N altrexone has been used in the treatment of opiate addiction for nearly 30 years. 1 It has proven helpful in specific subgroups of patients (eg, nurses, 2 highly motivated businessmen, 3 prisoners in release programs), 4 but not in general opiate addicts. 5 In treatment of the general opiate addict treatment retention is low (<10%at 6 months), but retention as high as 20%at 6 months has been reported. 1 One explanation for the poor results obtained in the general addict population A Pilot Double Blind Placebo Controlled Trial of Sertraline with Naltrexone in the Treatment of Opiate Dependence Conor K. Farren, M.D., Ph.D., Stephanie O’Malley, Ph.D. Naltrexone has been used for thirty years as an aid to maintenance of opiate abstinence with limited success. One reason is that naltrexone does not appear to reduce craving in opiate addiction, unlike in alcoholism. The authors con- ducted this trial of naltrexone in combination with the SSRI sertraline to assess treatment retention with combination pharmacotherapy. They used a double-blind placebo controlled trial of naltrexone 50mg qd with placebo versus naltrexone 50 mg plus sertraline 50 mg qd in 13 recently nondepressed abstinent opiate addicts followed over a 12 week period. Both groups had a similar side effect profile and while there was an initial trend in increased retention in the combination therapy group, there was no difference in reten- tion by the end of the study. There was a fall in the Beck Depression Inven- tory scores in both groups over time, and there was a significant negative correlation between BDI scores and duration in treatment in the combination therapy group. There was a fall in opiate craving, as measured by an opiate craving questionnaire, over time in both groups. The authors conclude that combination pharmacotherapy appeared to be well tolerated and was initially successful in increasing treatment retention relative to naltrexone alone, but this effect tended to diminish over time. (Am J Addict 2002;11:228- 234) 228 Received March 7, 2000; revised April 28, 2000; accepted August 27, 2000. From the Department of Psychiatry, Yale University School of Medicine, New Haven, Conn. (Drs. Farren and O’Malley); and Department of Psychiatry, Mount Sinai School of Medicine, New York, NY (Dr. Farren). Address correspondence to Dr. Farren, Bronx VA Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468. E-mail: conor.farren@ med.va.gov. The American Journal on Addictions 11:228- 234, 2002 Published by Brunner-Routledge # 2002 American Academy of Addiction Psychiatry 1055-0496/02 $12.00 + .00 DOI: 10.1080/10550490290088009

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  • N altrexone has been used inthe treatment of opiate addictionfor nearly 30 years.1 It has proven helpful inspecific subgroups of patients (eg, nurses,2

    highly motivated businessmen,3 prisonersin release programs),4 but not in general

    opiate addicts.5 In treatment of the generalopiate addict treatment retention is low(

  • may be that there is residual craving foropiates. Naltrexone itself appears to haveno anti-opiate craving activity; it simplyblocks opiate receptors. It thus may act as akind of ``behavioral pharmacotherapy,with no demonstrable efficacy aboveplacebo, but can be useful in the context ofa behavioral opiate abstinence program.No research to date has suggested thatnaltrexone alone produces any anti-opiatecraving activity. Naltrexone may causedysphoria in abstinent opiate addicts.6 Thismay be one reason for the poor retentionrate in opiate treatment. Targeting relief ofthat dysphoria might be one strategyfor increasing treatment retention. Oneobvious method of relieving dysphoria(namely, the use of antidepressants in con-junction with naltrexone) has never beensystematically evaluated.

    There appears to be some interactionbetween serotonin agonists and the opiatesystem in the locus coeruleus, as indirectserotonin agonists including sertraline canattenuate neuronal opiate withdrawal.7

    There is also some clinical evidence formoderate benefits in treatment retentionwith the addition of a selective serotoninreuptake inhibitor (SSRI) to a naltrexonefor opiates regime in a few clinical trials inEurope,8,9 and in a treatment trial forco-morbid opiate and alcohol abusers.10

    One of these studies8 was a large trial (56subjects per group), and suggested a ben-efit in treatment retention rates in thefluoxetine supplemented group. However,none of these trials were randomizeddouble blind placebo controlled trials ofcombination pharmacotherapy, depressivestatus was not clarified, and there were nomeasurements of opiate craving in any ofthem.

