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Compliance with disulfiram treatment of alcoholism
0021-96X1.83.020161-10$03.00
0
CopyrIght 0 IY83 Pergamon Press Ltd
COMPLIANCE
RICHARD
WITH DISULFIRAM OF ALCOHOLISM FULLER,
HAROLD
ROTH
TREATMENT
and SUSAN LONG
Departments of Medicine and Biometry, Cleveland VA Medical Center and Case Western Reserve University School of Medicine. Cleveland. OH 44106, U.S.A (Received
in rerisrd.form
5 August 1982)
Abstract--One hundred twenty-four men were randomly assigned to receive disulfiram with a riboflavin marker or riboflavin alone. During a one year follow-up urine specimens were collected at each visit and analyzed for riboflavin. There was a strong relationship between excellent attendance and infrequent drinking. For subjects taking disulfiram there was a high correlation between a subject submitting 15 or more positive urines during follow-up and infrequent drinking. For the disulfiram patients there was also a strong relationship between continuous usage of disulfiram and infrequent drinking. However, the correlation between percentage of urine specimens positive for the riboflavin marker and infrequent drinking was slight. This occurred because a person who was drinking tended to return for follow-up only when he was not drinking and thus submitted only a few specimens of which the majority were positive. We conclude that (1) excellent attendance, (2) submission of a large number of positive urines and (3) a period of continuous compliance to the disulfiram regimen were highly associated with infrequent drinking.
INTRODUCTION
or adherence to treatment regimen has been defined as the extent to which a person’s behavior coincides with medical advice [l]. Disulfiram (Antabuse@) is a drug prescribed for the treatment of alcoholism. Disulfiram is different from other drugs because its effectiveness is probably due to the patient’s expectation of becoming sick from the disulfiram-ethanol reaction rather than a direct pharmacological effect [2]. Thus, when a patient agrees to a disulfiram program, he indicates a commitment to abstinence and willingness to use the drug to help himself keep that commitment. It has been suggested that its effectiveness is limited because alcoholics can simply stop taking the medication and drink [3]. A measure of compliance to the disulfiram regimen might provide an indication of the patient’s continuing commitment and the likelihood that he will remain abstinent. However, studies of patients’ voluntary intake of disulfiram over a period of follow-up have not been done. In two studies [3,4] intake was monitored in patients followed over a period of time but the intake was not voluntary. Patients were told to return to the clinic regularly and take the drug under the direct observation of the staff. This is not the usual clinic practice. Usually, disulfiram is prescribed and compliance is left to the discretion of the patient. The purpose of this study was to repeatedly and unobtrusively measure compliance to disulfiram treatment during a one year period among men who had agreed to take the drug. This work was part of a prospective, randomized double-blind clinical trial we did in 128 men to evaluate the efficacy of disulfiram. The study had been described in detail elsewhere [S] and previous reports presented data on the efficacy of the drug [S, 61. In this report we present data on the adherence to the disulfiram regimen and examine its relationship to abstinence and frequency of drinking. We also evaluate the usefulness of compliance as a predictor of drinking behavior. COMPLIANCE
Supported
by funds from the Medical
Research
Service of the Veterans 161
Administration.
RICHARU FCLLER rt al
162
METHODS
Subjects Participants in this study were recruited from all patients who came to Cleveland Veterans Administration Medical Center from 2 January 1971 to 15 June 1974 requesting treatment for their alcoholism or who were admitted to the medical service for an alcohol-related illness. Potential subjects were not included if they refused to participate. were not living with a relative (relatives were required as a source of information about the subject’s behavior during follow-up), were 60 yr of age or older, or had an illness which was a contraindication to the use of disulfiram. Five hundred and five men were potential candidates for this study. 377 were ineligible for the following reasons: 133 refused to participate, 113 had an illness for which disulfiram is contraindicated. 112 lived alone, and 19 were 60 yr old or older. 128 men participated. Their average age was 42.6 + 8.5 yr. 51”/, were black, 65:/ were married, 56% were unemployed and 86’j,Awere in the two lowest social classes by the Hollingshead criteria 171. Study design The 128 subjects were randomly assigned to one of three treatment groups: (1) 43 to a standard disulfiram regimen, i.e. 500 mg disulfiram daily for one week and 250 mg daily thereafter; (2) 43 to a daily 1 mg disulfiram regimen; and (3) 42 to a no disulfiram regimen. The latter two groups were controls. The 1 mg disulfiram group was a control for the threat of disulfiram-ethanol reaction since this dose is not sufficient to cause a disulfiram-ethanol reaction. The members of the two disulfiram groups were told they were receiving disulfiram. They received identical instructions for taking the drug and received capsules that were identical in appearance. They were not told there were two dosage levels. The no disulfiram group was a control for the counseling and medical care that all the subjects received. The members of this group were told they were not receiving disulfiram but that they were receiving riboflavin, a vitamin. They were given 50 mg riboflavin tablets, and instructed to take one tablet daily. All subjects were also given Orexin, a multiple vitamin B preparation that does not contain riboflavin and were asked not to take other vitamin B preparations. Details of the design selection of subjects, characteristics of the study sample and methods of procedure and analysis are described elsewhere [S]. All subjects were scheduled for a series of 19 return visits during the year of follow-up and a record of attendance was kept. Measure
qf’adherence
to drug regimen
To monitor compliance, 50 mg riboflavin was incorporated into the two dosage forms of disulfiram. Subjects were asked to provide urine specimens at all return visits, scheduled and unscheduled, as part of their health assessment and all specimens were tested for the presence of protein and glucose by a dipstick technique (Ames Multistikm). This explanation for the collection of the urine specimens was intended to allay possible suspicion by the patients that their adherence to the drug regimen was being tested. Four subjects never gave a follow-up specimen. Two were in the 1 mg disulfiram group and two were in the riboflavin group. Compliance data is, thus, available for 124 of the 128 men. The urine specimens were analyzed for riboflavin by the fluorometric method of Hobby and Deuschle 181. A specimen was defined as positive for the medication marker if the concentration of riboflavin was 1.5 ,ng/ml or greater (the upper limit of urinary riboflavin excretion observed with a normal diet) [S]. To determine the duration of excretion of riboflavin after ingestion of the last dose, studies were conducted on 74 hospitalized men. These subjects were given 50 mg riboflavin orally daily for three days. After the third and last dose urine specimens were collected every 3 h for 15 hr and then a final specimen was collected 24 hr after the last dose of riboflavin. 97”,, (72/74) had “positive” urines (urinary riboflavin concentration of 1.5 Llg/ml or more) at the first urine collection. i.e. by 3 hr after ingestion of the last dose.
