A D D I C T I O N T R E A T M E N T
`
`Forum
`
`
`N A L T R E X O N E C L I N I C A L U P D A T E
`
`Evidence for the Efficacy of Naltrexone
`
`in the Treatment of
`
`Alcohol Dependence (Alcoholism)
`
`
`Stewart B. Leavitt, PhD, Editor
`
`ABSTRACT
`Each year, more than 1.5 million Americans seek treatment for quantity of alcohol consumption in those who do drink, and alco­
`alcohol-related problems. In 1994, naltrexone became only the hol craving.
`second drug approved to date for treating alcoholism by the U.S.
`In brief, naltrexone is significantly beneficial in helping those
`FDA. Naltrexone blocks opioid receptors in the brain, stemming patients who cannot remain abstinent to reduce their drinking
`the endorphin-mediated reinforcing effects of drinking alcohol.
`behaviors, breaking the vicious, self-destructive cycle in alcoholics
`Recognizing that healthcare providers need credible scientific whereby one drink leads to another, and allowing more quality time
`information for decision-making purposes when considering phar-
`for psychosocial therapy to be productive. Naltrexone has demon­
`macotherapies for alcoholism, such as naltrexone, this report
`strated effectiveness in a variety of alcohol-treatment settings
`focuses on the highest level of clinical evidence – randomized con-
`using adjunctive psychosocial therapies that provide motivation to
`trolled trials (RCTs). Through year 2001 there were 14 RCTs
`stay in treatment, avoid relapses, and take medications.
`assessing the effectiveness of naltrexone compared with placebo
`Individualized, flexible naltrexone dosing can be of benefit.
`for treating alcoholism, enrolling 2127 subjects, in five countries.
`Longer-term naltrexone therapy extending beyond three months
`An analysis of these trials, consistent with prior systematic may be most effective, and naltrexone might be used on an as-
`reviews and meta-analyses, concludes: A) RCTs of naltrexone in needed, “targeted,” basis indefinitely. It is expected that the infor­
`the treatment of alcoholism are recent, extensive, and of good mation in this report will help healthcare providers to better use this
`quality, B) There is strong evidence that naltrexone significantly
`effective medication.
`reduces alcohol relapses to heavy drinking, the frequency and
`
`From Snake Pits to Science
`About 14 million American adults meet diagnostic criteria for
`alcohol abuse or alcohol dependence (alcoholism). And, every year,
`more than 1.5 million seek treatment for their alcohol-related prob­
`lems (Highlights… 2000; Kurtzweil 1996).
`Throughout history, attempts to treat alcoholics have been ill-
`conceived and gave disappointing results. A first treatment for chron­
`ic drunkenness may have been devised by ancient Romans, who
`lowered habitual drunkards into snake-filled pits, thinking the terror
`would shock them into abandoning their wayward practices (Sournia
`1990).
`By the close of the 19th Century, Merck’s Manual of the
`Materia Medica (1899) was recommending such nostrums for alco­
`holism as arsenic, bromides, cocaine, chloral hydrate, opium, and
`strychnine. Roughly 50 years later, in 1948, disulfiram became the
`
`first U.S. Food and Drug Administration (FDA) approved drug for
`alcoholism treatment (Kurtzweil 1996). It induces nausea, vomiting,
`and other aversive reactions in those who drink alcohol while taking
`the medication.
`After nearly another half-century passed, in late 1994, naltrex­
`one became only the second drug approved to date for alcoholism by
`the FDA (Kurtzweil 1996).This new indication was authorized in
`part because of naltrexone’s accumulated record of safety during
`extensive prior use for opioid detoxification and in the treatment of
`heroin addiction (Naltrexone… 1997; Miller 1997, p75).
`A deciding factor, however, was results from two pivotal stud­
`ies demonstrating naltrexone’s usefulness as part of a clinical pro­
`gram for treating alcoholism (O’Malley et al. 1992; Volpicelli et al.
`1992). In its approval, the FDA recommended that naltrexone also be
`used with adjunctive psychosocial therapies for alcoholism.
`
`1
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`AMN1022
`IPR of Patent No. 7,919,499
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`

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`Naltrexone
`is not addictive
`and does not react
`aversively with
`alcohol.
