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Chronic heroin use during methadone treatment: A test of the efficacy of high maintenance doses
Addictive Behaviors, Vol. 9, pp. V-65, Printed in the USA. All rights reserved.
1984 Copyright
0306-4603/84 $3.00 + .OO D 1984 Pergamon Press Ltd
CHRONIC HEROIN USE DURING METHADONE TREATMENT: A TEST OF THE EFFICACY OF HIGH MAINTENANCE DOSES BARBARA
E. HAVASSY
University of California, San Francisco School of Medicine, Department of Psychiatry and
JEANNE
M. TSCHANN
University of California, Santa Cruz Department of Psychology Abstract-A pilot study was conducted at two maintenance programs to test the effect of increasing the methadone dose of clients who continue chronic heroin use after stabilization on methadone. Program 1 subjects (Group 1) received substantial dose increases for a 14-week period; Program 2 subjects (Group 2) received no dose modifications during the same period. Results show Group 1 reported an alleviation of physical and psychological complaints but did not decrease illicit opiate use. Group 2 maintained the low level of complaints reported at baseline and, unexpectedly, decreased opiate abuse. Because the two maintenance programs differed in clinical practices and in enforcement of rules, it was concluded that clients who continue chronic heroin use need not only long-term dosage increases, but also clear, consistently applied program policies.
A major concern in maintenance treatment is that considerable numbers of clients who are apparently stabilized on methadone continue to use heroin frequently, as evidenced by the results of weekly urinalyses. Treatment staff initiate a variety of strategies in response to these clients and question the appropriate course of treatment. A common strategy employed in these circumstances is a dose adjustment. In some cases the dose is increased, based on the concept of heroin blockade (Dole & Nyswander, 1965). In other cases, the dose is decreased, often for psychological rather than pharmacological effects. Alternative strategies often involve psychological manipulations in which the relationship between client and staff is altered. A final strategy, though not a solution, is to involuntarily detoxify and terminate the client from treatment. There is little research directed at this particular group of “problem” clients, and none of this research directly addresses the dosage question for this group. A small study by Stitzer, Bigelow and Liebson (1980) focused exclusively on maintenance clients who were continuing heroin users, but did not pose the question of inadequate dosage and did not employ dosage manipulation as the intervention. Instead, contingency management was utilized as the intervention. Seven subjects, black male chronic heroin users, received reinforcement contingent upon providing morphine-free urines during randomly selected weeks. Five of the seven showed marked reductions during contingent reinforcement weeks as compared to pre-study weeks. Overall, the rate of morphinepositive samples was less during contingent weeks than in pre-study weeks (p < .Ol). These results are suggestive of possible interventions; however, they are limited due to This research was supported by a grant from the National Institute on Drug Abuse, #DA 01936. The authors wish to thank Sharon M. Hall, for reading an earlier draft of this paper. Address reprint requests to Barbara Havassy, University of California Psychiatry Service, 1001 Potrero Avenue, 7M, San Francisco, CA 94110. 57
58
BARBARA
E. HAVASSY
and
JEANNE
M. TSCHANN
small sample size and the fact that the reinforcer most frequently chosen was a $15 payment per opiate-free urine specimen-a practice not easily incorporated into the procedures of many maintenance programs. Research that compares the effectiveness of different dose levels with regard to certain outcome criteria (Berry & Kuhn, 1973; Garbutt & Goldstein, 1972; Goldstein & Judson, 1973, 1974) has not taken into account the continuing heroin user. In these studies heroin use was a measure of outcome rather than a criterion for subject selection, so that the extent to which the results (i.e., large differences in dosage yield little or no differences in outcomes) can be generalized to clients with a continuing heroin use problem is not known. Another limitation of these dosage level studies, for our purposes, is that they are fixed dose level studies. There is no provision in these studies for comparing outcomes of the same subjects at different dosages. Thus it is not possible to know whether subjects who used opiates while maintained on 30 mg methadone would have also used them when maintained on 50 or 100 mg. Evidence that higher doses might be more effective or have greater therapeutic value comes from the Veterans Administration methadyl acetate (LAAM) study (Ling, Charuvastra, Kiam, & Klett, 1976) which compared heroin addicts given 50 or 100 mg methadone daily or 80 mg of LAAM three times a week. There were significant differences between the 50 and 100 mg methadone groups: the 50 mg group had significantly higher frequency of complaints of aching bones and joints and of insomnia than the 100 mg group, and also had significantly greater heroin use than the 100 mg group. Additional evidence that higher methadone doses are more efficacious than lower ones may be found in Berry and Kuhn (1973); Chambers and Taylor (1973); Garbutt and Goldstein (1972); Goldstein and Judson (1973, 1974); Jaffe (197 1); Langley, Norris, and Parker (1973); McGlothlin and Anglin (1981); Wieland and Moffett (1970). The Langley et al. (1973) data indicate clients at higher doses provided fewer drugpositive urines. In a (six-to-seven year) follow-up study McGlothlin and Anglin (1981) found longer retention and lower rates of opiate abuse among clients from programs with higher doses and flexible termination policies, compared with clients from a program with low doses and a strict termination policy. This pilot study addressed the issue of whether continued heroin use observed in maintenance clients who are stabilized on methadone is a dosage related phenomenon. The target group was composed of clients who continued to use heroin to the extent that they were about to be terminated from treatment. We hypothesized that subjects who received a substantial dose increment would reduce the frequency of their use of illicit opiates more than subjects whose dose was not incremented. We also hypothesized that subjects who received dose increments would complain of fewer symptoms and report better mood and affect than subjects whose dose was not incremented. METHODS
Design This pilot study was designed as a two treatment double-blind random assignment study at three methadone maintenance clinics, two administered by one program and one by another program. One treatment was dosage increments, the other was stable dosage. At the initiation of recruitment in each program, substantial resistance to random assignment was manifested. Resistance came from the staff of one program (who opposed dosage increments) and from the director of the other program (who valued dosage increments and opposed random assignment). These circumstances forced abandonment of random assignment and the adoption
Chronic
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59
treatment
of a quasi-experimental design, the non-equivalent control group (see Campbell & Stanley, 1963). In this design each program had only one of the treatments implemented: subjects from Program 1 received the dosage increment and subjects from Program 2 received stable dosage. Clin its
Potential subjects were identified from the client population of the three San Francisco clinics. The three clinics are similar in many ways, including the size of the client populations, client characteristics, and in policies regarding continued drug abuse. Clients readily transfer between programs and clinics. Sample
The sample consisted of 31 men (57%) and 23 women (43%). Their average age was 33 years. The majority were presently not married (44% never married, 32% divorced or separated, 19% presently married). The sample had a mean of 5.7 previous treatment attempts. Additional descriptive data may be found in Table 1. Procedures
Clients who were identified as potential subjects were approached at their clinic by research staff who explained the study and requested participation. Clients who agreed provided informed consent and completed the Profile of Mood States (POMS) and the Symptom Questionnaire (description follows) to provide baseline information. Thereafter, subjects completed the two questionnaires on a weekly basis for the duration of the study. Subjects completed the questionnaires on the same day each week, immediately before or after receiving their doses. All aspects of subjects’ treatment (i.e., medical, legal, and program) during their study participation were monitored by research staff. Treatments. Subjects in Program 1 (n = 29) had their dose increased over a 2-week period at the rate of 10 mg or less every three days. They remained at the elevated doses for the next 12 weeks. The schedule for increasing doses was based on baseline methadone dose and varied from a 100% increase for subjects at 20 mg/day at baseline to a 50% increase for subjects at 80 mg/day at baseline. These subjects’ urines were collected as usual, but there were no consequences during the study for providing specimens containing opiates or for failing to provide specimens. Results of urinalyses were reviewed by clinic staff at the end of the study, however, and were used in deciding whether involuntary detoxification would proceed. All of this was explained to subjects. Table
1.