    We thus decided to conduct a pilotrandomized placebo controlled trial ofnaltrexone with the SSRI sertraline versusnaltrexone with placebo in a group of absti-nent opiate addicts to assess the safety andtolerance of this combination and to make

    preliminary estimates of potential efficacysize.


    Thirteen opiate-dependent subjects withno co-morbid psychopathology (includingdepression) were admitted onto the nal-trexone for opiates program at Yale Uni-versity Substance Abuse Treatment Unitover the period of one year. Subject charac-teristics are detailed on Table 1. Subjectsreceived a comprehensive psychiatric eval-uation, full physical examination, andblood screening, and they signed a writtenconsent. Subjects were initiated into a10-week treatment program, with weeklygroup opiate abstinence therapy, weeklyurine monitoring, and weekly interviewwith a research assistant. Subjects com-pleted a baseline structured psychiatricinterview, Beck Depression Inventory(BDI),11 an Obsessive-Compulsive Opiate-Craving Scale (OCOS) based on theObsessive-compulsive Drinking Scale,12

    and a baseline urine toxicology screen.Opiate addiction was verified by a historyof positive urine toxicology or a history ofmethadone maintenance, and visible needletracks in the subjects arm.


    After 5 to 30 days of abstinence fromopiates, subjects were admitted to treat-ment. Subjects received naltrexone 12.5mgascending to 50mg over one week andwere randomized to receive either placeboor sertraline 50mg after one week. Subjectswere monitored for a 2-hour period afteradministration of naltrexone, and with-drawal symptoms were treated. Subjectswere then placed on a thrice-weeklynaltrexone administration regime, generallyMonday, Wednesday, and Friday, and allnaltrexone was given in a supervisedadministration setting.

    Farren & OMalley


  • Subjects were given the sertraline/placebo themselves, and after adminis-tration of the first dose under supervision,were given their medication to takehome weekly at first, and then biweeklyafter a 4-week period. Urine drug screens,BDI scales, OCOS scales, and side effectlists were taken weekly for 4 weeks andthen biweekly for the remaining 6 weeks.


    Baseline characteristics of the two groupswere analyzed using t tests for continuousvariables, and chi-square test for categoricalvariables. Tests of group differences onoutcome variables were conducted onan intention to treat analysis plan thatincluded all randomized subjects. Treat-ment retention rate was tested usingsurvival methods. Analysis of group differ-ences in number of days in treatment,craving scale, and depression scale wereexamined by t tests. Correlation betweentreatment retention and depression scalewas calculated using Pearsons correlationcoefficient.


    There was a fall in retention in both groupsover time, with a difference at 2 weeks thatapproached significance with 100% reten-tion in the combination group and 66%retention in the monotherapy group, andat 4 weeks with 85% retention in thecombination group and 50% in the mono-therapy group. At 10 weeks, there was nodifference in retention between the twogroups at 57% and 50%, respectively,p ns. There was no significant differencein duration in study, with a mean 55 daysand 44.6 days, respectively, p ns. This isrepresented in Figure 1.

    There was a significant differencebetween baseline and mean BDI scoresduring the study, p< 0.0l. The fall in BDIscores was maximal in the combinationpharmacotherapy group over the first 2- 4weeks, but there was no difference betweengroups on study completion. There was asignificant negative correlation betweenBDI scores and duration in treatment,p< 0.01, and this was only significant inthe combination therapy group, p< 0.05.

    TABLE1. Demographic Prole of Opiate Addicts

    CombinationTherapy Mono-therapy PValue

    Age (yrs.) 29 (2.6) 32 (3.4) n.s.Gender 7M 5M, 1F n.s.Race 4 C, 1 Native, 1 Mix 6 C, 1 Hisp n.s.Marital status 5 S, 1 Cohab 6 S, 1 Div n.s.Age education completed 17 (0.9) 17.4 (0.5) n.s.Total no. jobs 5.6 (1.2) 6.5 (2.7) n.s.Previous OPD tx. 0.4 (0.2) 6 (0.9) < 0.05Previous In-pt tx. 1.2 (0.3) 2.6 (0.1) n.s.Duration addiction (mths.) 82 (32) 120 (43) n.s.Bags heroin/day 13.7 (11) 8.6 (2.6) n.s.IV use 2 3 n.s.Current marijuana 2 0 n.s.Current alcohol 1 0 n.s.Current cocaine 2 1 n.s.Current abstinence (days) 22.4 (4.2) 35 (10.2) n.s.

