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1446494332

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1446494332

     J Clin Psychopharm: 21(3)287-292, 2001

    Targeted use of naltrexone without prior detoxification in the treatment of alcohol dependence: A factorial double-blind placebo-controlled trial

     ;1,21,31P. Heinälä (MD), H. Alho (MD, PhD), K. Kiianmaa (PhD), J. Lönnqvist (MD, 111PhD), K. Kuoppasalmi (MD, PhD), and J. D. Sinclair (PhD).

     1National Public Health Institute, Department of Mental Health and Alcohol Research, Helsinki, Finland; 23Finnish Foundation for Alcohol Studies, Helsinki, Research Unit of Alcohol Diseases, University of

    Helsinki, Finland.

    Key words: naltrexone, alcoholism, targeted medication, randomized clinical trial

    ABSTRACT

    Several studies have shown the opioid antagonist naltrexone to be effective when com-

    bined with psychosocial therapies for the treatment of alcoholics with fixed medication

    and time (12 weeks). In this study, 121 non-abstinent alcohol-dependent (DSM-IV) out-

    patients were treated with sessions of cognitive coping skills (n=67) or supportive (n=54)

    therapy and either 50 mg/day of naltrexone (n=63) or placebo (n=58) daily for the first

    12 weeks and thereafter for 20 weeks only when craving alcohol (i.e., “targeted

    medication”) in a prospective one-center dual double-blind, randomized clinical trial.

    The dropout rate for all subjects was 16.5% during the first twelve-week period and

    approximately twice that level by the end of the study. There were no significant group

    differences in study completion and therapy participation rates. After the continuous

    medication (12 weeks), the Coping/Naltrexone group had the best outcome and

    Coping/Placebo had the worst. This difference remained during the targeted medication

    period (the following 20 weeks). Naltrexone was not better than placebo in the

    supportive groups, but it had a significant effect in the coping groups: 27 % of the

    Coping/Naltrexone patients had no relapses to heavy drinking throughout the 32 weeks

    compared to only 3 % of the Coping/Placebo patients. Our data confirms the original

    finding of the efficacy of naltrexone in conjunction with coping skills therapy. In addi-

    tion our data show that detoxification is not required, and that targeted medication taken

    only when craving occurs is effective in maintaining the reduction to heavy drinking.

Targeted naltrexone in the treatment of alcoholism

    that naltrexone continues to be efficacious as long as INTRODUCTION

    The use of naltrexone in the treatment of it is administered, but the benefits begin fading (10)alcoholism is well supported by several . This gradually once the medication is terminated (1,2,3,4)controlled clinical trials . A double-suggested that treatment should be continued beyond blind, placebo-controlled trial by Volpicelli et the three or six months periods previously tested. (1) al.firstshowed clinically that naltrexone The aim of our study was to replicate the (1,2,3,4,11) reduced alcohol drinking and especially reported data and test these new strategies for relapsing to heavy drinking. Naltrexone-treated increasing the efficacy of naltrexone in the treatment patients had a lower overall number of drinking of alcohol dependence. This report presents the days and a lower craving than the placebo-findings from a prospective one-center randomized, treated individuals. double-blind 32-week trial of the efficacy of

    The study was replicated by O’Malley et naltrexone or placebo started without detoxification, (2)(12)al. who showed that naltrexone in general added to manual-guided cognitive behavioral

    decreased relapse rates, the percentage of group therapy allowing some drinking or group drinking days, and the total number of drinks therapy supporting total abstinence for out-patient during the study in comparison with placebo. An alcoholics. The first 12 weeks are seen as an induction interaction between the medication and the period and the final 20 weeks with “targeted” psychotherapy was found, in that naltrexone had medication (taken only when craving was high) as the a significant effect on craving and relapse to test period.

    heavy drinking in the coping groups but not the

    supportive ones. METHOD

    One important limitation to any The study subjects were persons seeking pharmacological treatment is subject compliance. outpatient treatment for alcoholism who responded to This is well demonstrated with the usage of advertisements for the research study. 326 individuals naltrexone for alcoholism treatment, as shown were screened over the telephone, and 302 were by Volpicelli et al. who found that compliance invited for in-person screening. Of these, 137 were with medication played an important role in the screened in person, and 121 gave written informed (3)increased efficacy of naltrexone over placebo. consent and were randomized for the study after one In this study detoxified patients received either week’s run-in trial with a riboflavin-marked placebo. daily 50 mg of naltrexone or placebo and relapse The inclusion criteria were 1) age 2165 years, 2)