Some demographic and treatment characteristics and treatment program clients.
Percent Male Ethnicity % Caucasian Vo Black % Latin Percent Employed (full or part) Time in Treatment Episode (median) Mean Mg Methadone Percent Opiate-Positive in 90 Days
of the study subjects
Sample (n = 54)
Program I (n = 413)
Program 2 (n = 188)
57
62
76
76 6 15 26 8 mos 62 30.3
63 13 8 40 24 mos 60 6
65 10 16 63 13 mos 48 9
BARBARA
60
Subjects the study treatment resources urinalysis group.
E. HAVASSY
and
JEANNE
M. TSCHANN
in Program 2 (n = 25) were not given any dose changes for the 14 weeks of but did receive a 14-week moratorium on involuntary detoxification and termination. These subjects were encouraged to utilize program and other available to them to assist them to avoid or decrease heroin use. The use of results was the same for the stable-dose group as for the dose-increment
Measures Subjects’ urinalysis results, methadone dosage, and demographic data were collected as described. Subjects completed two questionnaires, the Profile of Mood States (POMS) and the Symptom Questionnaire.
Urinalyses. Urine specimens were routinely collected by the clinics on a random schedule. Specimens were analyzed by means of thin-layer chromatography, with confirmations for drug-positive specimens. Urinalysis results were collected on subjects for 14 weeks before the study (the baseline period), and for each of the 14 weeks during the study (the study period). There were two urine scores calculated for each subject: one, a baseline period score; the other, a study period score. Each urine score reflected only the proportion of opiate-positive specimens provided. It did not take missed or refused specimens into account. Dose. Subjects’ study participation
methadone dosage began (study-start
level was recorded daily, from the day before dose) and throughout the study.
Demographic data. Program entry information was collected from the Client Oriented Data Acquisition Process (CODAP) forms. Client information at study-start, such as employment status, was obtained from counselling records. Profile of Mood States (McNair, Lorr & Droppleman, 1971). This self-administered instrument consists of 65 5-point items describing mood that constitute six subscales: tension-anxiety, depression-dejection, anger-hostility, vigor-activity, fatigue-inertia, and confusion-bewilderment. Internal consistency has been shown to be high (r = .84 to .95). Tests for validity, including the administration of psychoactive drugs, have been positive. In the present study, subjects were asked to report their mood states “today.” Symptom Questionnaire. Developed by the authors for use in this study, this questionnaire contains 31 4-point items to assess withdrawal and over-sedation symptoms, some of which are attributable to the class “opiates,” and others of which are commonly attributed to methadone alone. Also included are several items to assess general health states. Subjects were asked to report how they felt “ rday.” RESULTS
Demographic characteristics The two treatment groups were first tested for major demographic and program differences. The chi squares for sex, ethnicity, marital status and employment status were non-significant. The t-tests on age were also non-significant (Group 1 mean = 29 yrs.; Group 2 mean = 33 yrs.); number of prior admissions to any drug treatment (Group 1 mean = 6.1; Group 2 mean = 5.2); months in treatment (Group 1 mean = 10.5 mos.; Group 2 mean = 16.4 mos.) and baseline opiate use (Group 1 mean = 33%; Group 2 mean = 28% opiate positive in 90 days). The t-test on starting dose was significant at p < .001; t(52) = 3.87, Group 1 mean = 70 mg; Group 2 = 52 mg).
Chronic
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treatment
Illicit opiate use All of the results reported in this section employ urine scores reflecting opiate-positive specimens as percent of urine specimens provided. Initial analyses indicated that this score yielded clearer results than a score derived by including missed or refused specimens as opiate-positive specimens. Baseline opiate use was intended as a covariate. Since there was significant interaction of baseline opiate use and treatment group F(1,47) = 9.62, p < .Ol in a multiple regression with hierarchical inclusion, regressing study opiate use on baseline opiate use, starting dose, treatment group and their interactions), baseline opiate use was used as an independent variable in subsequent analyses. Baseline opiate use was a significant predictor of study opiate use for Group 1, r(26) = 0.86, p < .OOl, but not for Group 2 (r(22) = 0.06, ns.) There was no interaction of starting dose and treatment group. To test the main hypothesis that the dose-increment group would reduce opiate use during the study more than the stable-dose group, a repeated measures analysis of covariance (ANCOVA) was conducted. The covariate was starting dose and the two time periods were the 14 baseline weeks (baseline opiate use) and the 14 study weeks (study opiate use). There was a significant main effect for the repeated measure, F(1,50) = 4.40, p c .05, with study opiate use being less frequent than baseline opiate use. The overall proportion of opiate-positive specimens for both groups together decrease from a mean of 30.9% during baseline to a mean of 24.7% during the study. (When each group was examined individually, the stable-dose group had a marked decrease, from 28.1% to 17.2%, while the dose-increment group had virtually no decrease, 33.3% to 31.1%.) There were no other significant effects. ANCOVA results are shown in Table 2. These findings do not support the hypothesis that subjects who receive dose increments would have a lower rate of opiate use than stable-dose subjects. Mood, affect, and symptoms POMS. Scores on each of the six POMS scales were analyzed in a two-way repeated measures analysis of covariance to test the score differences between groups for significance and to examine whether there were changes over time. Group and time were the independent variables. The time periods were baseline, weeks 1-2, weeks 3-6, and weeks 7-10. Starting dose was the covariate. There was a significant interaction of treatment group and repeated measure for four of the six POMS scales: Tension, Depression, Anger, and Fatigue. These results are summarized in Table 3. The results indicate that Group 1 scores declined over time while Group 2 remained stable. Post hoc t-tests were conducted on the four POMS scales that yielded significant interactions of treatment and time. The t-tests show that for each of these scales, Group 1 Table 2.