`
`Naltrexone’s pharmacologic actions are
`fairly straightforward. Alcohol is a complex
`substance, affecting a number of chemical sys­
`tems in the brain. Among other effects, it is
`suspected that, when an alcoholic imbibes, the
`brain’s opioid system releases endorphins
`triggering reinforcement that entices the
`person to drink more (Goldstein 1997;
`Naltrexone…1997; O’Brien 1997; O’Malley
`1998, Swift 1995).
`Unlike earlier drugs used to treat alco­
`holism, naltrexone is not addictive and does
`not react aversively with alcohol. It blocks opioid receptors in the
`brain (it is an antagonist), and this has been proposed as stemming
`the endorphin-mediated reinforcing effects of drinking alcohol. The
`validity of this concept has been supported by observations that
`alcoholics experience increased opioid system activity in response to
`alcohol (Herz 1997; Miller 1997).
`Some controversy has surrounded the use of naltrexone for
`alcoholism (Freed and York, 1997). First, healthcare providers, and
`patients themselves, sometimes question the value of using any drug
`to treat drug or alcohol addiction. Second, research on the effective­
`ness of naltrexone and how best to use it in treating alcoholism has
`evolved rapidly during just the past decade and cumulative findings
`are not widely known or appreciated.
`In this era of managed care and increasing pressures of account­
`ability, healthcare providers need credible scientific information for
`decision-making purposes in recommending medications such as nal­
`trexone. They need to respond authoritatively to questions such as:
`• Where did you learn that naltrexone is effective in treating
`alcoholism?
`• How do you know the information is reliable and valid?
`• What results do you expect from using naltrexone?
`These questions serve as the foundation of this clinical update
`report. The goal is to provide healthcare providers with useful, evi­
`dence-based answers.
`
`Treatment Expectations
`It has been stressed that both alcoholics and alcohol abusers
`need treatment, although the goals may differ. According to the FDA,
`“In most cases of alcohol abuse, the goal is to limit drinking, while
`for alcoholism, it is to stop drinking altogether” (Kurtzweil 1996).
`The immediate goal of most recovery programs is alcohol absti­
`nence, yet that is often too strict a standard. According to some stud­
`ies, about half of patients experience a relapse to heavy drinking
`within 12 weeks of beginning treatment, and up to 90% will relapse
`at least once during four years following treatment. (Kurtzweil 1996;
`Nathan 1986; Volpicelli et al. 1992).
`When sustained abstinence cannot be achieved, other goals,
`such as reducing the number, frequency, or severity of relapses could
`be of significant clinical value. A great potential benefit of naltrex­
`one, in combination with appropriate psychosocial therapy, would be
`providing the patient relief from the self-destructive cycle of intoxi­
`cation to enhance engagement in treatment and achieve long-term
`recovery objectives (Miller 1997, p59).
`Volpicelli et al. (1992) have suggested that the ideal pharmaco­
`logical agent for use in alcoholism treatment would, first, decrease
`alcohol craving and reduce the initial motivation to drink. Second, if
`drinking does occur, the agent should block the reinforcing or desir­
`
`2
`
`able qualities of alcohol to decrease further
`drinking behavior, so a “lapse” does not
`progress to a relapse. Naltrexone’s ability to
`fulfill those requirements is examined in the
`research evidence.
`
`Evidence Selection
`The various types of research study
`
`designs may be ranked according to a “hierar­
`chy of evidence,” based on their relative
`strengths for providing results that are likely to
`be valid and free of bias. Randomized con­
`trolled clinical trials (RCTs) are considered by many as the “gold
`standard” when addressing questions of a drug’s therapeutic efficacy
`(Guyatt and Drummond 1993; Sackett et al. 1997), and are the focus
`of this report.
`
`Naltrexone Clinical RCTs
`Through year 2001 there were 14 clinical RCTs to assess the
`effectiveness of naltrexone for treating alcoholism, enrolling 2127
`subjects, and conducted in five countries.
`Table 1 presents summaries of those trials. For some of the ear­
`lier studies, multiple published articles have discussed data from the
`same treatment population and are grouped together. Unless noted
`otherwise, all of the RCTs reported in Table 1 had the following char­
`acteristics in common:
`• Subjects met criteria for alcohol dependence according to the
`Diagnostic and Statistical Manual of Mental Disorders 3rd or
`4th editions (DSM 1987, 1994), had a recent history of alcohol
`intoxication, and were between 18 and 65 years of age.
`• Subjects were excluded if they had significant liver disease, a
`psychiatric diagnosis beyond alcohol dependence that was being
`treated with psychotropic medication, or substance abuse (other
`than alcohol and excluding nicotine or occasional marijuana use).
