Narcotic Antagonist Treatment of Addict ParoleesThe Failure of an Effective Approach

Thomas E. Hanlon, 0. Lee McCabe, Charles Savage, and Albert A. Kurland

ONTEMPORARY TREATMENT APPROACHES for the chronic narcotic abuser may be subsumed under two major models: maintenance and abstinence. Prototypes of the maintenance model are the “British system” of legalized narcotics prescription and the “American system” of daily methadone administration. Included under the abstinence model are various procedures aimed at eliminating drug-seeking behavior and, ironically, establishing the goal of treatment, i.e., abstinence, as a condition of continued participation from the very outset. Procedures used in attempts at achieving the abstinence goal range from traditional and behavior therapy to more exotic methods such as transcendental meditation. One of the more recently applied abstinence methods is the narcotic antagonist approach, the rationaleof which is anchored in learning theory/behavior modification principles implemented through the use of a chemical agent. The apparently sound theoretical basis for the application of this approach, together with promising early clinical trials, have produced not only an unusual amount of enthusiasm and activity among scientists and clinicians in the tield but also a corresponding supportive commitment from the United States Federal Government. The massive expenditures of time, effort, and money to date not withstanding, there are still unsettling questions which need to be answered before generalizations about the efficacy of available narcotic antagonists can be made. In fact, our own previous work with these substances, as well as the pioneering efforts of other investigators, have raised as many questions as they have answered. Issues which appear to be of special relevance are the following: a) What specific therapeutic actions do antagonists have when placebo and programmatic elements are controlled? b) Must antagonists be administered daily, or can they be effectively utilized on a “crisis-intervention” basis? c) Do so-called “pure” antagonists such as naloxone have any significant side effects; particularly those which might bias outcome in favor of patients not receiving active medication’? d) On the other hand, are some secondary effects remedial, i.e., might not the best antagonist be one with a slight agonistic property of its own? e) Do some types of addicts respond better to antagonist treatment than others? f) Is antagonist treatment uniformly effective over diverse outcome criteria’?

C

From the Maryland Psychiarric Research Center and rhe V:! Hospital. Baltimore. Md. Thomas E. Hanlon, Ph.D.: ChieJ’o/ Socioenvironmenral Research. and 0. Lee McCabe. Ph.D.: Chief’?/ .4ddkrions Research, Maryland Psychiatric Research C‘enier, Charles Savage, M.D.: Chiei oJ Psychiatric and Chiej’oj the Drug Dependenre Treatment L/nits. If.3 Hospital. Albert A. Kurland. M.D.: Superintendent, Maryland Psychiatric Research Center. allof Baltimore. Md. 21228. Supported by the Division of Research. National tnsfirure on Drug .4buse, NID.4 Grani D.3004IC. and the Drug .4 buse .Administration oJlheSlatt,o/‘Mar~land. Reprint requessrs should be addressed to Thomas E. Ha&on. Maryland P.yychiarric Reseawh Center, Baltimore. Md. 21228. L 1977 bv Grune & Strarron. Inc.
211

Comprehensive

Psych/atry, Vol 18, No. 3

(May/June)

1977

212

HANLON

ET AL.

Addressing itself to many of the above issues, the present study is the latest in a series of studies on the effectiveness of narcotic antagonists in the treatment of narcotic addict parolees newly released from the Maryland correctional system to a narcotic clinic in metropolitan Baltimore. It is the concluding report on the “contingent” approach to the use of antagonists in this setting, offering a summarization of all of our experiences to date. The overall program of research, which was superimposed on an ongoing abstinence program,’ started several years ago with the introduction of the promising agent, naloxone (N-allylnoroxymorphone), a pure antagonist relatively free of side effects. The scarcity and expense of naloxone at the time and the natural reluctance on the part of most parolees to take medication daily prior to the manifestation of need made the administration of naloxone contingent upon narcotic drug use seem both economical and clinically appropriate. Early clinical experiences and subsequent pilot research2-4 were encouraging enough to prompt a series of controlled clinical trials, the latest of which is herein reported.
MATERIALS
Having volunteered narcotic addicts were referred to an abstinence Upon referral,