Illicit opiate
Source Covariate: Starting Dose Treatment Group (G) Error Repeated Measure (R) RxG Error ‘p < .05
use during
baseline
and study periods:
results
of repeated
measures
ANCOVA
ss
df
MS
F
,135 ,066 6.316 .111 ,050 1.266
1 1 49
.135 ,066 ,129 .lll .050 ,025
1.04 1 .o
I 1 50
4.40’ 1.98
62
BARBARA
Table 3.
POMS
Scale
Tension (T) Depression (D) Anger (A) Vigor (V) Fatigue (F) Confusion (C)
Starting F 1.02 < 1 <1
POMS
Dose
df 1,44 1,44 1,44 1,44 1,44 1,44
E. HAVASSY
scales scores:
and
JEANNE
results of repeated
Treatment Group (G) F df 3.33* 4.20** 3.551 1.76 1.69 3.53*
M. TSCHANN
1,44 1,44 1,44 1.44 I,44
I,44
measures
ANCOVA.
Repeated Measure (R) F df 4.31*** 3.19”
1.03 2.68** <1 <1
3,135 3,135 3,135 3,135 3,135 3,135
Interaction: RxG F 2.90** 2.80** 4.62*** < 1 3.41** 1.16
df 3,135 3,135 3,135 3,135 3,135 3,135
‘p < .I0 l*p < .05 ***p < .Ol
has significantly
higher scores at baseline than Group 2 (Tension:
t(43) = 3.58,
p < .OOl; Depression: t(43) = 3.25,~ < .003; Anger: t(39) = 3.95,~ < .OOl; Fatigue: f(45) = 3.06, p < .004). For the Anger and Fatigue scales, the two groups were not
significantly different at any other time period. On the Tension and Depression scales, however, the groups were also significantly different at weeks 1-2, when Group 1 was receiving dose increments. At this time Group 1 was again at a significantly higher level than was Group2 (Tension: t(44) = 1.94,~ < .06; Depression: t(43) = 2.17,~ < .04). The POMS data were also compared to scores generated by normative samples. The mean scores of both groups of subjects fell within “normal” ranges when compared to POMS normative samples of male outpatients (n = 350), female outpatients (n = 650), male college students (n = 350), and female college students (n = 516). The upper graph in Figure 1 shows the POMS profiles of Group 1 at baseline and at weeks 7-10 along with those of two norming groups. The lower graph similarly shows the Group 2 profiles. Examination of these profiles indicates that at baseline the Group 1 profile most closely resembles that of the “psychiatric” samples and the Group 2 profile most closely resembles the “no treatment” or “normal” samples. At weeks 7-10, Group 1 scores have declined so that their profile resembles that of the “normals” and of Group 2. Group 2 shows little change over time. The results lend support to the hypothesis that dose-increment subjects would report a positive change in mood states after receiving a dose increment. Symptom Questionnaire. The 31 items on the Symptom Questionnaire were factor analyzed using an oblique rotation. The four factors obtained accounted for 75% of the variance. The items loading L .38 on each factor were standardized and summed to create four composite variables: Major Withdrawal Symptoms; Secondary Withdrawal Symptoms; General Opiate Effects; and Methadone-specific Effects. A series of two-way repeated measures ANCOVAs were conducted, one for each symptom composite variable as the dependent variable. Group and time were the independent variables, time periods were the same as for the POMS analyses. Starting dose was employed as the covariate. There were significant main effects of treatment group on Major Withdrawal Symptoms (F(1,45) = 6.17, p < .005) and of the repeated measure (F(3,138) = 6.17, p < .0006) but the interaction only approached significance (F(3,138) = 2.34, p < .08). The main effects indicate that the dose-increment group reported more withdrawal symptoms overall and that both groups reported a decreased number of major withdrawal symptoms over time. For Secondary Withdrawal Symptoms, there was a significant interaction of treatment group and the repeated measure (F(3,138) = 2.83,
Chronic
heroin
use during
methadone
POMS FACTOR SCALES: M
treatment
GROUP
63
1
30
E A N S C
25
20
A L
15
E S
10
C 0 R
5
E S
0 -l-
I
I
T
0
A
V
POMS FACTOR SCALES: M
N S C
C
GROUP 2
30
E A
F
r-l
25
20
A
A L
15
E S
10
C 0 R
5
E S
0
I T
D
A
V
I
I
F
C
Fig. I. Comparison of study groups’ POMS profiles to patients needing psychotherapy (n = 358), and normal college males (n = 350). T = Tension, D = Depression, A = Anger, V = Vigor, F = Fatigue, C = Confusion. Legend: Patients needing psychotherapy (POMS normative sample) 0 A Group I, baseline A Group 1, weeks 7-10 0 Group 2, baseline l Group 2, weeks 7-10 College males (POMS normative sample) +
64
BARBARA
E. HAVASSY
and JEANNE M. TSCHANN
p < .05). The interaction
indicates that the dose-increment group reported more secondary withdrawal symptoms, but that their complaints decreased over time. Nevertheless, at each time period the dose-increment group complained of significantly more secondary withdrawal symptoms than did the stable-dose group (baseline: t(41) = 4.73, p < .OOl; weeks l-2: t(45) = 3.88,~ < .OOl; weeks 3-6: t(46) = 2.61,~ < .02; weeks 7-10: t(46) = 2.81, p < .04). The stable-dose group had a relatively low rate of complaints that did not change over time. There was a significant main effect of the repeated measure on General Opiate Effects, F(3,138) = 6.20, p < .0006, with both groups reporting fewer effects of opiate use over time. There was a nearly significant main effect of treatment group on Methadone-specific Effects, F( 1,450) = 3.17, p < .09, with the stable-dose group reporting more of methadone effects than the dose-increment group.