`Pregnant women or those likely to become pregnant while on
`naltrexone also were excluded.
`• Subjects were withdrawn (detoxified) from alcohol and abstinent
`for a period of time prior to administration of study medication.
`An exception was the RCT by Heinala et al. (2001), in which
`prior alcohol abstinence was not required.
`• Subjects were randomly assigned to treatment groups and there
`were no significant demographic differences between groups at
`the start.
`• Naltrexone (NTX) was compared to an identical-appearing inert
`substance (placebo, PBO). The naltrexone dose was equivalent to
`50 mg/day, except in the study by Monterosso et al. (2001;
`100 mg/day).
`• Neither subjects nor investigators knew if NTX or PBO was
`being taken (double-blind).
`
`Outcome Measures
`Table 1 shows seven outcome measures used to compare the
`efficacy of naltrexone with placebo. The first two – abstinence and
`time to first drink – portray alcohol avoidance during the respective
`trial.
`The next four are alcohol consumption outcomes in those sub­
`jects who were not abstinent: number of drinking days, drinks per
`drinking day, relapse rate, and days of heavy drinking. In most stud­
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`AMN1022
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`Table 1: R
`CTs
`
`
`
`(Randomized,
`
`
`
`Controlled Clinical Trials) – Naltrexone (NTX) vs Placebo (PBO)
`
`Notes
`
`NTX Efficacy Outcomes
`
`Craving Score
`
`Drinking
`
`Days Heavy
`
`Relapse
`
`Drinking Day
`Drinks per
`
`Drinking Days
`
`Time to 1st Drink
`
`Abstinence
`
`Study*
`(Authors/Year
`Country, Sites)
`
`N
`
`Study
`Dura­
`tion
`
`Type of
`Psycho­
`social
`Therapy
`
`O’Malley et al. 1992,
`1996a, 1996b; Jaffe
`et al. 1996.
`USA-single site.
`
`Volpicelli et al. 1992,
`1995b.
`USA-single site.
`
`Volpicelli et al.1995a,
`O’Brien et al. 1996.
`USA-single site.
`
`Balldin et al. 1997;
`Bergland 1997,
`Mansson et al. 1999.
`Sweden-multisite.
`
`Oslin et al. 1997.
`USA-single site.
`
`97
`
`12 wk CST vs ST
`
`NS
`
`++ + ++
`
`++
`
`+
`
`70
`
`12 wk
`
`TAU
`
`NS
`
`99
`
`12 wk
`
`TAU
`
`NS
`
`120 24 wk CST vs ST
`
`NS
`
`NS
`
`44
`
`12 wk
`
`ST
`
`NS
`
`NS
`
`+
`
`+
`
`+
`
`+
`
`+
`
`CST had the significant effects on all outcomes, and
`results were better in trial completers. During a 24 wk
`off-tx followup, NTX group had fewer heavy drinking days
`and fewer redeveloped the full syndrome of alcoholism.
`++ NTX had greatest effect in decreasing subsequent drink­
`ing once drinking occurred. Besides reducing relapse
`rate, NTX significantly increased the time to relapse.
`++ NTX reduced the risk of excessive drinking in the event
`of a slip. (Some subjects in this study overlap with those
`in the earlier report by Volpicelli et al. 1992.)
`
`+
`
`+
`
`NS
`
`NS
`
`Effects seen only in the NTX/CST group, and persisted
`during 24 wk off-treatment follow-up period. ST was
`described as Treatment As Usual by the authors and
`was abstinence-oriented.
`
`Studied older men (mean age 58 years). Relapse was 20%
`less in NTX group, but was NS. NTX significantly reduced
`relapse progression in subjects sampling any alcohol.
`
`97
`
`12 wk
`
`CST
`
`NS
`
`+
`
`NS
`
`Volpicelli et al. 1997.
`USA-single site.
`
`Anton et al. 1999,
`2001.
`USA-single site.
`
`Chick et al. 2000.
`UK-multisite.
`
`Kranzler et al. 2000.
`USA-single site.
`
`Heinala et al. 2001.
`Finland-single site.
`
`Monterosso et al.
`2001.
`USA-single site.
`
`Monti et al. 2001.
`USA-single site.
`
`Morris et al. 2001.
`Australia-single site.