    prevention therapy. The treatment outcome meeting the DSM-IV criteria for alcohol dependence, was dependent upon compliance: among the 3) consumption, on average, of five or more drinks highly compliant subjects, there was a per day in the last 30 days, and 4) a stable living significant negative correlation between situation and availability of a collateral reporter. medication compliance with naltrexone and The exclusion criteria were 1) other current drug percentage of days of drinking during the study. abuse or dependence (including marijuana), 2) ever In contrast, among less compliant subjects having abused opiates, 3) a current major psychiatric naltrexone produced significant benefits only on disorder as determined by the Structured Clinical liver enzyme markers of drinking. However, Interview for DSM IV (SCID), 4) a serious or there was no significant difference in craving unstable medical condition, 5) current use of psych-between the naltrexone-treated and the placebo-otropic or anti-seizure medications or disulfiram, 6) treated subjects between the treatment groups. liver function test results (alanine aminotransferase

     Preclinical findings and the results and aspartate aminotransferase) greater than 250 (IU). from these and other earlier clinical trials Each patient signed a written informed consent, suggested that the efficacy of naltrexone may be and the study was conducted according ICH’s GCP dependent upon the protocol with which it is (Good Clinical Practice) and Helsinki 1964 (4,5,6,7,8)used . Clinical trials with support of Declaration. Ethical permission for the study was abstinence and preclinical studies in which granted by the A-Clinic Foundation Ethical opioid antagonists were given only during Committee (permission #101096).

    abstinence had not found significant benefits Reasons for nonparticipation among the 302 from naltrexone, but trials with instructions that individuals invited to be screened in person included did not preclude all drinking and preclinical the following: 55% chose not to participate, 1% had studies in which animals got antagonists while other psychiatric diagnoses, 2% had exclusionary (9)drinking had found positive effects . This medical conditions, and 2% lacked social stability. suggested that a protocol might be used in which 121 patients were included: 86 males (71.1%) and prior detoxification was omitted and that 35 females (28.9%). The mean age was 45.5 years naltrexone could be given in a targeted manner, (? 7.8).

    i.e., only when patients are drinking. The patients were treated with group sessions Furthermore, the previous results had suggested of cognitive coping skills (n=67) or supportive (n=54)

Targeted naltrexone in the treatment of alcoholism

    behavioral therapy and either 50 mg/day of drinking, in accordance with previous naltrexone (1,2,4)naltrexone (n=63) or placebo (n=58) started clinical trials. Other measures taken included without prior detoxification. In a dual double-alcohol consumption (measured with drinking diaries), blind, randomized clinical trial, medication was craving (measured with a Finnish translation of the provided daily for the first 12 weeks and Obsessive Compulsive Drinking Scale, OCDS) thereafter for 20 weeks only when alcohol adverse events, liver enzymes, and urinary riboflavin drinking was likely (i.e., “targeted medication”). levels, which were assessed biweekly or monthly. In the latte target part of the study (weeks 13 to Patients were seen in a visit one week prior to 32), subjects in both the coping and supportive the start of treatment, at the start of treatment, and groups were instructed to take the medication thereafter in weeks 1, 2, 3, 5, 8, 12, 16, 24, and 32. only in situations for which they considered They were contacted by telephone on weeks 20 and there was a risk of sampling alcohol or when 28. Drinking diaries (in which the patients had they felt that their craving would probably over-recorded their daily intakes of alcohol as the number whelm their ability to resist drinking. of standard 12 g drinks) were collected at each visit

    The study medication was purchased including the telephone contacts. They received

    either coping or supportive therapy at four visits, in (ReVia) and specially prepared for this study

    weeks 1, 2, 5, and 12. The coping (or “coping with by the University Pharmacy, Helsinki Univer-

    drinking”) groups received cognitive behavioral sity. Identical opaque capsules containing

    therapy in a group setting according to the manual either naltrexone hydrochloride 50 mg or (12)used at Järvenpää Addiction Hospital . The inactive placebo were made, both with 100 mg

    emphasis in the therapy was coping with a slip when riboflavin added to monitor compliance. A study

    the patient samples alcohol so as to prevent it from pharmacist delivered the study medication at

    proceeding on to a binge of drinking. The supportive each visit to the subject.

    (or “support of abstinence”) groups met in a similar The primary outcome measure for

    group setting, but here the emphasis was on support of evaluation of the efficacy of naltrexone was

    complete abstinence from all drinking. chosen prior to the study and filed with the A-

    The outlines of study flow are presented in Fig. 1. Clinic Foundation Ethical Committee. This

     chosen measure was the relapse to

     heavy

    Fig. 1.