Treatment acceptability All 54 subjects completed at least 5 weeks of study participation, but 19 did not complete all 14 weeks. Group 1 remained in the study somewhat longer than Group 2: Group 1 mean = 12.7 weeks of participation, Group 2 mean = 11.2 weeks. This difference only approached significance (t(39) = 1.78, p < .08). When the reasons for study attrition were examined, they were found to be unrelated to study participation. DISCUSSION
The study results were that the group receiving a dosage increment (clients of Program 1) did not decrease illicit opiate abuse as hypothesized, but did show decreasing levels of psychological and physical complaints as hypothesized. The stable-dose group (clients of Program 2) decreased their rate of illicit opiate abuse and reported little physical or psychological distress at baseline and throughout the study period. It is important to note here that despite apparent similarities between programs in rules and regulations, it became evident that the two programs were quite different in actual practices. Program 1 was less strict in enforcing drug abuse rules than was Program 2. In Program 1, continued opiate use had uncertain consequences for clients. In Program 2, clients had ample evidence that continued opiate abuse would result in involuntary detoxification from methadone and treatment termination. No reduction in rate of illicit opiate use In considering causes for the failure to observe a decrease in rate of opiate abuse of subjects receiving increased methadone dose, two are most compelling. First is that though the increases in dose were substantial (50-100% increase over baseline), they may not have been enough, or for a sufficiently long time period. In the early days of methadone maintenance, doses of 160 mg or more were common (Goldstein & Judson, 1973; McGlothlin & Anglin, 1981). Such higher doses may be necessary to achieve the hypothesized blockade effect (Dole & Nyswander, 1965). Second, we think that the evidence points to the importance of program practices. That is, methadone dosage level alone cannot explain opiate abuse, even for this subgroup of maintenance clients. Rather, program practices also have a strong effect on illicit opiate use. This interpretation is supported by our finding that the abuse rate of stable-dose subjects during the study was significantly less than their baseline abuse rate, while the abuse rate of dose-increment subjects did not change. Since it was observed that the two treatment programs were not equally stringent or consistent about requiring clients to reduce or discontinue illicit opiate use, it is likely that stable-dose subjects were motivated to decrease opiate abuse by the threat of detoxification, and that dose-increment subjects were not.
Chronic
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65
Improvement in physical and psychological state The report of mood improvement and decreased symptom complaints by doseincrement subjects again forces consideration that these subjects needed the increased methadone dosage. Another explanation is that they deliberately manipulated the baselines on the Symptom Questionnaire and the POMS in an attempt to achieve a particular end. That is, they reported feeling badly in order to ensure a dosage increment, and once the increment was received, they reverted to “normal” levels. We consider the first explanation most likely: that the increased dosage of the intervention caused the observed improvement in perceived psychological and physical states. To “fake bad” on the POMS is not easy, and the POMS and the Symptom Questionnaire showed very similar patterns of improvement over time. More importantly, the total six-scale POMS profile for the dose-increment group at baseline approximates that for groups with various levels of psychiatric involvement. By weeks 7-10, the profile is changed and approximates profiles of groups not requiring psychiatric treatment. It is not likely that subjects could have “faked” such changes in profiles. The results of this study illustrate how treatment interventions do not occur in a vacuum but in complex, complicated, social environments. Aspects of programs not seemingly involved can attenuate or enhance treatment effects. Based on our findings and observations, we suggest that clients who present the problem of continued heroin use after apparent stabilization on methadone need at the minimum the following interventions: (a) substantial increase in dose for a period of longer than 3 months, (b) a clear understanding that they are in violation of program policies and of the consequences of continued heroin use, and (c) consistent enforcement of these policies. REFERENCES G., & Kuhn, K. Dose-related responses to methadone: Reduction of maintenance dose. Proceedings of the Fifth National Conference on Methadone Treatment, 1973, New York: NAPAN, 2, 972-9. Campbell, D., & Stanley, J. Experimental and quasi-experimental designs for research. Chicago: Rand Berry,
McNally, 1963. Chambers, C.D., &Taylor, W.J. The incidence and patterns of drug abuse during maintenance therapy. In C. Chambers & L. Brill (Eds.) Methadone: Experience and issues. New York: Behavioral Publications, 1973. Dole, V., & Nyswander, M.E. A medical treatment for diacetylmorphine (heroin) addiction: A clinical trial with methadone hydrochloride. Journal of the American Medical Association, 1965, 193, 80-3. Garbutt, G.D., &Goldstein, A. Blind comparison of three methadone maintenance dosages in 180 patients. Proceedings of the Fourth National Conference on Methadone Treatment, 1972, New York: NAPAN, 41 l-4. Goldstein, A., & Judson, B. Efficacy and side effects of three widely different methadone doses. Proceedings of the Fifth National Conference on Methadone Treatment, 1973, New York: NAPAN, 1, 21-44. Goldstein, A., & Judson, B. Three critical issues in the management of methadone programs. In P. Bourne (Ed.) Addiction. New York: Academic Press, 1974. Jaffe, J. Methadone maintenance: Variation in outcome criteria as a function of dose. Proceedings of Third National Conference on Methadone Maintenance, 1971, Washington, D.C.: USPHS, 37-44. Langley, M., Norris, B., & Parker, L. Methadone dosage levels, positive urine tests and length of time in a methadone treatment program. Proceedings of the Fifth National Conference on Methadone Treatment, 1973, New York: NAPAN, 2, 963-71. Ling, W., Charuvastra, C., Kaim, S., & Klett, C.J. Methadyl acetate and methadone as maintenance treatments for heroin addicts. Archives of General Psychiatry, 1976, 33, 709-20. McGlothlin, W.H., & Anglin, D. Long-term follow-up of clients of high- and low-dose methadone programs. Archives of General Psychiatry, 1981, 38, 1055-63. McNair, D.M., Lorr, M., & Droppleman, L.F. Profile of Mood States. San Diego: Educational and lndustrial Testing Service, 1971. Stitzer, M., Bigelow, G., & Liebson, I. Reducing drug use among methadone maintenance clients: Contingent reinforcement for morphine-free urines. Addictive Behaviors, 1980, 5, 333-40. Wieland, W.F., & Moffett, A.D. Results of low dosage methadone treatment. Proceedings of Third National Conference on Methadone Treatment, 1970, Washington, D.C.: USPHS, 48-9.