`
`+
`
`131 12 wk
`
`CST
`
`NS
`
`NS
`
`+
`
` ++
`
` +
`
`175 12 wk
`
`TAU
`
`NS
`
`NS
`
`NS
`
`+
`
`124 12 wk
`
`CST
`
`NS
`
`NS
`
`NS
`
`NS
`
`NS
`
`121 12 wk CST vs ST
`
`NS
`
`NS
`
`++
`
`183 12 wk
`
`TAU
`
`+
`
`128 12 wk CST vs ST
`
`NS
`
`+
`
`NS
`
`+
`
`111
`
`12 wk
`
`CST
`
`NS
`
`NS ++ ++
`
`Krystal et al. 2001.
`USA-multisite.
`
`627 13 wk &
`52 wk
`
`ST
`
`NS
`
`NS
`
`NS
`
`Outcomes are expressed for study completers; ITT
`analyses demonstrated weaker effects of NTX. Subjective
`“high” associated with drinking was reduced by NTX.
`
`NS
`
`For those who drank, NTX significantly increased number
`of days between episodes. By the end of a 14-wk off-tx
`followup period, significant benefits of NTX had faded.
`++ Outcomes are expressed for completing & compliant
`subjects. Only craving remained significant in ITT analysis.
`
`NTX-compliant patients had better outcomes, but these
`were NS compared with PBO. Only study in which reten­
`tion and compliance were significantly lower in NTX group.
`
`NTX/CST had the primary effect. There was a 20 wk
`followup using NTX on a “targeted” basis, during which
`reduced relapse rates persisted in NTX/CST group.
`
`+
`
`NTX dose was 100 mg/day (50 mg BID). NTX was
`associated with significantly less clinical deterioration.
`Positive NTX effects were associated with higher initial
`craving and a greater family history of alcoholism.
`+ More significant effects seen in patients compliant with
`medication and in the CST group. Compliant patients
`also had fewer relapses, but was NS. Beneficial NTX
`effects faded during off-tx followup at 6 and 12 months.
`
`Outcomes are for study completers. ITT analysis for re­
`lapse was NS, but time to relapse was highly significant.
`
`NTX tx was either 13 wk or 52 wk vs PBO 52 wks. ITT
`analyses shown; however, in all groups, more compli­
`ant subjects and those attending more therapy or AA
`sessions had better outcomes.
`
`*Multiple analyses of the same patient population are grouped together as one study. NTX dose = 50 mg/day, except Monterosso et al. 2001.
`Psychosocial Therapy: CST = Coping Skills (relapse prevention) Therapy; ST = Supportive (abstinence-oriented) Therapy; TAU = Treatment As Usual or “standard therapy.”
`Outcomes: Favoring NTX: + - p< 0.05; ++ - p< 0.01. NS = No Significant Difference (equivalent). Blank means the outcome was not reported in the study.
`Abbreviations: NTX = naltrexone; PBO = placebo; wk = week; ITT = intention-to-treat (includes dropouts & noncompliers); tx = treatment.
`
`3
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`AMN1022
`IPR of Patent No. 7,919,499
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`

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`NTX Outcome Measures
`
`1.2
`
`1
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`
`NTX Evidence Score
`
`0
`
`
`b
`
`A
`
`e
`stin
`T i m
`
`n
`
`e
`c
`e t o 1
`
`k
`st D rin
`# D rin
`
`kin
`
`a
`
`y s
`k s / D rin
`
`g D
`D rin
`
`y
`
`a
`
`k D
`
`g
`
`kin
`
`e
`v y D rin
`
`ela
`
`R
`
`s
`
`p
`
`a
`
`e
`
`H
`
`g
`
`vin
`
`C r a
`
`Figure 1: NTX score measures the strength of evidence favoring naltrexone, rep­
`resented by averaging efficacy scores for all RCTs in Table 1 that measured the
`particular outcome. Points were assigned as: 0 (NS), 1 (+), and 2 (++). Score of 1
`or above represents statistically significant advantage of NTX over PBO.
`
`alcohol-sampling episode or “slip.” Whereas, almost all (95%)
`placebo-treated subjects who slipped proceeded to relapse, those tak­
`ing naltrexone typically drank less during a slip and only half of them
`actually relapsed to heavy drinking.
`Volpicelli and colleagues (1995a, 1995b) also observed that nal­
`trexone-treated subjects reported that the subjective “high” or eupho-
`
`The Significance of “Significance”
`The RCTs evaluated for this report compared naltrexone with placebo
`on each particular outcome measure studied to determine superiority of
`one over the other. Statistical analyses were used by the researchers to
`evaluate and quantify the significance of any differences, with a stan­
`dard cut-off point for significance of p < 0.05 (designated ‘+’ in Table 1).
