinuers. Naltrexone is known to occupy mu receptors for several days, with an 18-hour terminal half-life of the active metabolite, 6-β-naltrexol [18]. This gives some support to the adequacy of taking several doses per week.

Compliance Enhancement Method

Other reports have demonstrated that medication compliance can be enhanced in studies of treatment for alcoholism. For example, Sullivan et al. [19] used several indirect measures to estimate compliance rates ranging from 78% to 97%. They used stringent selection and reinforcement methods to achieve high rates of compliance. In our trial, we used the same eligibility criteria as in other naltrexone trials. The additional method employed to enhance medication compliance was the inclusion of the MUSE-P medication feedback program. Our research coordinator saw the patient once a month for data collection, MEMS data download, and feedback. The review of MEMS data took only a few minutes, including review of cues. We postulate that the MUSE-P was equivalent to low-intensity motivational enhancement. It was focused exclusively on taking the medication daily, not on suggesting that the medication would reduce drinking. Patients knew that naltrexone was not an aversive treatment like disulfiram. They were told that it was not a cure, but was thought to reduce craving. The development of a cue was a successful intervention because the majority of doses were taken within the time frame, or dose window, selected by the individual. This finding suggests the usefulness of this simple intervention to improve compliance.

Compliance with Medication for Other Medical Disorders

The adequacy of daily compliance rates and duration of treatment persistence can be demonstrated by comparisons to other medical disorders. A review of studies in which hypertensive patients were prescribed a once-daily medication showed an average compliance rate of 76%, with a wide range of 53% to 85%. Nevertheless, 56% of people prescribed medication to control blood pressure discontinue in 6 months. A study showed that 28% of insulin-dependent diabetes patients obtained less than the prescribed amount of insulin [20]. Persistence with oral diabetes medication also was poor, with only 18% of patients continuing to take acarbose for 1 year [21].

Thus, taking 71% of doses during the first 13 weeks, and 43% of doses over 52 weeks appears to have been reasonable. Persistence with treatment for 1 year by 48% of patients demonstrated a high commitment to the medication program.

Predictors of Medication Compliance

The second aspect of these analyses was to determine whether patient characteristics could be used to predict medication compliance. A series of analyses was undertaken including multiple baseline characteristics and instrument scores to look for significant predictors of high medication compliance. Four issues were weakly predictive of higher compliance in these models. High OCDS scores indicating high levels of obsessiveness and compulsiveness for drinking, and a higher percentage of drinking days predicted lower medication compliance rates. Roberts et al. [22] demonstrated that higher OCDS scores indicated low resistance and control, high obsession, and high interference of drinking with life. Addiction severity and drinks per drinking day were significantly correlated with OCDS scores. Nevertheless, in their population, high OCDS scores, and high number of drinks per drinking day, predicted earlier relapse to heavy drinking. Among the other predictors of medication compliance, we interpret the predictive value of having a significant other person willing to be interviewed as a sign that the patient had some support for participation in this treatment trial. Finding that use of any other medication for a medical disorder predicted compliance suggests that the patient's health beliefs supported medical interventions.

Medication Compliance as a Predictor of Drinking Outcomes

Fuller et al. [1,23] demonstrated a result similar to ours in a study of disulfiram and placebo. No differences were seen between treatments, but treatment compliers had better success than noncompliers. This finding would have been expected for disulfiram because it is an aversive treatment, but aversion cannot explain the results with placebo. Lithium also was found to be ineffective for treatment [2,24]. The compliance result was confirmed in a VA study of lithium that showed significant differences in drinking between compliers and noncompliers without an effect for lithium [3,4]. Our results parallel these earlier trials.

Medication Compliance in Other Naltrexone Trials

Unlike the other studies that demonstrated better NTX efficacy among high compliers, we found no differences between NTX and placebo treatments at any compliance rate. Three previous naltrexone trials assessing medication compliance found efficacy for the drug among patients who took the largest amount of medication. Volpicelli et al. [5] reported that naltrexone improved relapse rates and number of drinking days only among patients who took more than 90% of medication, by pill count, with no difference in craving. Namkoong et al. [6] found better outcomes among patients who had higher rates of compliance with the study medication in a placebo-controlled trial using electronic monitoring. Rohsenow et al. [7] reported that medication compliance, based on urinary riboflavin measurement, was higher among patients who believed that the medication would help them stop drinking, but not based on commitment to abstinence or self-efficacy about abstinence. They also found higher compliance rates among patients with strong urges to drink, based on a laboratory model. Better compliance has been found among patients who believed that the medication would help them stay sober [7,25], but not among those who were committed to abstinence [7]. Medication compliance rates during the first 13 weeks were almost as high in this trial, 71% of doses, as in the short term study that also used MEMS (80%) [6]. Among those continuing, medication was taken for mean 44 weeks during the year of treatment.

Our analyses demonstrated better control of drinking among higher compliers, but no effect of treatment. Namkoong et al. [6] used a median split, at 87% compliance by MEMS, to determine two groups taking naltrexone as high and low compliers. The higher compliance group did significantly better on abstinence and never relapsed during treatment. Volpicelli et al. [5] used pill counts and self-reports to measure compliance instead of electronic monitoring. They found significantly better outcomes among patients taking more than 90% of naltrexone doses than in the placebo group or among lower compliers that we did not replicate.