Compliance
wrth Drsulfiram
Treatment
of Alcoholism
I63
Hours after the ingestion of the last 50 mg dose of riboflavin FIG. 1. Cumulative number and percentage of urme specimens becoming negative for rrbofavin over time. The open bar represents the cumulative number of specimens becoming negative for riboflavin at the time interval after the last ingestron of 50 mg of riboflavin given daily for three days. The shaded bar represents the cumulative percentage of specimens becoming negative for riboflavin at the time interval after the last dose of riboflavin.
The remaining 3”,, were “positive” by 6 hr. The urine specimens first became “negative” (urinary ribollavin concentration below 1.5 /c&/ml) at times varying from 6 hr after ingestion to 24 hr for 58”,, (Fig. 1). The remaining 42”,, became negative after 24 hr.
To determine abstinence, at each clinic visit the physician treating the patient asked him if he had been drinking. In addition, the patients were interviewed and examined bimonthly by physicians not involved in their treatment. At the bimonthly sessions blood specimens were obtained for blood ethanol assays and liver function tests. A relative with whom the man was living also was interviewed bimonthly by physicians who did not treat the patients. To be judged abstinent, a man had to be abstinent by all of the following: (1) his reports, (2) his relative’s reports; (3) all blood tests negative for alcohol; and (4) the physical examinations and liver function tests not indicative of the development or progression of an alcohol-related illness. If a patient and/or relative reported drinking, they were asked how many days the patient drank since the last interview.
Analysis was designed to determine how well specific measures of compliance provided an indication of abstinence. Four measures of patient cooperation with the drug regimen were obtained for each subject: (1) the percentage of appointments kept; (2) the percentage of urine specimens positive for riboflavin; (3) the total number of positive urine specimens during the one-year follow-up period ( a measure related to the two previous measures): and (4) the pattern of positive specimens throughout the year. Patients were defined as “compliant” by two separate analyses: (1) 70()/Lor more positive urines and (2) 15 or more positive urines. The Chi square test [9] was used to test for statistically significant associations. The analysis of variance [lo] was used to test for significant differences in means among the three treatment groups. The t-test was used to determine if the correlation coefficients were significantly greater than zero [ 1I].
RICIIAKD FULLER H al.
164
The predictive value of each of the measures of compliance for predicting abstinence or drinking was determined by a method analogous to determining the predictive value of a screening test for the presence of a disease. The measure of compliance is analogous to the screening test, abstinence is analogous to the presence of the disease, and drinking is analogous to the absence of the disease. The predictive value of a positive test for compliance is the likelihood that an individual with a positive test is abstinent and is calculated by dividing the number of true positives by the sum of the true positives and false positives and multiplying by 100 to yield a percent. Likewise, the predictive value of a negative test for compliance is the liklihood that a person with a negative result is not abstinent, i.e. drinking, this is calculated by dividing the true negatives by the sum of true negatives and false negatives multiplied by 100. RESULTS
Twenty-five men were abstinent for the year, 9 of whom were in the 500/250 mg disulfiram group, 11 in the 1 mg disulfiram group, and 5 in the no disulfiram (riboflavin only) group. The two disulfiram regimes were equally efficacious, i.e. the proportion of abstinent patients in each group was approximately the same. Therefore, the two disulfiram groups are combined for purposes of analysis. Although a larger proportion of the patients receiving disulfiram than those receiving riboflavin were abstinent, the difference is not statistically significant. Relationship
between
attendance
and abstinence
Attendance provided a good indication of abstinence (Fig. 2). When all patients were ranked according to percentage of scheduled appointments kept, there was a distinct difference between those with percentages above and below 85%. Of the 24 patients with greater than 850/, scheduled appointments kept. 14 (5893 were totally abstinent. In contrast, of the 100 patients with 85oi, or less attendance, only 11 (I I’%,) were abstinent (x2 = 26.94, p < 0.001). The relationship between excellent attendance and abstinence was observed whether the patients received disulfiram or riboflavin. 59% (10/17) of those given disulfiram and who had excellent attendance, i.e. kept more than 850/, of their appointments, were abstinent compared to 15% (10/67) of those who attendance was worse (x2 = 14.40,
A
90-8 =. : z r C 5
@I70-m 60so-’
, b
‘c o
40-
z 2
30-
5 z
20-
t
q
IO --L 0 I
0
I
IO
I 20
Porcontago
II 30
I
40
so
of schodulod
II
60
70
I
60
appointments
I
90
c8 I
100
kept
FIG. 2. Relationship between attendance (percentage of scheduled appointments kept) and the percentage of drinking days during the year of follow-up. Each symbol represents an individual patient. The circles are those given 500/250mg disulfiram, the squares are those given I mg disulfiram. and the triangles those given riboflavin (no disulfiram).
Compliance
with Disulfiram
TABLE I. URINE SPECIMLM
OBTAINHI FLAVlh
Me&cation
group
Number of subjects
150 mg disulliram* I mg disulfiram” 50 mg I-iboflavin *Contarned
43 41 40
Treatment AND
165
of Alcoholism
PEKCENTAW
POSITIVI-
FOR
RIBO-
MARKER
Mean number of urine specimens per subject
Mean percentage positive per subject
17.3 17.4
IS.2
5.5 I 59.8 48.7
50 mg rlbotlavin.
p < 0.001). Similarly, 57% (4/7) of those given riboflavin who attended faithfully were abstinent compared to 3% (l/33) who did not return as regularly (1” = 15.46, p < 0.001). Thus, excellent attendance has value for predicting abstinence. Abstinence as defined in our study is a stringent criterion. If one calculates the likelihood of excellent attendance predicting drinking on only 5% or fewer of the days during the year of follow-up as well as complete abstinence, the predictive value of excellent attendance is 83%. The predictive value of poorer attendance indicating drinking on more than 5% of follow-up days is 840/,. Percentage
qf urines positic,e for the ribqflatlin murker
For the 124 men as a group the percentage of urines positive for riboflavin was 54.6%. Table 1 shows there were no significant differences among the three treatments groups (F = 1.62, NS). Relationship
between percentage
qf positise urines and abstinence
Percentage of positive urines provided a poor indication of abstinence. When the patients were ranked according to the percentage of positive urines, there was no sharp demarcation between those who were abstinent and those who were not. When a comparison was made with the percentage of drinking days rather than total abstinence, there was a very modest (r = -0.23) albeit statistically significant correlation (i.e. significantly greater than no relationship whatsoever) between percentage of positive urines and percentage of drinking days (Fig. 3). The correlation was negative as might be expected. As the intake of drug increased, as indicated by an increase in the percentage of positive urines, there was a slight decrease in the percentage of drinking days. While there was no sharp demarcation when patients were ranked by percentage of positive urines, there was a difference in abstinence between those with 70y0 or more positive urines (arbitrarily defined as complaint) and those with less than 70%. Of the 84 patients assigned to either dose of disulfiram, 34 (40%) were compliant. 38;,;, of those 34 men were abstinent compared to 14”/, (7/50) of the men given disulfiram who were not compliant (x2 = 6.55, p < 0.02). A trend in the same direction, although not statistically significant, was noted among those who were given riboflavin, i.e. 20”/) of the compliant patients were abstinent whereas only 10% of the less compliant men were abstinent (x2 = 0.69, not significant). While a patient who has 70% or more of his urines positive for the disulfiram marker is more likely to be abstinent than one who has a lesser percentage, the predictive value for total abstinence is still only 38%. The percentage of positive urine tests can be misleading for the subjects who provided only a few specimens. This is illustrated by the experience with the eleven men in this study who had lOOo/, of their urines positive for riboflavin. 10 of the 11 men were not abstinent. The 10 nonabstinent men gave on the average (median) only 3 urine specimens (range: 1-9) and five of them gave only one or two. The one abstinent man in the group gave 18 specimens.