`
`Probability- or p-values are considered in this report as a relative indi­
`cator of effect size and strength. In a broad sense, a p < 0.05 means that
`the observed benefit for naltrexone on the particular outcome measure
`is large enough to be considered a true and “significant” advantage; that
`there is less than a 5% probability that the effect occurred merely due
`to chance. Put another way, with a p-value of 0.05 or less there is at
`least a 95% certainty that the observed effect is “real” and valid, rather
`than being merely a coincidence.
`
`Probability-values less than 0.01 (designated ‘++’ in Table 1) suggest the
`effect favoring naltrexone is even stronger. There is 99% certainty the
`effect is not due to chance.
`
`Conversely, any p-value greater than the 5% cut-off point (e.g., p =
`0.06), suggests that differences between groups may be due merely to
`chance and are not statistically significant (designated NS in Table 1). In
`essence, the effect of naltrexone, although possibly appearing to be
`favorable in terms of absolute value, must be considered as no better
`than placebo on the particular measure.
`
`Hypothetically, it is possible to have negative effects; that is, naltrexone
`producing worse results than those observed in the placebo group.
`
`However, this was not observed in any of the clinical RCTs to date.
`
`Also, it is important to note that an outcome may not be statistically sig­
`nificant but still have clinical significance. For example, due to study lim­
`itations or variability in results, an overall 20% reduction in relapse rate
`associated with naltrexone may not reach statistical significance (as in
`the study by Oslin et al. 1997). However, this still can be clinically valu­
`able by preventing full-blown relapse in one additional patient for every
`five treated with naltrexone.
`
`ies, relapse was defined as having 5 or more drinks on any single
`occasion for men and 4 or more drinks for women, or drinking 5 or
`more days within one week, or attending a treatment session intoxi­
`cated. “Heavy” drinking was commonly defined as more than five
`
`drinks, which would make this measure equivalent to a relapse day.
`Finally, nine studies evaluated craving, although this was vari­
`ously defined by investigators using different assessment instruments
`to arrive at a patient-determined score. Often, craving at the beginning
`of treatment was compared with craving at end of treatment to note
`differences.
`
`Unfortunately, there is no standard set of efficacy outcome mea­
`sures used in all studies. Blank boxes in Table 1 indicate those mea­
`sures not mentioned in the respective published RCT reports.
`
`Adjunctive Psychosocial Therapy
`Researchers have paired naltrexone and placebo with different
`psychosocial therapies to compare the combined efficacy. Table 1
`indicates three general types that have been variously described and
`used:
`Supportive Therapy (ST) – focuses on abstinence from alco­
`hol, without teaching specific coping skills to avoid relapse. ST
`may be 12-step oriented and include encouragement to attend
`Alcoholics Anonymous meetings.
`Coping Skills Therapy (CST) – also called relapse prevention
`therapy or cognitive behavioral therapy (CBT) – teaches
`patients ways of dealing with situations and feelings that pro­
`voke a return to drinking, and how to keep a drink (“slip”) from
`leading to a relapse.
`Therapy As Usual (TAU) – is the “Standard Therapy” at the
`particular study center and may mix components of CST and/or
`ST modalities. If it could be determined that TAU seemed slant­
`ed toward either supportive or coping skills therapy, the psy­
`chosocial therapy was respectively coded ST or CST in Table 1.
`Research teams appeared to modify psychosocial approaches
`based on their clinical experience, so there may have been some dif­
`ferences in how the same type of therapy was structured in various
`RCTs. For the two multisite RCTs, there also is the question of
`whether the same therapy was delivered consistently at various loca­
`tions by different therapists.
`
`Summary of RCT Results
`Drinking Outcomes
`Outcome values in Table 1 are denoted in terms of the statistical
`significance of data comparing naltrexone with placebo (see sidebox
`on “Significance”). Thus, on each particular measure, the effects of
`naltrexone were either comparable to placebo (NS or nonsignificant),
`of significant advantage (+), or very significantly beneficial (++). In
`no case was naltrexone of less benefit than placebo.
`Figure 1 graphically summarizes the advantages of naltrexone
`relative to placebo. It represents for each outcome an averaging of
`results across all RCTs that reported the measure.