    Baseline121 Alcoholics (DSM-IV)No Detoxification7 Days with Placebo

    Coping/PlaceboSupportive/PlaceboCoping/NaltrexoneSupportive/Naltrexonen=33, 00 mg/dayn=25, 00 mg/dayn=34, 50 mg/dayn=29, 50 mg/day12 Weeks12 Weeks12 Weeks12 WeeksGroup TherapyGroup TherapyGroup TherapyGroup Therapy

     Targeted-medicationTargeted-medicationTargeted-medicationTargeted-medicationonly when cravingonly when cravingonly when cravingonly when craving20 Weeks20 Weeks20 Weeks20 Weeks

Targeted naltrexone in the treatment of alcoholism

    measure: the Kaplan-Meier survival analysis for the RESULTS

    The salient demographic variables for the 121 entire 32 weeks was significant (p=0.0397) (see Fig 2).

    randomly assigned subjects are presented in An interaction was found between the medication and Table 1. There were no significant differences the type of therapy, with the Coping/Naltrexone group between the four groups on any variable. In gen-having the best outcome.

    eral, the individuals in this study were well edu-The result is seen more clearly in the per-cated, employed, married, and socially stable. centage of patients never relapsing to heavy drinking All subjects met the diagnostic criteria for alco-during the entire 32 weeks. (Fig 3). Naltrexone was hol dependence (DSM-IV). There was no sig-highly significantly better than placebo in the coping nificant difference in any measure of severity of groups (Fisher’s exact probability test, p=0.008). In

    alcoholism between the treatment groups. Over-contrast, naltrexone tended to be slightly worse than all, 83.5% (N=101) of the randomized subjects placebo in the supportive groups, although the completed the first twelve weeks of the study difference was not significant. The Coping and 69.4% (N=84) completed the whole program: /Naltrexone group did significantly better than the i.e., the dropout rate for all subjects was 16.5% Supportive/Naltrexone group (p=0.041). These re-

    during the first twelve-week period and 30.6% sults are from analyses of all patients (i.e., intent to by the end of the study. The study completion, treat patients) and not just those completing the study and therapy participation, rates in the trial were or those with high compliance.

    high, with no differences between treatment The same relation is found among the patients groups. ever relapsing to heavy drinking: 19.1% of the

     Coping/Naltrexone patients did so only once in the 32

     weeks, but only 3.2% of the Coping/Placebo patients

    had only one relapse; the rates were similar in both Table 1.

    Sociodemographic characteristics of the whole supportive groups: 12.5% with naltrexone and 10.0% material (no significant differences between the with placebo. In the Coping/Naltrexone group, treatment groups). 38.2 % had at most 1 relapse in 32 weeks, compared

    with only 6.1% in the placebo/coping group, 17.2% Age (years), mean ? SD 45.5 ? 7.8 in the Supportive/Naltrexone group, and 20.0 % in the Gender, n(%) 2Supportive/Placebo group (interaction, [with Yate’s Male 86(71.1)

    correction, 1 df] =12.02, p<0.001). Female 35(28.9)

    During the targeted-medication phase (last 20 Marital status, n(%)

    weeks), the only significant difference in the number Single 14(11.6)

    of pills taken weekly was that the Supportive/ Married 88(72.7)

    Naltrexone group consumed significantly more (3.4 ? Divorced or widowed 19(15.7)

    0.3) than the Coping/Naltrexone group (2.1 ? 0.2 )(see Living conditions, n(%)

    Table 2). Alone 25(20.7)

     Together with family 90(74.4)

     Together with children 6(5.0)

     Employment, n(%)

    Table 2. Number of pills per week during last 20 Unemployed 16(13.2)

    weeks (mean ? SE) Employed 91(75.2)

     Coping Supportive Retired or student 14(11.6)

    Naltrexone 2.1 ? 0.2** 3.4 ? 0.3 Previous alcohol treatments, n(%)

    Placebo 2.7 ? 0.3 2.4 ? 0.5 None 78(64.5)

    **p=0.005 vs. Supportive/Naltrexone Detoxification (but currently drinking) 14(11.6) The group differences in reported alcohol Therapy at A-clinic 16(13.2) drinking showed a pattern similar to that for relapses Institutional therapies 13(10.7) to heavy drinking , with the Coping/Naltrexone group tending to do better than the other three groups. The pattern become more pronounced during the course of The main outcomes are presented in Figs. the study and only became significant in the last 8 2 & 3. The primary outcome measure, chosen weeks, when the reported drinking (gm/week) was: prior to the study, was the rate of relapse to 231 ? 40 for the Coping/Naltrexone group; 354 ? 62 heavy drinking defined as having 5 or more for Coping/Placebo; 357 ? 81 for Supportive drinks (12 g ethanol each) on one occasion, /Naltrexone; 326 ? 80 for Supportive/Placebo (t test having 5 or more drinking occasions in one assuming unequal variances comparing Coping week, or arriving at a visit intoxicated. Overall /Naltrexone with the other three groups combined: there was a significant effect of treatment on this t(75)=1.99, p=0.05.)