I66
,
I
0
IO
I
20
Percentage
I
30
I 40
I so
of urines
I 60
IDI 70
60
I 90
I 100
positive for riboflavin
FIG. 3. Relationship between the percentage of urines positive for riboflavin and the percentage of drinking days during the year of follow-up. Each symbol represents an individua! patient. The circles represent those patients given 500~250 mg disulfiram, the squares represent those patients given 1 mg disulfiram. and the triangles represents those given ribollavin alone (no disulfiram).
Totul number qfpositice
urines
Another measure of compliance that provided a good indication of abstinence was a result of both attendance and percentage of positive urines, i.e. the sum of positive urines per patient for the year of follow-up. The mean number of urine specimens collected over the year of study was 16.7 + 10.7 per patient. Of these, the mean number of urines that were positive for the riboflavin marker per patient was 9.6 + 8.4. There were no significant differences among the three treatment groups in the number of positive urines per subject (F = 2.03, NS). Figure 4 shows the relationship between the number of positive urines per patient and the percentage of days the patient drank during the year. This figure shows that most patients who had 15 or more positive urines either were abstinent or drank infrequently. 27 (22%) of the 124 men had 15 or more positive urines. 21 of these men were assigned to disulfiram. 11 of these 21 (52%) were completely abstinent compared to 14:<, (9/63) of those with a lesser number of positive urines (x2 = 12.60, p < 0.01). The predictive value for abstinence is 527; for a disulfiram patient who had 15 or more positive urines. The likelihood that a disulfram patient who had less than 15 positive urines was drinking is 860/,. Patterns
of‘ compliance
Almost all of the 124 patients had a series of urinary riboflavin tests obtained during the year of follow-up. However, when we analysed these series we found that 51 patients (410/,) had major interruptions of follow-up, i.e. a total of 6 or more months with no specimens, in gaps of one or more months. Among the 73 patients (59”/,) who did not have major interruptions in follow-up, we could identify four patterns of compliance over time (see Table 2): (1) consistent medication usage throughout the year. 13% (16/124); (2) consistent medication usage initially for a minimum of four months followed by abrupt cessation or irregular usage, 13% (15/124); (3) irregular usage or periodic alteration between use and non-use, 25% (31/124); or (4) consistent non-usage, 976 (I l/124). The non-users returned regularly for follow-up but had 25:‘<, or less of their specimens positive for the marker.
Compliance
with Disulfiram
Treatment
I67
of Alcoholism
70=. :
60 -
z 'Z c
50 -
5 b
40 -
8” a
0
E t t a
a 30 -
0
Oo
1
0
a0
a
a
0
8
20-
0 8
I
AA
I 20
I
IO
0 Number
of urine
I 30
specimens
I 40
positive
for
riboflavin FIG. 4. Relationship between the total number of urine specimens positive for riboflavm and the percentage of drinking days during the year of follow-up. Each symbol represents an individual patient. The circles are those given 500/250mg disulfiram, the squares are those given 1 mg disulfiram. and the triangles those given riboflavin (no disulfiram),
Relationship
of patterns qf’compliance
to abstinence
Continuous compliance throughout the year was an excellent indication of abstinence or infrequent drinking. Of the 16 men with continuous compliance throughout the year of follow-up. 9 were completely abstinent and 5 of the remaining patients drank less than 16 days during the year. However, of the 15 men who had continuous compliance initially for a minimum of four months and then stopped taking the drug or took it irregularly, 6 were abstinent. Analyzing the data from a different perspective, i.e. comparing abstainers with nonabstainers shows that a major difference between abstainers and non-abstainers was that a majority (600/,) of the abstainers demonstrated at least an initial period of continuous
TABLL 2. PATT~KM
OF MEDICATION INTAKE
Subjects Abstainers Number Percentage
Patterns
exhibiting
pattern
Non-abstainers Number Percentage
All patients Percentage Number
9
36”,,
7
7. I lB(,
16
12.9”,,
6
24”,0
9
9.1”,,
15
l?.l”,,
Pel-iodlc or irregular use
6
24”<,
25
x.2’:,,
31
25”;,
Consistent
0
O’>,,
II
I I I “(,
II
X.9”,,
4
I 6” o
47
41.5”,,
51
41.1”,,
100”()
99
I cm”,,
124
I 00”(,
Consistent
use
Consistent use followed abrupt cessation or irregular use
non-use
unable to classify (Major interruptlons in follow-up. 6 months) Total
bq
25
168
RICHAKD
FULLFR ~'tol.
usage whereas only 16’2, of the non-abstainers did (x2 = 20.46. p < 0.001). This 60% included two patterns. (1) 36”‘; of the abstainers took their medication continuously during the entire follow-up period. Only 7’;; of the non-abstainers did (x2 = 14.86, p < 0.001). (2) Steady intake of medication initially for a minimum of four months and then cessation or irregular use was observed in 24”),, of abstainers but only 99:: of the non-abstainers (x2 = 4.17. p < 0.05). Another major difference between the abstainers and the non-abstainers was that the patients who did not have distinct patterns of compliance because of interruptions in their follow-up were largely non-abstainers. Only 169,, (4/25) of the abstainers were in this category whereas 47:; (47/99) of the non-abstainers were. (x2 = 8.17, p < 0.01). A third difference is that none of the abstainers were consistently noncompliant whereas 1 I ‘JOof the non-abstainers were. Combination
of’ attendance
and number qf’positirv
urines
The combination of excellent attendance and submission of 15 or more positive urines provided a good indication of abstinence and an excellent prediction of infrequent drinking. 59q;, (10/17) of the men who kept more than SS”/, of their scheduled appointments and provided 15 or more positive urines were abstinent throughout the year compared to 14”/;; (15/107) whose attendance was less good and submitted fewer positive urines (z’ = 18.29, p < 0.001). Thus, the predictive value of this combination of excellent attendance and number of positive urines for abstinence is 52’%, and the likelihood of drinking for a patient who did not exhibit this combination is 860{,. The difference is more striking if infrequent drinking, i.e. drinking on 59; or fewer days during the year, as well as abstinence is considered a good outcome. 94’:(, (16/17) of the men who kept more than 85% of their scheduled appointments and submitted more than 15 positive urines were completely abstinent or drank on 5”,, or fewer days compared to 19”/, (20/107) whose attendance was worse and submitted fewer positive urines (x2 = 40.51. p < 0.001). The predictive value of this combination of attendance and number of positive urines for abstinence and infrequent drinking is 94”)“. Conversely, the likelihood of drinking for a man who did not have this combination is 81%.