1984 Copyright
0306-4603/84 $3.00 + .OO D 1984 Pergamon Press Ltd
CHRONIC HEROIN USE DURING METHADONE TREATMENT: A TEST OF THE EFFICACY OF HIGH MAINTENANCE DOSES BARBARA
E. HAVASSY
University of California, San Francisco School of Medicine, Department of Psychiatry and
JEANNE
M. TSCHANN
University of California, Santa Cruz Department of Psychology Abstract-A pilot study was conducted at two maintenance programs to test the effect of increasing the methadone dose of clients who continue chronic heroin use after stabilization on methadone. Program 1 subjects (Group 1) received substantial dose increases for a 14-week period; Program 2 subjects (Group 2) received no dose modifications during the same period. Results show Group 1 reported an alleviation of physical and psychological complaints but did not decrease illicit opiate use. Group 2 maintained the low level of complaints reported at baseline and, unexpectedly, decreased opiate abuse. Because the two maintenance programs differed in clinical practices and in enforcement of rules, it was concluded that clients who continue chronic heroin use need not only long-term dosage increases, but also clear, consistently applied program policies.
A major concern in maintenance treatment is that considerable numbers of clients who are apparently stabilized on methadone continue to use heroin frequently, as evidenced by the results of weekly urinalyses. Treatment staff initiate a variety of strategies in response to these clients and question the appropriate course of treatment. A common strategy employed in these circumstances is a dose adjustment. In some cases the dose is increased, based on the concept of heroin blockade (Dole & Nyswander, 1965). In other cases, the dose is decreased, often for psychological rather than pharmacological effects. Alternative strategies often involve psychological manipulations in which the relationship between client and staff is altered. A final strategy, though not a solution, is to involuntarily detoxify and terminate the client from treatment. There is little research directed at this particular group of “problem” clients, and none of this research directly addresses the dosage question for this group. A small study by Stitzer, Bigelow and Liebson (1980) focused exclusively on maintenance clients who were continuing heroin users, but did not pose the question of inadequate dosage and did not employ dosage manipulation as the intervention. Instead, contingency management was utilized as the intervention. Seven subjects, black male chronic heroin users, received reinforcement contingent upon providing morphine-free urines during randomly selected weeks. Five of the seven showed marked reductions during contingent reinforcement weeks as compared to pre-study weeks. Overall, the rate of morphinepositive samples was less during contingent weeks than in pre-study weeks (p < .Ol). These results are suggestive of possible interventions; however, they are limited due to This research was supported by a grant from the National Institute on Drug Abuse, #DA 01936. The authors wish to thank Sharon M. Hall, for reading an earlier draft of this paper. Address reprint requests to Barbara Havassy, University of California Psychiatry Service, 1001 Potrero Avenue, 7M, San Francisco, CA 94110. 57
58
BARBARA
E. HAVASSY
and
JEANNE
M. TSCHANN
small sample size and the fact that the reinforcer most frequently chosen was a $15 payment per opiate-free urine specimen-a practice not easily incorporated into the procedures of many maintenance programs. Research that compares the effectiveness of different dose levels with regard to certain outcome criteria (Berry & Kuhn, 1973; Garbutt & Goldstein, 1972; Goldstein & Judson, 1973, 1974) has not taken into account the continuing heroin user. In these studies heroin use was a measure of outcome rather than a criterion for subject selection, so that the extent to which the results (i.e., large differences in dosage yield little or no differences in outcomes) can be generalized to clients with a continuing heroin use problem is not known. Another limitation of these dosage level studies, for our purposes, is that they are fixed dose level studies. There is no provision in these studies for comparing outcomes of the same subjects at different dosages. Thus it is not possible to know whether subjects who used opiates while maintained on 30 mg methadone would have also used them when maintained on 50 or 100 mg. Evidence that higher doses might be more effective or have greater therapeutic value comes from the Veterans Administration methadyl acetate (LAAM) study (Ling, Charuvastra, Kiam, & Klett, 1976) which compared heroin addicts given 50 or 100 mg methadone daily or 80 mg of LAAM three times a week. There were significant differences between the 50 and 100 mg methadone groups: the 50 mg group had significantly higher frequency of complaints of aching bones and joints and of insomnia than the 100 mg group, and also had significantly greater heroin use than the 100 mg group. Additional evidence that higher methadone doses are more efficacious than lower ones may be found in Berry and Kuhn (1973); Chambers and Taylor (1973); Garbutt and Goldstein (1972); Goldstein and Judson (1973, 1974); Jaffe (197 1); Langley, Norris, and Parker (1973); McGlothlin and Anglin (1981); Wieland and Moffett (1970). The Langley et al. (1973) data indicate clients at higher doses provided fewer drugpositive urines. In a (six-to-seven year) follow-up study McGlothlin and Anglin (1981) found longer retention and lower rates of opiate abuse among clients from programs with higher doses and flexible termination policies, compared with clients from a program with low doses and a strict termination policy. This pilot study addressed the issue of whether continued heroin use observed in maintenance clients who are stabilized on methadone is a dosage related phenomenon. The target group was composed of clients who continued to use heroin to the extent that they were about to be terminated from treatment. We hypothesized that subjects who received a substantial dose increment would reduce the frequency of their use of illicit opiates more than subjects whose dose was not incremented. We also hypothesized that subjects who received dose increments would complain of fewer symptoms and report better mood and affect than subjects whose dose was not incremented. METHODS
Design This pilot study was designed as a two treatment double-blind random assignment study at three methadone maintenance clinics, two administered by one program and one by another program. One treatment was dosage increments, the other was stable dosage. At the initiation of recruitment in each program, substantial resistance to random assignment was manifested. Resistance came from the staff of one program (who opposed dosage increments) and from the director of the other program (who valued dosage increments and opposed random assignment). These circumstances forced abandonment of random assignment and the adoption
Chronic
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treatment
of a quasi-experimental design, the non-equivalent control group (see Campbell & Stanley, 1963). In this design each program had only one of the treatments implemented: subjects from Program 1 received the dosage increment and subjects from Program 2 received stable dosage. Clin its
Potential subjects were identified from the client population of the three San Francisco clinics. The three clinics are similar in many ways, including the size of the client populations, client characteristics, and in policies regarding continued drug abuse. Clients readily transfer between programs and clinics. Sample
The sample consisted of 31 men (57%) and 23 women (43%). Their average age was 33 years. The majority were presently not married (44% never married, 32% divorced or separated, 19% presently married). The sample had a mean of 5.7 previous treatment attempts. Additional descriptive data may be found in Table 1. Procedures
Clients who were identified as potential subjects were approached at their clinic by research staff who explained the study and requested participation. Clients who agreed provided informed consent and completed the Profile of Mood States (POMS) and the Symptom Questionnaire (description follows) to provide baseline information. Thereafter, subjects completed the two questionnaires on a weekly basis for the duration of the study. Subjects completed the questionnaires on the same day each week, immediately before or after receiving their doses. All aspects of subjects’ treatment (i.e., medical, legal, and program) during their study participation were monitored by research staff. Treatments. Subjects in Program 1 (n = 29) had their dose increased over a 2-week period at the rate of 10 mg or less every three days. They remained at the elevated doses for the next 12 weeks. The schedule for increasing doses was based on baseline methadone dose and varied from a 100% increase for subjects at 20 mg/day at baseline to a 50% increase for subjects at 80 mg/day at baseline. These subjects’ urines were collected as usual, but there were no consequences during the study for providing specimens containing opiates or for failing to provide specimens. Results of urinalyses were reviewed by clinic staff at the end of the study, however, and were used in deciding whether involuntary detoxification would proceed. All of this was explained to subjects. Table
1.