    () ( / s.e.m.)

    Sertraline with Naltrexone for Opiate Dependence

    230 VOLUME 11 NUMBER 3 SUMMER 2002

  • There was a significant fall in meanOCOS scores over time in both groups,p< 0.02, but no difference overallbetween the craving scores in the twogroups. There was no correlation betweenOCOS scores and retention in treatmentoverall or in either group. This isrepresented in Figure 2.

    There was no difference betweengroups in reported side effects. Only 28%of the combination group complained ofany side effects, mainly nausea andheadache, and then only 50% of the timeon the medication. 17% of the mono-therapy group complained of side effects,mainly nausea, 22% of the time on themedication.


    This pilot double blind treatment trialfound reasonable tolerance and safety of acombination of naltrexone and sertralineversus naltrexone alone in a group ofnondepressed opiate addicts. The sideeffect profile of the two groups appearedsimilar, and there were no serious adverseeffects during the study. This is consistentwith the finding that the addition of anantidepressant to naltrexone in the treat-ment of alcoholism did not adversely affectthe side effect profile of naltrexone in alarge group of alcoholics.13 No differenceswere found in treatment retention, levels ofcraving, or depressive response, although

    FIGURE 1. Treatment retention in both groups over the 10-week study. There were no overall differences in ret-ention between the combination pharmacotherapy and the monotherapy groups.

    Farren & OMalley


  • the study was not powered to detect thesedifferences. Other treatment trials in opiateaddicts using a combination of an SSRIwith naltrexone have made claims for treat-ment efficacy of this combination.8-10 Oneof these studies found a large effect size forthe addition of fluoxetine 20mg to stan-dard naltrexone for opiate therapy, usingan N of 56.

    There were a number of design differ-ences between this and the other trials.Firstly, this was a double blind placebocontrolled trial unlike all the others, wherethe patients were either randomized totreatment or non-treatment groups withouteither a single or double blind,8 or dividedinto treatment or non-treatment groups byunspecified criteria.10,9 Secondly this treat-ment trial excluded those with a diagnosisof major depression at time of inductiononto the program. This was done to assess

    the effects of the combination on relativelypure opiate addiction, rather than com-orbid depression and opiate addiction. Theother trials did not exclude depression anddid not characterize their subjects accord-ing to depressive symptoms. Thirdly, thistrial monitored levels of craving biweeklyusing a craving scale modeled upon theObsessive Compulsive Drinking Scale12 inan attempt to determine if any beneficialeffects of the combination pharmaco-therapy were attributable to differences inlevels of craving. The other trials did notuse comprehensive assessments of craving.

    There were some initial differences inretention in the combination therapy groupthat were not sustained over the dura-tion of the trial. There was no increasein depressive scores in the naltrexonealone group, suggesting that naltrexone atleast did not produce dysphoria in the

    FIGURE 2. Relationship between opiate craving (Obsessive-Compulsiv e Opiate Scale) and treatment retention in bothgroups. There was a significant fall in craving in both groups over time, p< 0.02, but no difference between groups duringthe study.

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    232 VOLUME 11 NUMBER 3 SUMMER 2002

  • non-depressed opiate addicts, but it is poss-ible that those subjects that dropped out inthe few weeks in the monotherapy groupdid suffer dysphoric symptoms but did notreturn to the study to report them. Pre-vious researchers have noted that nal-trexone may cause dysphoria in opiateaddiction.6

    There was an initial fall in the BDI inthe combination pharmacotherapy groupin the first two weeks of therapy. This maybe attributable to an initial antidepressanteffect, which can occur in the first weeksafter initiation of therapy in depression, butthis was not sustained over the course oftreatment. This may alternatively representa diminution in the dysphoric symptomsinduced by naltrexone and not reflected inan increase in the BDT scores in themonotherapy group due to initial drop-outs. It should be noted that all subjectshad completed full withdrawal fromopiates prior to initiation of anypharmacotherapy, so precipitation of with-drawal symptoms by naltrexone wouldtheoretically be unlikely. Nonetheless, therelative difference in BDI scores was notsustained over time.

    There was a significant correlationbetween treatment retention and lowbaseline BDI scores in the combinationpharmacotherapy group. This suggeststhat the least depressed subjects mightbe most responsive to the combination,a somewhat counter-intuitive finding.