DlSCUSSlON
The disulfiram treatment of alcoholism is potentially different from other drug regimes. For most disorders good compliance to the drug regimen results directly in control or cure of the disorder, whereas disulfiram does not directly cure alcoholism. It merely provides help to the patient who wants to abstain from alcohol. The patient does not have to take the drug to accomplish this. Some patients are able to control their drinking without using disulfiram. Therefore, one might not expect a close correlation between the percentage of urines positive for the drug marker and a low percentage of drinking days. In our study attendance at clinic was a better predictor of abstinence than intake of medication. Excellent attendance was evidence that the patient was doing well. Less than excellent attendance in our study was highly suggestive of drinking. Perhaps many alcoholic patients tended to come to clinic only if they had been sober and thus their frequency of attendance at clinic depended on whether they were drinking or not. While attendance provided a good measure of compliance in this study, the percentage of prescribed medicine taken provided only a poor measure of drinking behavior. This poor correlation could be explained by the observation that several of the patients with a very high percentage of positive urines returned to clinic infrequently and provided only a few specimens. One may speculate that these patients only returned for follow-up when sober and at those times they were taking their disulfiram. Another possible explanation for a high percentage of positive urines submitted by patients who were drinking is that they suspected we were collecting the urines to measure compliance to the drug regimen and only submitted a urine sample when they were taking the drug. We do not believe this occurred although we did not question the patients at the end of their year of
Comphance
with Disulfiram
Treatment
of Alcoholism
169
follow-up to determine if they were suspicious about the true reason for collecting the urine specimens. We were concerned that those patients questioned might communicate the purpose of the collection of urine specimens to those patients who were still being followed. However, we do not believe the patients suspected that we were checking the urine for a drug marker because none raised that possibility. On the other hand, several patients suspected that we were testing the urines for ethanol because they told the treatment physician that he would find no alcohol in their urines. The percentage of positive urines was not a useful indicator of drinking behavior but measures that depended on attendance as well as percentage of positive urines were useful. The number of positive urines and patterns of medication usage represent such measures. Those patients who gave 15 or more positive specimens were likely to be abstinent or drinking infrequently. When this measure is combined with the record of attendance, together they provide the best predictor of abstinence. In our study urine specimens were collected repeatedly, i.e. at each clinic visit during the year of follow-up and tested to monitor compliance. This made it possible for us to make an assessment of the pattern of compliance that includes attendance and positive urines over time. If a patient missed a total of 6 months or more, we did not consider it possible to identify a valid pattern but the vast majority of such patients were not abstinent. On the other hand, a pattern of continuous compliance to disulfiram throughout the year was an excellent indication that the patient was abstinent or drinking infrequently. While continuous compliance was a strong indicator of abstinence or infrequent drinking, this successful reduction in drinking may not be a direct result of continuous compliance. It is possible that the abstinence (or infrequent drinking) and continuous compliance are two separate manifestations of an underlying determination to remain sober. An initial period of a minimum of 4 months of continuous compliance was also seen in the abstinent patients given disulfiram. Comments made by two of those patients suggest that they needed the drug initially to control their urge for drinking but did not need it later in the year because they had learned to cope without resorting to the use of alcohol. However. in the patients who did stop taking their disulfiram after an initial period of continuous compliance less than half (40%) remained sober. Thus the therapist must be concerned when the patient stops taking his disulfiram regularly. Our results must be considered in light of the fact that our patients may not be representative of all alcohol abusers. Each of our patients admitted he had a problem with alcohol and expressed a willingness to take disulfiram. The majority were unemployed but all were living with a relative. And they received the medication at no expense to themselves. The criteria we have identified in this study may be useful in following patients who are receiving disulfiram. Attendance at clinic, a useful criterion by itself, can be recorded easily. Evidence as to whether or not the patient is taking disulfiram can be more difficult to determine. In this study the patient’s report of intake of disulfiram was not accepted as an accurate measure of compliance. We relied on an objective test-the measurement of a marker for disulfiram in the patient’s urine. Other investigators [2, 121 have studied compliance to a disulfiram regimen and have compared the patients’ statements with an objective measure. They checked compliance to the drug regimen by urine and breath tests. They found that 80 and 67% of patients, respectively, were truthful when they said they were taking the drug. However, they only checked intake at a single visit. The occurrence of false reports might be compounded over repeated visits making it difficult to decide about the pattern of intake during the entire period of follow-up. It is possible, however. to measure the catabolic products of disulfiram in urine [2,13] and breath [12] and, thus, to verify the patient’s statement when it seems necessary. REFERENCES I.
Haq~xs RB. Taylor Press. lY7Y. pp. I
DW. Sackett
2
DL: Compliance
in Health Care. Baltimore:
Johns
Hopkins
University
4.
5, 6.
Gallant and,or
DM. Bishop MP. Faulkner MA. ct trl A compl~ancc antabuse) and voluntary treatment of chronic nlcoholic 9: 306 310. 197X Fuller RK. Roth HP: Disulfiram treatment of i~lcohollm. An 901 YO3. 1979 Fuller RK. Willlford WO: Life table analvsts of abstlncncc 111a
Alcoholism: 7. X. 9. IO. I I. 12. 13.
Clin Exp Res 4: 29X-301, 19x0 DG: Social Class and Family Life. NW York.
cvaluatlon municipal evaluation stud\
of compulsory court off‘cndw III I25
c\aluatlna
(group
rnel~. Ann
the cliicacv
therapy
Psychosomatics Int
Med
00:
of dlhulliram.