Summary

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Summary
  8. References

The medication feedback and monitoring programs were important features to demonstrate that lack of treatment effect was not due to poor compliance. Medication compliance data supported the internal validity of the trial by demonstrating that good compliers had better outcomes, irrespective of treatment with NTX or placebo. The computer-based feedback methodology is feasible for use in multicenter trials, whereas the simple cue-development program might be transferable to routine clinical practice.

This study was Supported by the Department of Veterans Affairs, Medical Research Service, Cooperative Studies Program. Naltrexone (ReVia) was provided by Du Pont Pharmaceuticals.

References

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Summary
  8. References
  • 1
    Fuller RK, Branchey L, Brightwell DR, et al. Disulfiram treatment of alcoholism. A Veteran's Administration Cooperative Study. JAMA 1986; 256: 144955.
  • 2
    Fawcett J, Clark D, Aagesen C, et al. A double-blind, placebo-controlled trial of lithium carbonate therapy for alcoholism. Arch Gen Psychiatry 1987;44: 24856.
  • 3
    Dorus W, Ostrow DG, Anton R, et al. Lithium treatment of depressed and nondepressed alcoholics. JAMA 1989;262: 164652.
  • 4
    Collins JF, Dorus W. Patient selection bias in analyses using only compliant patients. In: CramerJA, SpilkerB, eds., Patient Compliance in Medical Practice and Clinical Trials. New York: Raven Press, 1991:33548.
  • 5
    Volpicelli JR, Rhines KC, Rhines JS, et al. Naltrexone and alcohol dependence: the role of subject compliance. Arch Gen Psychiatry 1997;54: 73742.
  • 6
    Namkoong K, Farren CK, O'Connor PG, O'Malley SS. Measurement of compliance with naltrexone in the treatment of alcohol dependence: research and clinical implications. J Clin Psychol 1999;60: 44953.
  • 7
    Rohsenow D, Colby SM, Monti PM, et al. Predictors of compliance with naltrexone among alcoholics. Alcohol Clin Exp Res 2000;24: 15429.
  • 8
    Krystal JH, Cramer JA, Krol WF, et al. Naltrexone in the treatment of alcohol dependence. N Engl J Med 2001;345: 17349.
  • 9
    Cramer JA. Medication use by the elderly: enhancing patient compliance in the elderly. Role of packaging aids and monitoring. Drugs Aging 1998;12: 715.
  • 10
    Cramer JA, Rosenheck R. Enhancing medication compliance for people with serious mental illness. J Nervous Mental Dis 1999;187: 524.
  • 11
    Project Match Research Group. MATCH: rationale and methods for a multisite clinical trial matching alcoholism patients to treatment. Alcohol Clin Exp Res 1993;17: 113045.
  • 12
    Nowinski J, Baker S, Carroll K. Twelve Step Facilitation Therapy Manual. A Clinical Research Guide for Therapists Treating Individuals with Alcohol Abuse and Dependence. NIAAA Project Match Monograph Series, Vol. 1, DHHS Publication No (ADM) 92–1893. Rockville: NIAAA, 1992.
  • 13
    Sobell LC, Sobell MB, Leo CI, Cancilla A. Reliability of a time-line method: assessing normal drinker's reports of recent drinking and a comparative evaluation across several populations. Br J Addict 1988;83: 393402.
  • 14
    Anton RF, Moak DH, Latham P. The Obsessive Compulsive Drinking Scale: a self-rated instrument for the quantification of thoughts about alcohol and drinking behavior. Alcohol Clin Exp Res 1995;19: 929.
  • 15
    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (4th ed.). Washington: American Psychiatric Association, 1994.
  • 16
    Pullar T, Kumar S, Tindall H, Feely M. Time to stop counting the tablets? Clin Pharmacol Ther 1989;46: 1638.
  • 17
    Rudd P, Byyny RL, Zachary V, et al. The natural history of medication compliance in a drug trial: limitations of pill counts. Clin Pharmacol Ther 1989;46: 16976.
  • 18
    Swift RM, Whelihan W, Kuznetsov O, et al. Naltrexone-induced alterations in human ethanol intoxication. Am J Psychiatry 1994;151: 14637.
  • 19
    Sullivan JT, Naranjo CA, Sellers EM. Compliance among heavy alcohol users in clinical dug trials. Int J Substance Abuse 1989;1: 18394.
  • 20
    Morris AD, Boyle DI, McMahon AD, et al. Adherence to insulin treatment, glycaemic control, and ketoacidosis in insulin-dependent diabetes mellitus. Lancet 1997;350: 150510.
  • 21
    Catalan VS, Couture JA, Lelorier J. Predictors of persistence of use of the novel antidiabetic agent acarbose. Arch Intern Med 2001;161: 110612.
  • 22
    Roberts JS, Anton RF, Latham PK, Moak DH. Factor structure and predictive validity of the Obsessive Compulsive Drinking Scale. Alcohol Clin Exp Res 1999;23: 148491.
  • 23
    Fuller RF, Roth H, Long S. Compliance with disulfiram treatment of alcoholism. J Chron Dis 1983;3: 16170.
  • 24
    Pisani VD, Fawcett J, Clark DC, McGuire M. The relative contributions of medication adherence and AA meeting attendance to abstinent outcome for chronic alcoholics. J Stud Alcohol 1993;54: 1519.
  • 25
    Swift RM, Duncan D, Nirenberg T, Femino J. Alcoholic patients’ experiences and attitudes on pharmacotherapy for alcoholism. J Addict Dis 1998;17: 3547.