    However, the numbers were too small tomake a comprehensive interpretation ofthis finding, and the study would have tobe repeated with a larger number oflow Beck score individuals to make aconclusion.

    There was no difference in opiatecraving scale responses between the twogroups. However, there was a significantdecrease in the craving scores over timein both groups, suggesting that opiatecraving falls as a factor of duration of absti-nence from opiates. Alternatively, throughnaltrexones strong blockade of the Muopiate receptor, there may be a down regu-lation of the opiate receptor and aconsequent diminution in craving. Thisreceptor blockade might make an opiateaddict more sensitive to the effects ofopiates on cessation of naltrexone andresumption of narcotic abuse. Indeed, therehave been reports of overdose from opiateson cessation of naltrexone.14

    Overall, the absence of differences intreatment retention and in opiate cravingbetween the two groups suggests that thiscombination of pharmacotherapy in opiateaddicts is no more successful that naltre-xone monotherapy. This study was carriedout on a well-defined and matched groupof addicts. The small numbers in the study,however, do render the findings open to apossible type 2 error, and a similar butlarger study could be undertaken to make adefinitive statement.

    1. Farren CK, OMalley S, Rounsaville B.Naltrexone and opiate abuse. In: Kosten TS,ed. New Treatments for Opiate Dependence: WhichTreatments for Which Patients? New York:Guilford Press; 1997:194- 232.

    2. Roth A, Hogan I, Farren CK. Group therapywith naltrexone in the treatment of opiate abus-ing health professionals. J Subst Abuse Treat.1997;14:1- 4.

    3. Washton A, Pottash A, Gold, MS. Naltrexonein addicted business executives and physicians.J Clin Psychiatry. 1984;45(9):39- 41.

    4. Brahen H, Henderson R, Capone T, Kondal N.Naltrexone treatment in a jail work releaseprogram. J Clin Psychiatry. 1984;45(9):49- 52.

    5. Bradford H, Hurley F, Golondzoeske O,Dorrier C. Interim report on clinic intakeand safety data from 17 NIDA funded


    Farren & OMalley


  • naltrexone centers. In: Julius D, Renault P,eds. Narcotic Antagonists: Naltrexone. NIDAResearch Monograph. Vol 9. Washington,DC: US Government Printing Office; 1975:163-171.

    6. Crowley T, Wagner J, Zerbe G, Macdonald M.Naltrexone induced dysphoria in former opiateaddicts. Am J Psychiatry. 1985;142:1081- 1083.

    7. Akaoka H, Aston-Jones G. Indirect sero-tonergic agonists attenuate neuronal opiatewithdrawal. Neuroscience. 1993;54(3):561- 565.

    8. Landabaso M, Iraurgi I, Jimenez-Lerma J, SanzJ, Fernadez de Corres B, Araluce K, Calle R,Gutierrez-Fraile M. A randomized trial ofadding fluoxetine to a naltrexone treatmentprogram for heroin addicts. Addiction. 1998;93(5):739- 744.

    9. Maremmani I, Zolesi O, Daini L,Castrogiovanni P, Tagliamonte A. Fluoxetineimproves outcome in addicted patients withopiate antagonists. Am J Addict. 1995;4:267- 271.

    10. Gerra G, Fertonani G, Zaimovic A, et al.Hostility in heroin abusers subtypes: fluoxetineand naltrexone treatment. Progres s in Neuro-psychopharmacology and Biological Psychiatry. 1995;19(8):1225- 1237.

    11. Beck A, Ward C, Mendelson M. An inventoryfor measuring depression. Arch Gen Psychiatry.1996;53:461- 471.

    12. Anton R, Moak DH, Latham P. Theobsessive-compulsive drinking scale: a newmethod of assessing outcome in alcoholismtreatment studies. Arch Gen Psychiatry. 1996;53:225- 231.

    13. Croop R, Faulkner E, Labriola D. The safetyprofile of naltrexone in the treatment ofalcoholism. Results from a multicenter usagestudy. Arch Gen Psychiatry. 1997;54:1130- 1135.

    14. Miotto K, McCann M, Rawson R, Frosh D,Ling W. Overdose, suicide attempts, and deathamong a cohort of naltrexone-treated opioidaddicts. Drug Alcohol Depend. 1997;45(1- 2):131-134.

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    234 VOLUME 11 NUMBER 3 SUMMER 2002