McKinlev The Free Press of Glcncoe. lYh4. n. 6X Hobby CL. Deuschle KW: The use of riboflavin as an ~nd~catot- of I\onia/ld Ingxtion 111self-medicated patlcnts. Am Rev Resp Dis 80: 41 423. lY5Y Steel RGD. Torrie JM: Principles and Procedures of Statistics. NW Yet-k: McCirawH~II. IY56. pp. 366 3s7 I/N/.. pp. 99 I3 I Ih,t/. p. I90 Paulson SM. Krause S, lber FL: Development and cvaluatlon of II compllancc tat fol- pattents taking thsulfiram. Johns Hopkins Med J I41 : I IY 175. lY77 Nclderhlscr DH. Fuller RK, Hejduk LJ. Roth HP: Method for the dctectlon of dleth\ilamlne. a mctaholltc of dlsulfiram 111urine. J Chromatogr 117: IX7 IY?. lY76
0
CopyrIght 0 IY83 Pergamon Press Ltd
COMPLIANCE
RICHARD
WITH DISULFIRAM OF ALCOHOLISM FULLER,
HAROLD
ROTH
TREATMENT
and SUSAN LONG
Departments of Medicine and Biometry, Cleveland VA Medical Center and Case Western Reserve University School of Medicine. Cleveland. OH 44106, U.S.A (Received
in rerisrd.form
5 August 1982)
Abstract--One hundred twenty-four men were randomly assigned to receive disulfiram with a riboflavin marker or riboflavin alone. During a one year follow-up urine specimens were collected at each visit and analyzed for riboflavin. There was a strong relationship between excellent attendance and infrequent drinking. For subjects taking disulfiram there was a high correlation between a subject submitting 15 or more positive urines during follow-up and infrequent drinking. For the disulfiram patients there was also a strong relationship between continuous usage of disulfiram and infrequent drinking. However, the correlation between percentage of urine specimens positive for the riboflavin marker and infrequent drinking was slight. This occurred because a person who was drinking tended to return for follow-up only when he was not drinking and thus submitted only a few specimens of which the majority were positive. We conclude that (1) excellent attendance, (2) submission of a large number of positive urines and (3) a period of continuous compliance to the disulfiram regimen were highly associated with infrequent drinking.
INTRODUCTION
or adherence to treatment regimen has been defined as the extent to which a person’s behavior coincides with medical advice [l]. Disulfiram (Antabuse@) is a drug prescribed for the treatment of alcoholism. Disulfiram is different from other drugs because its effectiveness is probably due to the patient’s expectation of becoming sick from the disulfiram-ethanol reaction rather than a direct pharmacological effect [2]. Thus, when a patient agrees to a disulfiram program, he indicates a commitment to abstinence and willingness to use the drug to help himself keep that commitment. It has been suggested that its effectiveness is limited because alcoholics can simply stop taking the medication and drink [3]. A measure of compliance to the disulfiram regimen might provide an indication of the patient’s continuing commitment and the likelihood that he will remain abstinent. However, studies of patients’ voluntary intake of disulfiram over a period of follow-up have not been done. In two studies [3,4] intake was monitored in patients followed over a period of time but the intake was not voluntary. Patients were told to return to the clinic regularly and take the drug under the direct observation of the staff. This is not the usual clinic practice. Usually, disulfiram is prescribed and compliance is left to the discretion of the patient. The purpose of this study was to repeatedly and unobtrusively measure compliance to disulfiram treatment during a one year period among men who had agreed to take the drug. This work was part of a prospective, randomized double-blind clinical trial we did in 128 men to evaluate the efficacy of disulfiram. The study had been described in detail elsewhere [S] and previous reports presented data on the efficacy of the drug [S, 61. In this report we present data on the adherence to the disulfiram regimen and examine its relationship to abstinence and frequency of drinking. We also evaluate the usefulness of compliance as a predictor of drinking behavior. COMPLIANCE
Supported
by funds from the Medical
Research
Service of the Veterans 161
Administration.
RICHARU FCLLER rt al
162
METHODS
Subjects Participants in this study were recruited from all patients who came to Cleveland Veterans Administration Medical Center from 2 January 1971 to 15 June 1974 requesting treatment for their alcoholism or who were admitted to the medical service for an alcohol-related illness. Potential subjects were not included if they refused to participate. were not living with a relative (relatives were required as a source of information about the subject’s behavior during follow-up), were 60 yr of age or older, or had an illness which was a contraindication to the use of disulfiram. Five hundred and five men were potential candidates for this study. 377 were ineligible for the following reasons: 133 refused to participate, 113 had an illness for which disulfiram is contraindicated. 112 lived alone, and 19 were 60 yr old or older. 128 men participated. Their average age was 42.6 + 8.5 yr. 51”/, were black, 65:/ were married, 56% were unemployed and 86’j,Awere in the two lowest social classes by the Hollingshead criteria 171. Study design The 128 subjects were randomly assigned to one of three treatment groups: (1) 43 to a standard disulfiram regimen, i.e. 500 mg disulfiram daily for one week and 250 mg daily thereafter; (2) 43 to a daily 1 mg disulfiram regimen; and (3) 42 to a no disulfiram regimen. The latter two groups were controls. The 1 mg disulfiram group was a control for the threat of disulfiram-ethanol reaction since this dose is not sufficient to cause a disulfiram-ethanol reaction. The members of the two disulfiram groups were told they were receiving disulfiram. They received identical instructions for taking the drug and received capsules that were identical in appearance. They were not told there were two dosage levels. The no disulfiram group was a control for the counseling and medical care that all the subjects received. The members of this group were told they were not receiving disulfiram but that they were receiving riboflavin, a vitamin. They were given 50 mg riboflavin tablets, and instructed to take one tablet daily. All subjects were also given Orexin, a multiple vitamin B preparation that does not contain riboflavin and were asked not to take other vitamin B preparations. Details of the design selection of subjects, characteristics of the study sample and methods of procedure and analysis are described elsewhere [S]. All subjects were scheduled for a series of 19 return visits during the year of follow-up and a record of attendance was kept. Measure
qf’adherence
to drug regimen
To monitor compliance, 50 mg riboflavin was incorporated into the two dosage forms of disulfiram. Subjects were asked to provide urine specimens at all return visits, scheduled and unscheduled, as part of their health assessment and all specimens were tested for the presence of protein and glucose by a dipstick technique (Ames Multistikm). This explanation for the collection of the urine specimens was intended to allay possible suspicion by the patients that their adherence to the drug regimen was being tested. Four subjects never gave a follow-up specimen. Two were in the 1 mg disulfiram group and two were in the riboflavin group. Compliance data is, thus, available for 124 of the 128 men. The urine specimens were analyzed for riboflavin by the fluorometric method of Hobby and Deuschle 181. A specimen was defined as positive for the medication marker if the concentration of riboflavin was 1.5 ,ng/ml or greater (the upper limit of urinary riboflavin excretion observed with a normal diet) [S]. To determine the duration of excretion of riboflavin after ingestion of the last dose, studies were conducted on 74 hospitalized men. These subjects were given 50 mg riboflavin orally daily for three days. After the third and last dose urine specimens were collected every 3 h for 15 hr and then a final specimen was collected 24 hr after the last dose of riboflavin. 97”,, (72/74) had “positive” urines (urinary riboflavin concentration of 1.5 Llg/ml or more) at the first urine collection. i.e. by 3 hr after ingestion of the last dose.
Compliance
wrth Drsulfiram
Treatment
of Alcoholism
I63
Hours after the ingestion of the last 50 mg dose of riboflavin FIG. 1. Cumulative number and percentage of urme specimens becoming negative for rrbofavin over time. The open bar represents the cumulative number of specimens becoming negative for riboflavin at the time interval after the last ingestron of 50 mg of riboflavin given daily for three days. The shaded bar represents the cumulative percentage of specimens becoming negative for riboflavin at the time interval after the last dose of riboflavin.