`Naltrexone does not appear to exert an influence compared with
`placebo on maintaining abstinence or in postponing the first drink in
`those patients who cannot avoid alcohol. However, there is clear and
`consistent evidence that naltrexone is significantly beneficial in help­
`ing those patients who cannot remain abstinent to reduce their drink­
`ing behaviors. They drink less often and in lower quantities, avoid­
`ing full-blown relapse.
`Volpicelli et al. (1992) reported that naltrexone appeared to be
`most effective in decreasing drinking in subjects who had at least one
`
`4
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`AMN1022
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`

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`chosocial therapy, since its goal was to avoid any drinking at all.
`In general, coping skills therapy (CST), emphasizing relapse-
`prevention strategies, proved much more effective than supportive
`therapy in achieving positive outcomes associated with naltrexone.
`“Treatment as usual” (TAU) therapies also were effective, and
`observed primarily in three investigations at University of
`Pennsylvania treatment centers (Volpicelli et al. 1992, 1995a;
`Monterosso et al. 2001). The approach here emphasized support of
`abstinence, including participation in group therapy stressing moti­
`vational enhancement, relapse prevention skills, and compliance
`with the medication regimen. Therapy was customized to patient
`needs and seemed to benefit from a synergism of the best that sup­
`portive and coping skills therapy might offer individually.
`
`Contrary Evidence
`Only 2 of 14 RCTs to date have failed to demonstrate signifi­
`cantly favorable effects of naltrexone: Kranzler et al. 2000 and, most
`recently, Krystal et al. 2001.
`Krystal and colleagues raised doubts about the utility of nal­
`trexone in older patients with chronic, severe alcohol dependence.
`They studied a population of men averaging 49 years of age and 20
`
`years of heavy drinking. However, their findings conflict with other
`RCTs, involving almost identical populations of older males with
`long drinking histories, which reported significantly favorable
`results for naltrexone in terms of relapse, frequency of drinking, and
`quantity of alcohol consumed (Morris et al. 2001; Oslin et al. 1997).
`A critical factor in the RCT by Krystal et al. was the adjunctive
`use of strictly abstinence-based therapy focusing on 12-step facilita­
`tion counseling. In prior research, this was not found to be effective
`in combination with naltrexone. Still, these researchers did observe
`that naltrexone treatment extended the time to relapse by nearly 70%
`and this might have been a significant benefit clinically. A survival
`analysis of the sort shown in Figure 2 was not reported.
`Finally, the Krystal et al. trial was conducted at 15 Veterans
`Affairs medical centers, so the quantity, quality, and consistency of
`psychosocial therapy across treatment centers is questionable. This
`intersite variability combined with relatively small numbers of
`patients at each center might have led to reduced effect sizes.
`This phenomenon also was evident in a multisite RCT by Chick
`et al. (2000) in which psychosocial therapy reportedly varied widely
`by center and naltrexone benefits were most significant for those
`patients staying in treatment and taking medication. In their trial,
`Krystal et al. did not report on the subgroup of completing and com­
`pliant patients.
`The earlier Kranzler et al. (2001) trial, was the only RCT to date
`in which naltrexone-treated patients exhibited significantly less med­
`ication compliance and more study withdrawals than the placebo
`group. In all other trials reporting the measures, naltrexone treatment
`was associated with greater or equivalent compliance and retention
`compared with placebo.
`Also in contrast to other RCTs, Kranzler and colleagues report­
`ed significantly more side effects with naltrexone, primarily gas­
`trointestinal-related (eg, nausea, vomiting, diarrhea). They observed
`that subjects with more GI complaints pretreatment were more sus­
`ceptible to subsequent GI symptoms when treated with naltrexone,
`resulting in less medication compliance and, eventually, early with­
`drawal from the study. Patients who were able to tolerate naltrexone
`had better outcomes, but the trends were not statistically significant.
`Although standard inclusion/exclusion criteria were used for
`subject selection by Kranzler et al., they reported enrolling 183 of
`
`Naltrexone-treated group
`Placebo-treated group
`
`Without Relapse
`
`Cumulative Proportion
`
`Number of Weeks Receiving Medication
`
`Figure 2: Progressive proportions of patients without relapse – “survival
`analysis” – for NTX vs PBO groups, significantly favoring NTX (data from
`Volpicelli et al. 1995a).
`
`ria produced by alcohol was significantly less than usual. This is con­
`sistent with naltrexone’s action in blocking opioid receptors and
`diminishing pleasurable effects associated with alcohol drinking.