AND METHODS’
program, 154 newly paroled male and offering clinic employing daily urine monitoring

for a six month narcotic antagonist treatment

weekly group psychotherapy. or placebo treatment

the parolees were randomly assigned to either a naloxone medication under double-blind conditions whenever

group and were administered

unexcused absences or urinalysis results were indicative of opiate drug use. Ranging from l-4 tablets per day, the equivalent of 500~2000 with continued urine specimens were obtained. each subsequent deviation. Criteria of treatment effectiveness included the number of unexcused absences, the number of opiate positive specimens, length of participation cidence of side effects, and global community for the entire 6 months. The Minnesota initially for descriptive and predictive by lack of adequate group representation, 6 month evaluation point. in the program, Personality reasons for termination, Inventory (MMPI) type and inmg of naloxone, dosage was escalated on a one tablet per day basis only after four successive negative was repeated with the six month period, this procedure evidence of opiate drug use and was discontinued Throughout

adjustment

ratings for those remaining on the program was administered at the its use as a criterion measure was curtailed

Multiphusic the MMPI

purposes. Although

was also administered

to study remainers

RESULTS Of the 154 parolees referred to the study and assigned to the two treatment conditions, 57 did not receive study medication for one reason or another and were necessarily excluded from the naloxone-placebo comparison. Thirty-three of the 57 nonmedicated parolees completed the prescribed six month abstinence program without a deviation in terms of unexcused absences or a positive urine specimen. The remaining 24 nonmedicated parolees either refused medication or absconded prior to the reception of medication. Resulting sample sizes of parolees receiving medication were 55 for naloxone and 42 for placebo. Descriptive characteristics for these parolees are presented in Table 1. Considering the total study sample of 97 parolees, the typical parolee was single, black, in his mid twenty’s, and had completed a junior high school level of education. He had experienced his first documented encounter with the law enforcement system at age 17 and was subsequently involved in an average of four more arrests, largely for drug-related reasons. The two subsamples showed no

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Table 1. Demographic

Characteristics

of the Two Subsamples
PIWhO

Naloxone
Group Charactenstxs N = 55

Group
N = 42

Mean Age Race Black White Marital Status Single Married Separated/Divorced Mean Years of Education Mean Age at First Arrest Mean Number of Arrests

266 54 1 43 7 5 92 173 52

26.0 38 4 32 6 4 90 164 5.9

substantial differences with respect to the demographic characteristics in question. The MMPI profile for the study sample was similar in most respects to that offered by Overall” as being the prototype for narcotic addicts. Its most salient feature was the 4-9 ‘code type,’ considered by Marks and Seeman to be indicative of a sociopathic-emotionally unstable personality with a high probability of drug usage or addiction, and by Gilberstadt and Duker’ as characteristic of individuals who, though superficially friendly, outgoing, and likeable, tend to be selfcentered, impulsive, and rebellious and to have a low standard of morality. The initial MMPI profiles for the two subsamples are presented in Fig. 1. Although there were no statistically significant differences between group means for any of the validity or clinical scales shown, the overall profile for the placebo group tended to have a slightly higher elevation. Completion and termination data for the two subsamples and for the total sample are presented in Table 2. The chi square value for the seemingly differential completion rate in favor of placebo noted in the table was found to be 3.27 (3.84 needed for significance at the 0.05 level for 1 df). Considering the reasons for termination, this rate must be viewed as a negative rather than a positive reflection of the pharmacological action

--

Nalorone PkWhO 100 90

Fig. 1. Initial MMPI profiles for the Naloxone (N = 43) and Placebo (N = 38) subsamples.