The remaining 3”,, were “positive” by 6 hr. The urine specimens first became “negative” (urinary ribollavin concentration below 1.5 /c&/ml) at times varying from 6 hr after ingestion to 24 hr for 58”,, (Fig. 1). The remaining 42”,, became negative after 24 hr.
To determine abstinence, at each clinic visit the physician treating the patient asked him if he had been drinking. In addition, the patients were interviewed and examined bimonthly by physicians not involved in their treatment. At the bimonthly sessions blood specimens were obtained for blood ethanol assays and liver function tests. A relative with whom the man was living also was interviewed bimonthly by physicians who did not treat the patients. To be judged abstinent, a man had to be abstinent by all of the following: (1) his reports, (2) his relative’s reports; (3) all blood tests negative for alcohol; and (4) the physical examinations and liver function tests not indicative of the development or progression of an alcohol-related illness. If a patient and/or relative reported drinking, they were asked how many days the patient drank since the last interview.
Analysis was designed to determine how well specific measures of compliance provided an indication of abstinence. Four measures of patient cooperation with the drug regimen were obtained for each subject: (1) the percentage of appointments kept; (2) the percentage of urine specimens positive for riboflavin; (3) the total number of positive urine specimens during the one-year follow-up period ( a measure related to the two previous measures): and (4) the pattern of positive specimens throughout the year. Patients were defined as “compliant” by two separate analyses: (1) 70()/Lor more positive urines and (2) 15 or more positive urines. The Chi square test [9] was used to test for statistically significant associations. The analysis of variance [lo] was used to test for significant differences in means among the three treatment groups. The t-test was used to determine if the correlation coefficients were significantly greater than zero [ 1I].
RICIIAKD FULLER H al.
164
The predictive value of each of the measures of compliance for predicting abstinence or drinking was determined by a method analogous to determining the predictive value of a screening test for the presence of a disease. The measure of compliance is analogous to the screening test, abstinence is analogous to the presence of the disease, and drinking is analogous to the absence of the disease. The predictive value of a positive test for compliance is the likelihood that an individual with a positive test is abstinent and is calculated by dividing the number of true positives by the sum of the true positives and false positives and multiplying by 100 to yield a percent. Likewise, the predictive value of a negative test for compliance is the liklihood that a person with a negative result is not abstinent, i.e. drinking, this is calculated by dividing the true negatives by the sum of true negatives and false negatives multiplied by 100. RESULTS
Twenty-five men were abstinent for the year, 9 of whom were in the 500/250 mg disulfiram group, 11 in the 1 mg disulfiram group, and 5 in the no disulfiram (riboflavin only) group. The two disulfiram regimes were equally efficacious, i.e. the proportion of abstinent patients in each group was approximately the same. Therefore, the two disulfiram groups are combined for purposes of analysis. Although a larger proportion of the patients receiving disulfiram than those receiving riboflavin were abstinent, the difference is not statistically significant. Relationship
between
attendance
and abstinence
Attendance provided a good indication of abstinence (Fig. 2). When all patients were ranked according to percentage of scheduled appointments kept, there was a distinct difference between those with percentages above and below 85%. Of the 24 patients with greater than 850/, scheduled appointments kept. 14 (5893 were totally abstinent. In contrast, of the 100 patients with 85oi, or less attendance, only 11 (I I’%,) were abstinent (x2 = 26.94, p < 0.001). The relationship between excellent attendance and abstinence was observed whether the patients received disulfiram or riboflavin. 59% (10/17) of those given disulfiram and who had excellent attendance, i.e. kept more than 850/, of their appointments, were abstinent compared to 15% (10/67) of those who attendance was worse (x2 = 14.40,
A
90-8 =. : z r C 5
@I70-m 60so-’
, b
‘c o
40-
z 2
30-
5 z
20-
t
q
IO --L 0 I
0
I
IO
I 20
Porcontago
II 30
I
40
so
of schodulod
II
60
70
I
60
appointments
I
90
c8 I
100
kept
FIG. 2. Relationship between attendance (percentage of scheduled appointments kept) and the percentage of drinking days during the year of follow-up. Each symbol represents an individual patient. The circles are those given 500/250mg disulfiram, the squares are those given I mg disulfiram. and the triangles those given riboflavin (no disulfiram).
Compliance
with Disulfiram
TABLE I. URINE SPECIMLM
OBTAINHI FLAVlh
Me&cation
group
Number of subjects
150 mg disulliram* I mg disulfiram” 50 mg I-iboflavin *Contarned
43 41 40
Treatment AND
165
of Alcoholism
PEKCENTAW
POSITIVI-
FOR
RIBO-
MARKER
Mean number of urine specimens per subject
Mean percentage positive per subject
17.3 17.4
IS.2
5.5 I 59.8 48.7
50 mg rlbotlavin.
p < 0.001). Similarly, 57% (4/7) of those given riboflavin who attended faithfully were abstinent compared to 3% (l/33) who did not return as regularly (1” = 15.46, p < 0.001). Thus, excellent attendance has value for predicting abstinence. Abstinence as defined in our study is a stringent criterion. If one calculates the likelihood of excellent attendance predicting drinking on only 5% or fewer of the days during the year of follow-up as well as complete abstinence, the predictive value of excellent attendance is 83%. The predictive value of poorer attendance indicating drinking on more than 5% of follow-up days is 840/,. Percentage
qf urines positic,e for the ribqflatlin murker
For the 124 men as a group the percentage of urines positive for riboflavin was 54.6%. Table 1 shows there were no significant differences among the three treatments groups (F = 1.62, NS). Relationship
between percentage
qf positise urines and abstinence
Percentage of positive urines provided a poor indication of abstinence. When the patients were ranked according to the percentage of positive urines, there was no sharp demarcation between those who were abstinent and those who were not. When a comparison was made with the percentage of drinking days rather than total abstinence, there was a very modest (r = -0.23) albeit statistically significant correlation (i.e. significantly greater than no relationship whatsoever) between percentage of positive urines and percentage of drinking days (Fig. 3). The correlation was negative as might be expected. As the intake of drug increased, as indicated by an increase in the percentage of positive urines, there was a slight decrease in the percentage of drinking days. While there was no sharp demarcation when patients were ranked by percentage of positive urines, there was a difference in abstinence between those with 70y0 or more positive urines (arbitrarily defined as complaint) and those with less than 70%. Of the 84 patients assigned to either dose of disulfiram, 34 (40%) were compliant. 38;,;, of those 34 men were abstinent compared to 14”/, (7/50) of the men given disulfiram who were not compliant (x2 = 6.55, p < 0.02). A trend in the same direction, although not statistically significant, was noted among those who were given riboflavin, i.e. 20”/) of the compliant patients were abstinent whereas only 10% of the less compliant men were abstinent (x2 = 0.69, not significant). While a patient who has 70% or more of his urines positive for the disulfiram marker is more likely to be abstinent than one who has a lesser percentage, the predictive value for total abstinence is still only 38%. The percentage of positive urine tests can be misleading for the subjects who provided only a few specimens. This is illustrated by the experience with the eleven men in this study who had lOOo/, of their urines positive for riboflavin. 10 of the 11 men were not abstinent. The 10 nonabstinent men gave on the average (median) only 3 urine specimens (range: 1-9) and five of them gave only one or two. The one abstinent man in the group gave 18 specimens.