    Targeted naltrexone in the treatment of alcoholism

     100%

    p=0.0397 survival analysis

    of all patients

    80%

    60%

    40%

    Coping/Naltrexone

    Percent of patients

    not having relapsed to heavy drinking20%

    Supportive/Placebo

    Supportive/Naltrexone

Fig. 2. Percentage of patients not relapsing to heavy drinking: i.e., 5 or more drinks on one occasion or 5 or 0%Coping/Placebomore drinking occasions in a week, or intoxicated at site visit. 01235812162432

    Kaplan-Meier survival analysis of all patients.

    Weeks

    30%

    Naltrexone

    25%

    *

    20%**

    15%

    Percent of patients PlaceboNaltrexone

    never relapsing to heavy drinking

    10%

Fig. 3. Percentage of patients that had no relapses in 32 weeks. Fisher’s exact probability test, ** p=0.008, * 0%p=0.041.

    5%Coping Supportive

    Placebo

Targeted naltrexone in the treatment of alcoholism

    Table 3 shows the side effects. No severe problems related to ethanol withdrawal were evident. Nal-

    trexone was well tolerated as compared to the placebo. The general rate of reporting adverse effects was high, 2but the number of patients reporting them was not significantly higher in the naltrexone than placebo groups (

    [1 df] = 2.91, p >0.05). No individual side effect was seen significantly more often in the naltrexone than pla-

    cebo groups. The prevalence of naltrexone-related side effects depended upon the type of therapy. Among the

    supportive groups, the percent of patients reporting side effects was significantly higher with naltrexone than 2placebo ( [1 df] = 5.77, p<0.05), but naltrexone did not cause a significant increase in side effects among the

    coping groups.

     Table 3. Number (percent) of patients showing various side effects, entire 32 weeks.

     Coping/ Coping/ Supportive/ Supportive/ Naltrexone Placebo

    naltrexone placebo naltrexone placebo n=63 n=58

    n=34 n=33 n=29 n=25

Intestinal 6(17.6) 3(9.1) 6 (20.7) 3(12.0) (19.0) (10.3) 12 6

    disorders

    Headache 4(11.8) 6(18.2) 2 (6.9) 4(16.0) (9.5) (17.2) 6 10

    Sexual 4(11.8) 2(6.1) 6 (20.7) 2(8.0) (15.9) (6.9) 10 4

    dysfunction

    Day-time 3(8.8) 2(6.1) 6 (20.7) 2(8.0) (14.3) (6.9) 9 4

    fatigue

    Nausea 3(8.8) 0(0.0) 4 (13.8) 2(8.0) (11.1) (3.4) 7 2

    Dry mouth 1(2.9) 1(3.0) 3 (10.3) 2(8.0) (6.3) (5.2) 4 3

    Pollacisuria 3(8.8) 2(6.1) 1 (3.4) 0(0.0) (6.3) (3.4) 4 2

    Insomnia 1(2.9) 2(6.1) 1 (3.4) 1(4.0) (3.2) (5.2) 2 3

    Other 7(20.6) 6(18.2) 11 (37.9) 6(24.0) (28.6) (20.7) 18 12

    17(50.0) 16(48.5) 21 (72.4)* 10(40.0) (60.3) (44.8) All 38 26

*Significantly higher than Supportive/Placebo group, p<0.05, no significant difference in any parameters

    between the other groups.

    benefits of naltrexone over placebo when used in DISCUSSION

    Naltrexone had significant benefits over placebo conjunction with coping therapy but neither has when used in conjunction with coping therapy on found any significant benefits from naltrexone used the pre-assigned end point measure: it reduced the together with supportive. This conclusion also rate of relapse into heavy drinking during the test can be made with regard to the original O’Malley et (2)period in the coping groups. Naltrexone did not . al. study

    significantly affect the ingestion of the first drink The fundamental major difference be-(either time to first drink or total abstinence rate). tween the two therapies was that the coping groups