L F Kti5

DH~WMIP~P~SCM~S, MMPI SCALES

214

HANLON

ET AL.

Table 2. Completion

and Termination
NSlOXO”e

Data for the Total and Two Subsamples Placebo Group N = 42 23 (55%) 19 (45%) 7 (17%) 8 (19%) 1 (2%) 3 (7%) Total Sample N = 97 43 (44%) 54 (56%) 18 (19%) 24 (25%) 8 (8%) 4 (4%)

Disposition Completed Terminated Absconded Refused Further Medication Institutionalized Transferred to Maintenance

Group N = 55 20 (36%) 35 (64%) 11 (20%) 16 (29%) 7 (13%) 1 (2%)

of naloxone, including, ironically, its antagonistic effect. Data relating to the length of program participation are consistent with completion rates. The average length of participation for the naloxone group was found to be 3.7 months vs. 4.8 months for the placebo group, most of this one month differential being accounted for by the shorter participation of naloxone patients once medication was begun. Results of urine monitoring procedures, in terms of unauthorized absences and the provision of either a QNS or opiate positive urine specimen, are presented in Table 3. Since the results of such procedures prior to the reception of medication were uninfluenced by specific treatment effects, only data occurring after the initiation of treatment were examined for comparative purposes. Also, to insure meaningfulness of the information involved, only those individuals who remained in the program for at least one month after their first dosage reception were included in the analysis of results. Comprising at least 75% of their respective samples, 41 naloxone and 37 placebo subjects were thus selected. Again reflecting the relative retention rates of the two treatments, those parolees receiving placebo tended to remain longer in treatment and to attend the clinic, providing an analyzable urine specimen, at least as reliably as those receiving naloxone. They were, however, providing positive urine specimens at a significantly higher rate (the proportional difference of 0.11 vs. 0.07 significant at p < .OOl). This result was largely accounted for by eight placebo cases whose rates were above that of 39%, the highest for the naloxone group, and was consistent with earlier reported findings of the relative effects of daily administered naloxone vs. placebo.8 In view of the causal relationship involved, the amount of medication dispensed in the contingent approach can be considered as another indication of the extent of narcotic drug use, i.e., the greater amount, the greater the narcotics use. On the average, treatment for both the naloxone and placebo groups was begun shortly after one month of abstinence program participation. Although there was an
Table 3. Resultsof Urine Monitoring Procedures After the Initiation of Medication Number of Analyzable
Specimens Provided

Percentageof Unexcused Numberof
Group Days Active Absences and ONS Specimens

Percentage
of Positive Specimens

Percentageof uncooparative Days

Naloxone (N = 41) Placebo (N = 37) -

98 114

21% 22%

73 90

7% 11%

25% 27%

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average of three contingent interventions for both treatment groups, the mean number of days medication was dispensed overall was 19 days for naloxone and 25
days for placebo, with average daily dosages being 757 mg and the equivalent of 1068 mg, respectively (total mg dispensed/total days of administration). Analysis of individual dosage schedules revealed that patients administered naloxone tended to moderate their narcotic drug intake when they were placed on the maximum dosage of 2000 mg. Whereas approximately one-third of the patients in both treatment groups were administered the maximum dosage at one time or another during the course of treatment, the average number of days this dosage was utilized in the treatment of these cases was only 5 days for naloxone vs. 22 days for placebo. This result was not explainable in terms of relative absence or dropout rates since these were found to be equivalent in the two treatment groups at the 2000 mg level. Of the 43 patients completing the prescribed treatment course, data on a locally devised community adjustment scale” were available for 36 patients, or 18 from each of the two treatment groups. Consisting of an average of IO-point ratings of abstinence and occupational, residential and interpersonal adjustment, this scale was completed by a social worker after an interview with the parole agent responsible for the supervision of the addict in the community. As in earlier studies in the same setting, the mean adjustment rating for the total sample of study completers at six months was approximately 7.0, indicative of “good overall adjustment,” with at least half of the sample demonstrating either no, or only slight (“chipping”), narcotic drug use. Mean adjustment ratings for the naloxone and placebo subsamples were almost identical. Side effect information was also in agreement with past experiences with naloxone. Somatic complaints were reported for a total of 26 patients, 16 of whom were receiving naloxone and 10 placebo. Accounting for the only significant difference in terms of side effects between drug or placebo, gastrointestinal distress (nausea, vomiting, and/or upset stomach) occurred in ten naloxone cases vs. only one placebo case. Although severe untoward reactions necessitating the termination of treatment did not occur, two naloxone patients refused further medication after experiencing gastrointestinal problems and one after unelaborated complaints of sickness, and three placebo patients refused further medication after respective complaints of rash, loss of appetite, and general malaise.
DISCUSSION AND OVERVIEW