I66
,
I
0
IO
I
20
Percentage
I
30
I 40
I so
of urines
I 60
IDI 70
60
I 90
I 100
positive for riboflavin
FIG. 3. Relationship between the percentage of urines positive for riboflavin and the percentage of drinking days during the year of follow-up. Each symbol represents an individua! patient. The circles represent those patients given 500~250 mg disulfiram, the squares represent those patients given 1 mg disulfiram. and the triangles represents those given ribollavin alone (no disulfiram).
Totul number qfpositice
urines
Another measure of compliance that provided a good indication of abstinence was a result of both attendance and percentage of positive urines, i.e. the sum of positive urines per patient for the year of follow-up. The mean number of urine specimens collected over the year of study was 16.7 + 10.7 per patient. Of these, the mean number of urines that were positive for the riboflavin marker per patient was 9.6 + 8.4. There were no significant differences among the three treatment groups in the number of positive urines per subject (F = 2.03, NS). Figure 4 shows the relationship between the number of positive urines per patient and the percentage of days the patient drank during the year. This figure shows that most patients who had 15 or more positive urines either were abstinent or drank infrequently. 27 (22%) of the 124 men had 15 or more positive urines. 21 of these men were assigned to disulfiram. 11 of these 21 (52%) were completely abstinent compared to 14:<, (9/63) of those with a lesser number of positive urines (x2 = 12.60, p < 0.01). The predictive value for abstinence is 527; for a disulfiram patient who had 15 or more positive urines. The likelihood that a disulfram patient who had less than 15 positive urines was drinking is 860/,. Patterns
of‘ compliance
Almost all of the 124 patients had a series of urinary riboflavin tests obtained during the year of follow-up. However, when we analysed these series we found that 51 patients (410/,) had major interruptions of follow-up, i.e. a total of 6 or more months with no specimens, in gaps of one or more months. Among the 73 patients (59”/,) who did not have major interruptions in follow-up, we could identify four patterns of compliance over time (see Table 2): (1) consistent medication usage throughout the year. 13% (16/124); (2) consistent medication usage initially for a minimum of four months followed by abrupt cessation or irregular usage, 13% (15/124); (3) irregular usage or periodic alteration between use and non-use, 25% (31/124); or (4) consistent non-usage, 976 (I l/124). The non-users returned regularly for follow-up but had 25:‘<, or less of their specimens positive for the marker.
Compliance
with Disulfiram
Treatment
I67
of Alcoholism
70=. :
60 -
z 'Z c
50 -
5 b
40 -
8” a
0
E t t a
a 30 -
0
Oo
1
0
a0
a
a
0
8
20-
0 8
I
AA
I 20
I
IO
0 Number
of urine
I 30
specimens
I 40
positive
for
riboflavin FIG. 4. Relationship between the total number of urine specimens positive for riboflavm and the percentage of drinking days during the year of follow-up. Each symbol represents an individual patient. The circles are those given 500/250mg disulfiram, the squares are those given 1 mg disulfiram. and the triangles those given riboflavin (no disulfiram),
Relationship
of patterns qf’compliance
to abstinence
Continuous compliance throughout the year was an excellent indication of abstinence or infrequent drinking. Of the 16 men with continuous compliance throughout the year of follow-up. 9 were completely abstinent and 5 of the remaining patients drank less than 16 days during the year. However, of the 15 men who had continuous compliance initially for a minimum of four months and then stopped taking the drug or took it irregularly, 6 were abstinent. Analyzing the data from a different perspective, i.e. comparing abstainers with nonabstainers shows that a major difference between abstainers and non-abstainers was that a majority (600/,) of the abstainers demonstrated at least an initial period of continuous
TABLL 2. PATT~KM
OF MEDICATION INTAKE
Subjects Abstainers Number Percentage
Patterns
exhibiting
pattern
Non-abstainers Number Percentage
All patients Percentage Number
9
36”,,
7
7. I lB(,
16
12.9”,,
6
24”,0
9
9.1”,,
15
l?.l”,,
Pel-iodlc or irregular use
6
24”<,
25
x.2’:,,
31
25”;,
Consistent
0
O’>,,
II
I I I “(,
II
X.9”,,
4
I 6” o
47
41.5”,,
51
41.1”,,
100”()
99
I cm”,,
124
I 00”(,
Consistent
use
Consistent use followed abrupt cessation or irregular use
non-use
unable to classify (Major interruptlons in follow-up. 6 months) Total
bq
25
168
RICHAKD
FULLFR ~'tol.
usage whereas only 16’2, of the non-abstainers did (x2 = 20.46. p < 0.001). This 60% included two patterns. (1) 36”‘; of the abstainers took their medication continuously during the entire follow-up period. Only 7’;; of the non-abstainers did (x2 = 14.86, p < 0.001). (2) Steady intake of medication initially for a minimum of four months and then cessation or irregular use was observed in 24”),, of abstainers but only 99:: of the non-abstainers (x2 = 4.17. p < 0.05). Another major difference between the abstainers and the non-abstainers was that the patients who did not have distinct patterns of compliance because of interruptions in their follow-up were largely non-abstainers. Only 169,, (4/25) of the abstainers were in this category whereas 47:; (47/99) of the non-abstainers were. (x2 = 8.17, p < 0.01). A third difference is that none of the abstainers were consistently noncompliant whereas 1 I ‘JOof the non-abstainers were. Combination
of’ attendance
and number qf’positirv
urines
The combination of excellent attendance and submission of 15 or more positive urines provided a good indication of abstinence and an excellent prediction of infrequent drinking. 59q;, (10/17) of the men who kept more than SS”/, of their scheduled appointments and provided 15 or more positive urines were abstinent throughout the year compared to 14”/;; (15/107) whose attendance was less good and submitted fewer positive urines (z’ = 18.29, p < 0.001). Thus, the predictive value of this combination of excellent attendance and number of positive urines for abstinence is 52’%, and the likelihood of drinking for a patient who did not exhibit this combination is 860{,. The difference is more striking if infrequent drinking, i.e. drinking on 59; or fewer days during the year, as well as abstinence is considered a good outcome. 94’:(, (16/17) of the men who kept more than 85% of their scheduled appointments and submitted more than 15 positive urines were completely abstinent or drank on 5”,, or fewer days compared to 19”/, (20/107) whose attendance was worse and submitted fewer positive urines (x2 = 40.51. p < 0.001). The predictive value of this combination of attendance and number of positive urines for abstinence and infrequent drinking is 94”)“. Conversely, the likelihood of drinking for a man who did not have this combination is 81%.