    The study design, and possibly the nature received cognitive behavioral therapy that did not of the cognitive coping skills and supportive group demand abstinence as a firm goal of treatment, therapy all led to high retention, completion, and whereas abstinence was strongly emphasized in the compliance in all treatment groups. This, combined supportive groups. Animal studies have also found with a low level of missing data and high internal that naltrexone was most effective when paired (15,16)validity, led to sufficient statistical power for deter-with alcohol drinking . This seems reasonable

    mining differences between groups. Thus a signif-because naltrexone is generally believed to affect icant difference was present in our total material alcohol drinking by blocking the effects of endor-without modification for completion or compliance. phins released by alcohol and this only occurs after

    Overall, the results of this trial support the drinking. The finding in the present study and in (1,2,3,4)observations made in earlier trials and par-nearly all previous clinical trials that naltrexone did ticular those reported from the recent clinical trial not significantly delay the time to the first drink is (13,14)in Sweden . The general conclusion from the also consistent with the conclusion that during Swedish trial and from ours is that naltrexone can abstinence naltrexone is not helping to prevent (17)be beneficial in the treatment of alcoholism but drinking from starting again , Two mechanisms

    only in combination with a suitable behavioral have been suggested for why naltrexone is more therapy. Both trials have found significant effective in conjunction with drinking than with

Targeted naltrexone in the treatment of alcoholism

    abstinence. First, drinking alcohol while the rein-The benefits from naltrexone together with forcement is blocked by naltrexone should extin-coping therapy that developed during the first 12 (15)guish the drinking behavior . Second, naltrexone weeks of continual medication persisted during the may allow the alcoholic to keep at least partial subsequent 20 weeks of targeted medication when control over alcohol consumption after a slip naltrexone was taken only when drinking was drinking episode either because it can reduce the likely. Targeted naltrexone has previously been (3,6)(18)(22)euphoria or block the stimulatory effect and open-label used in animal experiments (17, 20)from the alcohol in the first drink that otherwise studies , but this is the first controlled clinical may help release further imbibing. trial to demonstrated its efficacy. Comparing the (1,2,4)The results demonstrate the safety and ef-earlier clinical trials lasting 12 weeks , the (13)fectiveness of naltrexone in alcoholic patients who Swedish trial lasting 24 weeks , and the present

    have not first undergone detoxification and with-32 week treatment, shows that naltrexone continues drawal. Naltrexone has previously been used to provide benefits over placebo so long as the (19-21)without detoxification in open-label studies , medication is given, but follow-up studies indicate but this is the first controlled study to use that the benefits disappear gradually during the (13,14,9)naltrexone on currently drinking alcoholics. Little weeks after the medication is terminated .

    or no cross-dependence has previously been found This suggests that naltrexone treatment should con-between alcohol and opiate addictions. In tinue indefinitely. Taking the medication every agreement with this, no serious reactions were day is, however, expensive and is more likely to observed with the onset of medication in the produce supersensitivity of the opioid receptors and present study. Indeed, naltrexone seemed to be other side effects. The present finding that taking somewhat better tolerated than in previous clinical naltrexone only when craving is high is still effec-(1,2)trials in which naltrexone was used after tive provides a less expensive and perhaps safer detoxification. Here, there was no overall solution for continued alcoholism treatment. significant difference between the naltrexone and

    placebo groups in the number of patients reporting ACKNOWLEDGEMENTS

    side effects, primarily because it was so well This study was conducted at the Järvenpää Addic-tolerated in the Coping/Naltrexone group. The tion Hospital, and at the Department of Mental ability to use naltrexone without prior alcohol Health and Alcohol Research, National Public withdrawal is of particular relevance from a public Health Institute, Helsinki. The authors are thankful (17)health standpoint because it increases the total to the study nurse Mrs. Sirpa Päivinen for her ex-number of patients who can be treated. cellent assistance in the organization and data col-

    During the targeted-medication phase (last lection. The Finnish Alcohol Research Foundation 20 weeks), the only significant difference in the and the National Public Health Institute financially number of pills taken weekly was that the supported the study.

    Supportive/Naltrexone group consumed signifi-

    cantly more than the Coping/Naltrexone group.

    Since the instructions were to take a pill only when

    craving alcohol, the result suggests that the

    Supportive/Naltrexone group was craving alcohol

    more frequently than were the patients in the

    Coping/Naltrexone group. It also demonstrates

    that the superior relapse results in the Coping/

    Naltrexone group were not caused by their taking

    more naltrexone.

Targeted naltrexone in the treatment of alcoholism

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Targeted naltrexone in the treatment of alcoholism

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