Narcotic antagonists have been used for several years in the treatment of addiction, yet rarely has their use been put to controlled test. Originally, there seemed to be a universally held assumption that except for side effects, which until the introduction of naloxone had been the antagonists’ principal drawback, there was little question as to their utility. More recently, this assumption has been challenged, both in clinical practice and in studies, such as the currently reported one, designed to isolate their pharmacological contributions beyond the mere palliative value of pill taking. For a period of time, investigative efforts centered on the search for a “pure” antagonist, i.e., one that would demonstrate little or no action of its own other

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ET AL

than the theoretically crucial opiate blocking effect. Unfortunately, it is now becoming apparent that a pure antagonist may not necessarily be the best antagonist; at least, results of controlled studies on contingently and daily administered antagonists 4*8.‘” tend to support the conclusion that with the less motivated patient, effectiveness as an antagonist often precludes satisfactory treatment outcome. There is little reason to doubt that a pure antagonist successfully blocks the euphoric and analgesic effects produced by opiates, theoretically reducing an individual’s incentive to use narcotics while medicated. Rather than inhibiting the drug-taking behavior of the typical less motivated addict, however, the principal effect of such an agent appears to be that of reinforcing avoidance of medication and indulgence in otherwise uncooperative behavior. In the present employment of contingent administration, one-half of the naloxone patients (27 of 55) either refused to continue to take medication or absconded prior to the 6-month termination point. Although obviously contributory in both instances, the relative extent to which this noncompliance was the result of the narcotic antagonistic property of naloxone or of its contingent method of administration could not be determined on the basis of available evidence. Besides the narcotic blocking effect, other deterrent influences on continued treatment involvement were undoubtedly operating in the situation. Naloxone, for example, was not exactly pleasant to take, inasmuch as one out of every five patients complained of gastrointestinal distress at one point or another during treatment. Also, because of the relatively large dosage of naloxone required to achieve blockade, the consumption of as many as four large, bitter pills by the addict parolee was at times required. Considering these aversive circumstances, an increase in termination rate would not be unexpected. Should aversive and/or artifactual effects have less bearing on the acceptance of the newer antagonist, naltrexone,” controlled studies of this agent which are currently underway will hopefully offer more specific information on the relationship between blocking effect and retention in treatment. Another matter relating to retention in the present study bears consideration. Though not statistically significant, seven of the parolees administered naloxone, as opposed to only one administered placebo, were subsequently terminated from treatment because of the commission of a new offense. (One of the naloxone cases was incarcerated on the day he was first placed on medication.) Disquieting to some extent because of its implication, this finding was not generally explainable in terms of any discernible underlying pattern of reaction to naloxone. In evaluating any addiction treatment program, retention in program, i.e., simply whether a patient remains in the program or not, is a misleading criterion without consideration of the extent of narcotic drug use. Results illustrativeof this were obtained from a recently concluded study* of the daily use of naloxone in a “partial blockade” dosage as well as from the present study. Although as a group the placebo patients in both of these controlled studies tended to remain in treatment for longer periods of time than those administered naloxone, they were, nevertheless, deviating more in terms of narcotic drug use. Interestingly, the possibility that contingent administration might in itself have therapeutic value was also illustrated. Whereas, in the earlier study, one of every two patients administered daily placebo produced positive urine specimens at least 40% of the