Some demographic and treatment characteristics and treatment program clients.
Percent Male Ethnicity % Caucasian Vo Black % Latin Percent Employed (full or part) Time in Treatment Episode (median) Mean Mg Methadone Percent Opiate-Positive in 90 Days
of the study subjects
Sample (n = 54)
Program I (n = 413)
Program 2 (n = 188)
57
62
76
76 6 15 26 8 mos 62 30.3
63 13 8 40 24 mos 60 6
65 10 16 63 13 mos 48 9
BARBARA
60
Subjects the study treatment resources urinalysis group.
E. HAVASSY
and
JEANNE
M. TSCHANN
in Program 2 (n = 25) were not given any dose changes for the 14 weeks of but did receive a 14-week moratorium on involuntary detoxification and termination. These subjects were encouraged to utilize program and other available to them to assist them to avoid or decrease heroin use. The use of results was the same for the stable-dose group as for the dose-increment
Measures Subjects’ urinalysis results, methadone dosage, and demographic data were collected as described. Subjects completed two questionnaires, the Profile of Mood States (POMS) and the Symptom Questionnaire.
Urinalyses. Urine specimens were routinely collected by the clinics on a random schedule. Specimens were analyzed by means of thin-layer chromatography, with confirmations for drug-positive specimens. Urinalysis results were collected on subjects for 14 weeks before the study (the baseline period), and for each of the 14 weeks during the study (the study period). There were two urine scores calculated for each subject: one, a baseline period score; the other, a study period score. Each urine score reflected only the proportion of opiate-positive specimens provided. It did not take missed or refused specimens into account. Dose. Subjects’ study participation
methadone dosage began (study-start
level was recorded daily, from the day before dose) and throughout the study.
Demographic data. Program entry information was collected from the Client Oriented Data Acquisition Process (CODAP) forms. Client information at study-start, such as employment status, was obtained from counselling records. Profile of Mood States (McNair, Lorr & Droppleman, 1971). This self-administered instrument consists of 65 5-point items describing mood that constitute six subscales: tension-anxiety, depression-dejection, anger-hostility, vigor-activity, fatigue-inertia, and confusion-bewilderment. Internal consistency has been shown to be high (r = .84 to .95). Tests for validity, including the administration of psychoactive drugs, have been positive. In the present study, subjects were asked to report their mood states “today.” Symptom Questionnaire. Developed by the authors for use in this study, this questionnaire contains 31 4-point items to assess withdrawal and over-sedation symptoms, some of which are attributable to the class “opiates,” and others of which are commonly attributed to methadone alone. Also included are several items to assess general health states. Subjects were asked to report how they felt “ rday.” RESULTS
Demographic characteristics The two treatment groups were first tested for major demographic and program differences. The chi squares for sex, ethnicity, marital status and employment status were non-significant. The t-tests on age were also non-significant (Group 1 mean = 29 yrs.; Group 2 mean = 33 yrs.); number of prior admissions to any drug treatment (Group 1 mean = 6.1; Group 2 mean = 5.2); months in treatment (Group 1 mean = 10.5 mos.; Group 2 mean = 16.4 mos.) and baseline opiate use (Group 1 mean = 33%; Group 2 mean = 28% opiate positive in 90 days). The t-test on starting dose was significant at p < .001; t(52) = 3.87, Group 1 mean = 70 mg; Group 2 = 52 mg).
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Illicit opiate use All of the results reported in this section employ urine scores reflecting opiate-positive specimens as percent of urine specimens provided. Initial analyses indicated that this score yielded clearer results than a score derived by including missed or refused specimens as opiate-positive specimens. Baseline opiate use was intended as a covariate. Since there was significant interaction of baseline opiate use and treatment group F(1,47) = 9.62, p < .Ol in a multiple regression with hierarchical inclusion, regressing study opiate use on baseline opiate use, starting dose, treatment group and their interactions), baseline opiate use was used as an independent variable in subsequent analyses. Baseline opiate use was a significant predictor of study opiate use for Group 1, r(26) = 0.86, p < .OOl, but not for Group 2 (r(22) = 0.06, ns.) There was no interaction of starting dose and treatment group. To test the main hypothesis that the dose-increment group would reduce opiate use during the study more than the stable-dose group, a repeated measures analysis of covariance (ANCOVA) was conducted. The covariate was starting dose and the two time periods were the 14 baseline weeks (baseline opiate use) and the 14 study weeks (study opiate use). There was a significant main effect for the repeated measure, F(1,50) = 4.40, p c .05, with study opiate use being less frequent than baseline opiate use. The overall proportion of opiate-positive specimens for both groups together decrease from a mean of 30.9% during baseline to a mean of 24.7% during the study. (When each group was examined individually, the stable-dose group had a marked decrease, from 28.1% to 17.2%, while the dose-increment group had virtually no decrease, 33.3% to 31.1%.) There were no other significant effects. ANCOVA results are shown in Table 2. These findings do not support the hypothesis that subjects who receive dose increments would have a lower rate of opiate use than stable-dose subjects. Mood, affect, and symptoms POMS. Scores on each of the six POMS scales were analyzed in a two-way repeated measures analysis of covariance to test the score differences between groups for significance and to examine whether there were changes over time. Group and time were the independent variables. The time periods were baseline, weeks 1-2, weeks 3-6, and weeks 7-10. Starting dose was the covariate. There was a significant interaction of treatment group and repeated measure for four of the six POMS scales: Tension, Depression, Anger, and Fatigue. These results are summarized in Table 3. The results indicate that Group 1 scores declined over time while Group 2 remained stable. Post hoc t-tests were conducted on the four POMS scales that yielded significant interactions of treatment and time. The t-tests show that for each of these scales, Group 1 Table 2.