DlSCUSSlON
The disulfiram treatment of alcoholism is potentially different from other drug regimes. For most disorders good compliance to the drug regimen results directly in control or cure of the disorder, whereas disulfiram does not directly cure alcoholism. It merely provides help to the patient who wants to abstain from alcohol. The patient does not have to take the drug to accomplish this. Some patients are able to control their drinking without using disulfiram. Therefore, one might not expect a close correlation between the percentage of urines positive for the drug marker and a low percentage of drinking days. In our study attendance at clinic was a better predictor of abstinence than intake of medication. Excellent attendance was evidence that the patient was doing well. Less than excellent attendance in our study was highly suggestive of drinking. Perhaps many alcoholic patients tended to come to clinic only if they had been sober and thus their frequency of attendance at clinic depended on whether they were drinking or not. While attendance provided a good measure of compliance in this study, the percentage of prescribed medicine taken provided only a poor measure of drinking behavior. This poor correlation could be explained by the observation that several of the patients with a very high percentage of positive urines returned to clinic infrequently and provided only a few specimens. One may speculate that these patients only returned for follow-up when sober and at those times they were taking their disulfiram. Another possible explanation for a high percentage of positive urines submitted by patients who were drinking is that they suspected we were collecting the urines to measure compliance to the drug regimen and only submitted a urine sample when they were taking the drug. We do not believe this occurred although we did not question the patients at the end of their year of
Comphance
with Disulfiram
Treatment
of Alcoholism
169
follow-up to determine if they were suspicious about the true reason for collecting the urine specimens. We were concerned that those patients questioned might communicate the purpose of the collection of urine specimens to those patients who were still being followed. However, we do not believe the patients suspected that we were checking the urine for a drug marker because none raised that possibility. On the other hand, several patients suspected that we were testing the urines for ethanol because they told the treatment physician that he would find no alcohol in their urines. The percentage of positive urines was not a useful indicator of drinking behavior but measures that depended on attendance as well as percentage of positive urines were useful. The number of positive urines and patterns of medication usage represent such measures. Those patients who gave 15 or more positive specimens were likely to be abstinent or drinking infrequently. When this measure is combined with the record of attendance, together they provide the best predictor of abstinence. In our study urine specimens were collected repeatedly, i.e. at each clinic visit during the year of follow-up and tested to monitor compliance. This made it possible for us to make an assessment of the pattern of compliance that includes attendance and positive urines over time. If a patient missed a total of 6 months or more, we did not consider it possible to identify a valid pattern but the vast majority of such patients were not abstinent. On the other hand, a pattern of continuous compliance to disulfiram throughout the year was an excellent indication that the patient was abstinent or drinking infrequently. While continuous compliance was a strong indicator of abstinence or infrequent drinking, this successful reduction in drinking may not be a direct result of continuous compliance. It is possible that the abstinence (or infrequent drinking) and continuous compliance are two separate manifestations of an underlying determination to remain sober. An initial period of a minimum of 4 months of continuous compliance was also seen in the abstinent patients given disulfiram. Comments made by two of those patients suggest that they needed the drug initially to control their urge for drinking but did not need it later in the year because they had learned to cope without resorting to the use of alcohol. However. in the patients who did stop taking their disulfiram after an initial period of continuous compliance less than half (40%) remained sober. Thus the therapist must be concerned when the patient stops taking his disulfiram regularly. Our results must be considered in light of the fact that our patients may not be representative of all alcohol abusers. Each of our patients admitted he had a problem with alcohol and expressed a willingness to take disulfiram. The majority were unemployed but all were living with a relative. And they received the medication at no expense to themselves. The criteria we have identified in this study may be useful in following patients who are receiving disulfiram. Attendance at clinic, a useful criterion by itself, can be recorded easily. Evidence as to whether or not the patient is taking disulfiram can be more difficult to determine. In this study the patient’s report of intake of disulfiram was not accepted as an accurate measure of compliance. We relied on an objective test-the measurement of a marker for disulfiram in the patient’s urine. Other investigators [2, 121 have studied compliance to a disulfiram regimen and have compared the patients’ statements with an objective measure. They checked compliance to the drug regimen by urine and breath tests. They found that 80 and 67% of patients, respectively, were truthful when they said they were taking the drug. However, they only checked intake at a single visit. The occurrence of false reports might be compounded over repeated visits making it difficult to decide about the pattern of intake during the entire period of follow-up. It is possible, however. to measure the catabolic products of disulfiram in urine [2,13] and breath [12] and, thus, to verify the patient’s statement when it seems necessary. REFERENCES I.
Haq~xs RB. Taylor Press. lY7Y. pp. I
DW. Sackett
2
DL: Compliance
in Health Care. Baltimore:
Johns
Hopkins
University
4.
5, 6.
Gallant and,or
DM. Bishop MP. Faulkner MA. ct trl A compl~ancc antabuse) and voluntary treatment of chronic nlcoholic 9: 306 310. 197X Fuller RK. Roth HP: Disulfiram treatment of i~lcohollm. An 901 YO3. 1979 Fuller RK. Willlford WO: Life table analvsts of abstlncncc 111a
Alcoholism: 7. X. 9. IO. I I. 12. 13.
Clin Exp Res 4: 29X-301, 19x0 DG: Social Class and Family Life. NW York.
cvaluatlon municipal evaluation stud\
of compulsory court off‘cndw III I25
c\aluatlna
(group
rnel~. Ann
the cliicacv
therapy
Psychosomatics Int
Med
00:
of dlhulliram.
McKinlev The Free Press of Glcncoe. lYh4. n. 6X Hobby CL. Deuschle KW: The use of riboflavin as an ~nd~catot- of I\onia/ld Ingxtion 111self-medicated patlcnts. Am Rev Resp Dis 80: 41 423. lY5Y Steel RGD. Torrie JM: Principles and Procedures of Statistics. NW Yet-k: McCirawH~II. IY56. pp. 366 3s7 I/N/.. pp. 99 I3 I Ih,t/. p. I90 Paulson SM. Krause S, lber FL: Development and cvaluatlon of II compllancc tat fol- pattents taking thsulfiram. Johns Hopkins Med J I41 : I IY 175. lY77 Nclderhlscr DH. Fuller RK, Hejduk LJ. Roth HP: Method for the dctectlon of dleth\ilamlne. a mctaholltc of dlsulfiram 111urine. J Chromatogr 117: IX7 IY?. lY76