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ANTAGONIST

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217

time, only one of every four patients administered contingent placebo in the present study deviated to this extent. Reflecting this difference in response to daily and contingent administration, the average deviation rates for the respective placebo samples were 28% vs. 11%. Although somewhat higher with daily administration, narcotic positive rates for naloxone were less disparate under the two conditions, uniformly ranging below the 40% level and averaging less than 10%. Improved placebo effectiveness under contingent conditions was at least partially responsible for the lack of any substantial naloxone-placebo differences in the present study. Though statistically significant, the 4% differential in the 7% vs. 11% narcotic positive rates for naloxone and placebo, respectively, was principally due to the deviations of only a few of the placebo cases. It might be argued that for most patients, i.e., at least three out of four, the contingent administration of placebo was associated with relatively cooperative behavior (attending the clinic and providing a specimen at least 80% of the time) and positive outcome. Also, these patients tended to remain relatively longer in treatment over the 6 month period, and of course, experienced little or no “side effects.” Understandably, it would be difficult to convincingly demonstrate the worth of any pharmacologically active agent under such circumstances. As mentioned, 33 parolees, or slightly more than 20% of the original 154 referrals, did not demonstrate sufficiently deviant behavior during the 6-month abstinence program to require the prescription of medication. These individuals were identifiable as a group prior to program participation. Though configurally similar, their mean MMPI profile was found to be significantly lower than that for the remaining referrals on nine of the ten clinical scales examined. As further indication of the relative stability of this subgroup, their mean community adjustment rating at the 6-month evaluation point was 8.7, revealing good to excellent global adjustment. As also noted, another subgroup of initial referrals not included in the controlled study was comprised of 24 parolees who either absconded prior to the the reception of medication or refused to take medication during their participation in the abstinence program in spite of evidences of deviation. These parolees were indistinguishable in terms of pretreatment descriptive measures from those accepting medication who were thereby included in the study. On posttreatment assessment, however, the relatively unfavorable status of 12 parolees refusing medication who were available for evaluation at six months was revealed in a mean community adjustment rating of 4.2 indicative of poor overall adjustment, including fairly consistent narcotic drug use. Except for preliminary findings by Resnick and his coworkers’2 that bear replication, efforts at the prediction of treatment response in the area of drug addiction have been notoriously unrewarding. Meaningful analyses of the differences between responders and nonresponders in the present instance were precluded by the small number of successfully concluded cases. The findings of the present study relating to the effectiveness of placebo again highlight the importance of controlled research in the evaluation of any new treatment procedure. Prior to this controlled examination of the contingent use of naloxone in an ongoing abstinence program, results of pilot research conducted at

218

HANLON

ET AL.