Illicit opiate
Source Covariate: Starting Dose Treatment Group (G) Error Repeated Measure (R) RxG Error ‘p < .05
use during
baseline
and study periods:
results
of repeated
measures
ANCOVA
ss
df
MS
F
,135 ,066 6.316 .111 ,050 1.266
1 1 49
.135 ,066 ,129 .lll .050 ,025
1.04 1 .o
I 1 50
4.40’ 1.98
62
BARBARA
Table 3.
POMS
Scale
Tension (T) Depression (D) Anger (A) Vigor (V) Fatigue (F) Confusion (C)
Starting F 1.02 < 1 <1
POMS
Dose
df 1,44 1,44 1,44 1,44 1,44 1,44
E. HAVASSY
scales scores:
and
JEANNE
results of repeated
Treatment Group (G) F df 3.33* 4.20** 3.551 1.76 1.69 3.53*
M. TSCHANN
1,44 1,44 1,44 1.44 I,44
I,44
measures
ANCOVA.
Repeated Measure (R) F df 4.31*** 3.19”
1.03 2.68** <1 <1
3,135 3,135 3,135 3,135 3,135 3,135
Interaction: RxG F 2.90** 2.80** 4.62*** < 1 3.41** 1.16
df 3,135 3,135 3,135 3,135 3,135 3,135
‘p < .I0 l*p < .05 ***p < .Ol
has significantly
higher scores at baseline than Group 2 (Tension:
t(43) = 3.58,
p < .OOl; Depression: t(43) = 3.25,~ < .003; Anger: t(39) = 3.95,~ < .OOl; Fatigue: f(45) = 3.06, p < .004). For the Anger and Fatigue scales, the two groups were not
significantly different at any other time period. On the Tension and Depression scales, however, the groups were also significantly different at weeks 1-2, when Group 1 was receiving dose increments. At this time Group 1 was again at a significantly higher level than was Group2 (Tension: t(44) = 1.94,~ < .06; Depression: t(43) = 2.17,~ < .04). The POMS data were also compared to scores generated by normative samples. The mean scores of both groups of subjects fell within “normal” ranges when compared to POMS normative samples of male outpatients (n = 350), female outpatients (n = 650), male college students (n = 350), and female college students (n = 516). The upper graph in Figure 1 shows the POMS profiles of Group 1 at baseline and at weeks 7-10 along with those of two norming groups. The lower graph similarly shows the Group 2 profiles. Examination of these profiles indicates that at baseline the Group 1 profile most closely resembles that of the “psychiatric” samples and the Group 2 profile most closely resembles the “no treatment” or “normal” samples. At weeks 7-10, Group 1 scores have declined so that their profile resembles that of the “normals” and of Group 2. Group 2 shows little change over time. The results lend support to the hypothesis that dose-increment subjects would report a positive change in mood states after receiving a dose increment. Symptom Questionnaire. The 31 items on the Symptom Questionnaire were factor analyzed using an oblique rotation. The four factors obtained accounted for 75% of the variance. The items loading L .38 on each factor were standardized and summed to create four composite variables: Major Withdrawal Symptoms; Secondary Withdrawal Symptoms; General Opiate Effects; and Methadone-specific Effects. A series of two-way repeated measures ANCOVAs were conducted, one for each symptom composite variable as the dependent variable. Group and time were the independent variables, time periods were the same as for the POMS analyses. Starting dose was employed as the covariate. There were significant main effects of treatment group on Major Withdrawal Symptoms (F(1,45) = 6.17, p < .005) and of the repeated measure (F(3,138) = 6.17, p < .0006) but the interaction only approached significance (F(3,138) = 2.34, p < .08). The main effects indicate that the dose-increment group reported more withdrawal symptoms overall and that both groups reported a decreased number of major withdrawal symptoms over time. For Secondary Withdrawal Symptoms, there was a significant interaction of treatment group and the repeated measure (F(3,138) = 2.83,
Chronic
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POMS FACTOR SCALES: M
treatment
GROUP
63
1
30
E A N S C
25
20
A L
15
E S
10
C 0 R
5
E S
0 -l-
I
I
T
0
A
V
POMS FACTOR SCALES: M
N S C
C
GROUP 2
30
E A
F
r-l
25
20
A
A L
15
E S
10
C 0 R
5
E S
0
I T
D
A
V
I
I
F
C
Fig. I. Comparison of study groups’ POMS profiles to patients needing psychotherapy (n = 358), and normal college males (n = 350). T = Tension, D = Depression, A = Anger, V = Vigor, F = Fatigue, C = Confusion. Legend: Patients needing psychotherapy (POMS normative sample) 0 A Group I, baseline A Group 1, weeks 7-10 0 Group 2, baseline l Group 2, weeks 7-10 College males (POMS normative sample) +
64
BARBARA
E. HAVASSY
and JEANNE M. TSCHANN
p < .05). The interaction
indicates that the dose-increment group reported more secondary withdrawal symptoms, but that their complaints decreased over time. Nevertheless, at each time period the dose-increment group complained of significantly more secondary withdrawal symptoms than did the stable-dose group (baseline: t(41) = 4.73, p < .OOl; weeks l-2: t(45) = 3.88,~ < .OOl; weeks 3-6: t(46) = 2.61,~ < .02; weeks 7-10: t(46) = 2.81, p < .04). The stable-dose group had a relatively low rate of complaints that did not change over time. There was a significant main effect of the repeated measure on General Opiate Effects, F(3,138) = 6.20, p < .0006, with both groups reporting fewer effects of opiate use over time. There was a nearly significant main effect of treatment group on Methadone-specific Effects, F( 1,450) = 3.17, p < .09, with the stable-dose group reporting more of methadone effects than the dose-increment group.
Treatment acceptability All 54 subjects completed at least 5 weeks of study participation, but 19 did not complete all 14 weeks. Group 1 remained in the study somewhat longer than Group 2: Group 1 mean = 12.7 weeks of participation, Group 2 mean = 11.2 weeks. This difference only approached significance (t(39) = 1.78, p < .08). When the reasons for study attrition were examined, they were found to be unrelated to study participation. DISCUSSION
The study results were that the group receiving a dosage increment (clients of Program 1) did not decrease illicit opiate abuse as hypothesized, but did show decreasing levels of psychological and physical complaints as hypothesized. The stable-dose group (clients of Program 2) decreased their rate of illicit opiate abuse and reported little physical or psychological distress at baseline and throughout the study period. It is important to note here that despite apparent similarities between programs in rules and regulations, it became evident that the two programs were quite different in actual practices. Program 1 was less strict in enforcing drug abuse rules than was Program 2. In Program 1, continued opiate use had uncertain consequences for clients. In Program 2, clients had ample evidence that continued opiate abuse would result in involuntary detoxification from methadone and treatment termination. No reduction in rate of illicit opiate use In considering causes for the failure to observe a decrease in rate of opiate abuse of subjects receiving increased methadone dose, two are most compelling. First is that though the increases in dose were substantial (50-100% increase over baseline), they may not have been enough, or for a sufficiently long time period. In the early days of methadone maintenance, doses of 160 mg or more were common (Goldstein & Judson, 1973; McGlothlin & Anglin, 1981). Such higher doses may be necessary to achieve the hypothesized blockade effect (Dole & Nyswander, 1965). Second, we think that the evidence points to the importance of program practices. That is, methadone dosage level alone cannot explain opiate abuse, even for this subgroup of maintenance clients. Rather, program practices also have a strong effect on illicit opiate use. This interpretation is supported by our finding that the abuse rate of stable-dose subjects during the study was significantly less than their baseline abuse rate, while the abuse rate of dose-increment subjects did not change. Since it was observed that the two treatment programs were not equally stringent or consistent about requiring clients to reduce or discontinue illicit opiate use, it is likely that stable-dose subjects were motivated to decrease opiate abuse by the threat of detoxification, and that dose-increment subjects were not.
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65
Improvement in physical and psychological state The report of mood improvement and decreased symptom complaints by doseincrement subjects again forces consideration that these subjects needed the increased methadone dosage. Another explanation is that they deliberately manipulated the baselines on the Symptom Questionnaire and the POMS in an attempt to achieve a particular end. That is, they reported feeling badly in order to ensure a dosage increment, and once the increment was received, they reverted to “normal” levels. We consider the first explanation most likely: that the increased dosage of the intervention caused the observed improvement in perceived psychological and physical states. To “fake bad” on the POMS is not easy, and the POMS and the Symptom Questionnaire showed very similar patterns of improvement over time. More importantly, the total six-scale POMS profile for the dose-increment group at baseline approximates that for groups with various levels of psychiatric involvement. By weeks 7-10, the profile is changed and approximates profiles of groups not requiring psychiatric treatment. It is not likely that subjects could have “faked” such changes in profiles. The results of this study illustrate how treatment interventions do not occur in a vacuum but in complex, complicated, social environments. Aspects of programs not seemingly involved can attenuate or enhance treatment effects. Based on our findings and observations, we suggest that clients who present the problem of continued heroin use after apparent stabilization on methadone need at the minimum the following interventions: (a) substantial increase in dose for a period of longer than 3 months, (b) a clear understanding that they are in violation of program policies and of the consequences of continued heroin use, and (c) consistent enforcement of these policies. REFERENCES G., & Kuhn, K. Dose-related responses to methadone: Reduction of maintenance dose. Proceedings of the Fifth National Conference on Methadone Treatment, 1973, New York: NAPAN, 2, 972-9. Campbell, D., & Stanley, J. Experimental and quasi-experimental designs for research. Chicago: Rand Berry,
McNally, 1963. Chambers, C.D., &Taylor, W.J. The incidence and patterns of drug abuse during maintenance therapy. In C. Chambers & L. Brill (Eds.) Methadone: Experience and issues. New York: Behavioral Publications, 1973. Dole, V., & Nyswander, M.E. A medical treatment for diacetylmorphine (heroin) addiction: A clinical trial with methadone hydrochloride. Journal of the American Medical Association, 1965, 193, 80-3. Garbutt, G.D., &Goldstein, A. Blind comparison of three methadone maintenance dosages in 180 patients. Proceedings of the Fourth National Conference on Methadone Treatment, 1972, New York: NAPAN, 41 l-4. Goldstein, A., & Judson, B. Efficacy and side effects of three widely different methadone doses. Proceedings of the Fifth National Conference on Methadone Treatment, 1973, New York: NAPAN, 1, 21-44. Goldstein, A., & Judson, B. Three critical issues in the management of methadone programs. In P. Bourne (Ed.) Addiction. New York: Academic Press, 1974. Jaffe, J. Methadone maintenance: Variation in outcome criteria as a function of dose. Proceedings of Third National Conference on Methadone Maintenance, 1971, Washington, D.C.: USPHS, 37-44. Langley, M., Norris, B., & Parker, L. Methadone dosage levels, positive urine tests and length of time in a methadone treatment program. Proceedings of the Fifth National Conference on Methadone Treatment, 1973, New York: NAPAN, 2, 963-71. Ling, W., Charuvastra, C., Kaim, S., & Klett, C.J. Methadyl acetate and methadone as maintenance treatments for heroin addicts. Archives of General Psychiatry, 1976, 33, 709-20. McGlothlin, W.H., & Anglin, D. Long-term follow-up of clients of high- and low-dose methadone programs. Archives of General Psychiatry, 1981, 38, 1055-63. McNair, D.M., Lorr, M., & Droppleman, L.F. Profile of Mood States. San Diego: Educational and lndustrial Testing Service, 1971. Stitzer, M., Bigelow, G., & Liebson, I. Reducing drug use among methadone maintenance clients: Contingent reinforcement for morphine-free urines. Addictive Behaviors, 1980, 5, 333-40. Wieland, W.F., & Moffett, A.D. Results of low dosage methadone treatment. Proceedings of Third National Conference on Methadone Treatment, 1970, Washington, D.C.: USPHS, 48-9.