the clinic had been especially encouraging. In this initial work, criteria of effectiveness, including clinic attendance, the extent of narcotic drug use, and final disposition at six months, were viewed in relation to already established baseline results with a sample of patients processed through the same clinic over a five year period before the introduction of antagonist treatment. Comparative findings indicated longer program involvement, less narcotic drug use, and less reinstitutionalization with contingently administered naloxone. In view of presently reported results, however, it appears likely that placebo reactivity was to a large extent responsible for these initial favorable impressions. With some individuals in the present study, there did appear to be reinforcement value in the taking of antagonist medication. Although the evidence was not overwhelming, the capacity of naloxone to attenuate the narcotic drug intake of those addict parolees remaining in the abstinence program was at least demonstrable. It was principally in terms of treatment acceptance and dispositional data that naloxone, in the dosages and contingent schedules employed, failed to demonstrate its expected potential. Considering the generally low level of motivation in the population in question, however, there is reason to doubt the utility of any presently known narcotic antagonist administered under similar conditions. Present results, therefore, do not discount the potential usefulness of naloxone in other settings or under other conditions. Granted an innumerable array of causative factors, compulsive narcotic use appears to be partially attributable to diffuse psychophysiological discomfort, the alleviation of which is a significant reinforcer. The failure of chemotherapeutic intervention to deal directly with such discomfort will inevitably result in limited applicability and effectiveness. It is primarily for this reason that antagonists do not seem to offer substantial rehabilitative promise for the typical parolee or street addict. For many such individuals, there is simply no incentive or reward in the taking of a chemical that denies them the relief they obtain from narcotics. Thus viewed, antagonists can be expected to be no more effective in alleviating chronic narcotics use than disulfiram (Antabuse) has been in alleviating chronic alcohol use. Considering the above, it seems advisable to supplement the search for pure and longer-acting narcotic antagonists by further concentration on the development of antagonists with non- or minimally addicting agonistic properties that are more acceptable from the side effect standpoint than those that are presently available. Judiciously used during the early stages of treatment, such agents would be more likely to sustain the participation of less motivated addicts in therapeutic environments to which they might not otherwise be attracted.
SUMMARY

The results of a controlled study of the contingent administration of naloxone to newly released addict parolees were viewed in relation to the goals of the narcotic antagonist approach to the treatment of addiction. Program participation and narcotic usage data on 97 addict parolees, 55 of whom were assigned to naloxone and 42 to placebo, revealed that although demonstrating a capacity to attenuate narcotic drug intake, the use of naloxone in contingent dosages ranging from 500 to 2000 mg was associated with a relatively high dropout rate during a prescribed 6-

NARCOTIC

ANTAGONIST

TREATMENT

219

month treatment course. In view of the population and methodology employed, the unfavorable outcome result could not be regarded as discounting the potential usefulness of naloxone in other settings and under other conditions. Implications and possible causes of the findings of the study, including a surprising amount of placebo effectiveness under contingent conditions, were discussed and conclusions drawn regarding limitations of the antagonist approach for the less motivated addict.
ACKNOWLEDGMENTS
The authors Laboratories, loxone: physical Maryland, cotic Clinic wish to express Inc.. a subsidiary Medical to Dr. Robert appreciation to Dr. Ralph Center, Jacobsen. Deputy Medical Director supplies support of I-ndo of naand Narof E. I. Dupont Research J. Kokoski De Nemours Inc., & Co.. for furnishing administrative Laboratory.

to Friends facilities;

Science

for providing Friends

and his statf at the Drug to the

Abuse

Catonsville.

for the processing for their continued

of specimens; cooperation:

staff of the

Experimental

Outpatient and help.

and to Vasilios

Frankos

for his suggestions

REFERENCES
I. Paroled program: McCabe narcotic Results OL, Kurland AA, Sullivan I>: 7. Gilberstadt Clinical and Philadelphia, 8. Kurland McCabe pilot study. OL, Int OL, and J Hanlon Addict TE: Int OL: adtreatof Naloxone 1974 9. dict. 28:X08 Savage A C. McCabe therapy study. OL: Arch Residenttal adGen Psychiatr treatment of the narstudy of partial H, Duker J: A Handbook Interpretatwn. for addicts in a veritied study. abstinence Int J AdActuarial Saunders, AA, MMPI 1965, p 65 Hanlon TE, abuser: Int J Addict McCabe 9:663 OL: 672.

of a five-year

dict IO:21 I 228, 1975 2. Kurland TE: cotic I I:131 Contingent addict: 142. 1976 AA, the TE, McCabe paroled lO:l57, Kurland of research, Neurotherapy JE: MMPI Hanlon addict. McCabe narcotic naloxone(N-allylnoroxymorphone) of narcotic 1975 AA, AA, A naloxone

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