`Besides reducing overall relapse rates, naltrexone also appears
`to significantly prolong the relapse-free time in those who eventual­
`ly do relapse. Figure 2 depicts the typical relationship plotted over
`time, called a “survival curve,” comparing naltrexone with placebo
`(Morris et al. 2001, Volpielli et al. 1995a).
`Furthermore, Anton et al. (1999) found that naltrexone effec­
`tively doubled the time between a first relapse (or heavy drinking
`day) and a second such episode. Taken together, naltrexone’s effects
`
`in stemming relapse to heavy drinking allow more quality time for
`psychosocial therapy to be productive.
`
`Alcohol Craving
`Alcohol craving was measured and reported in 9 of 14 RCTs. As
`Figure 1 indicates, naltrexone therapy quite significantly reduced
`craving.
`Various researchers have noted that patients with higher initial
`craving appear to derive greatest benefit from naltrexone (Jaffe et al.
`1996; O’Malley et al. 1992; Monterosso et al. 2001). Volipicelli
`(2001) recently observed that naltrexone seems to have an immedi­
`ate effect of reducing the urge to drink and this can be very useful in
`helping patients focus on other issues besides alcohol craving, espe­
`cially during early stages of recovery.
`There is the question of why this reduced craving effect did not
`enhance abstinence in the RCTs. First, craving may be but one drive
`motivating drinking. Second, heavy drinking may itself induce crav­
`ing and, since naltrexone-group patients drank less often and in
`lower quantities, this helps explain their lower craving scores but
`only equivalent abstinence compared with placebo-treated subjects
`(Chick et al. 2000).
`
`Impact of Psychosocial Therapy
`RCT results suggest that the efficacy of naltrexone can be
`dependent on the type of psychosocial therapy with which it is
`paired. As Table 1 demonstrates, supportive, abstinence-oriented,
`therapy (ST) was largely ineffective in conjunction with naltrexone
`on any outcome measures, with the single exception of the trial by
`Oslin et al. (1997) in older patients.
`Oslin and colleagues found naltrexone significantly effective in
`reducing the extent of drinking and progression to relapse in subjects
`sampling alcohol. This was unlikely related to the supportive psy­
`
`5
`
`AMN1022
`IPR of Patent No. 7,919,499
`
`

`

`Table 2: Summary of Demographic Data
`Total: 14 RCTs; 2127 Subjects
`
`No.* Mean**
`14
`84%
`
`Range
`71% - 100%
`
`13
`
`12
`
`9
`
`7
`
`7
`
`44.5
`
`42%
`
`62%
`
`21
`
`12
`
`39 - 58
`
`16% - 73%
`
`27% - 84%
`
`15 - 30
`
`10 - 13.5
`
`and alcohol craving.
`It should be noted that
`advantages of naltrexone are
`also based on its specific nature,
`rather than simply study reten-
`tion and/or medication compli-
`ance. As Litten and Allen (1998)
`have observed, in most RCTs,
`patients do better with naltrex-
`one than placebo-treated sub-
`jects who are equally retained
`and compliant.
`
`194 persons recruited (94%).
`This is an unusually high accep-
`tance rate and it is possible that
`the study population was biased
`in some way, resulting in a
`greater proportion of subjects
`with predispositions to adverse
`reactions when taking psychoac-
`tive medications. For example, a
`separate arm of this trial investi-
`gated possible benefits of nefa-
`zodone, an antidepressant, and
`also observed significant increas-
`es in side effects in that group.
`On the basis of these two
`trials, any deficiencies of naltrex-
`one’s efficacy
`in particular
`patient populations cannot be
`concluded.
`
`Measure
`Males
`
`Age (years)
`
`Married
`
`Employed
`
`Years Drinking
`
`Drinks Per Day Prior
`
`Study Retention
`
`Naltrexone
`
`Placebo
`
`Medication Compliance***
`
`Naltrexone
`
`Placebo
`
`Interacting Factors
`The efficacy of naltrexone in
`treating alcoholism has been
`demonstrated across a range of
`treatment programs, internation-
`ally, using differing psychosocial therapies, and in diverse patient
`populations. Table 2 summarizes demographic data for all RCT
`participants.
`It should be noted, that RCTs to date have focused on males
`between 39 and 58 years of age, on average. Other factors also may
`interact to influence efficacy outcomes.
`
`Importance of Retention/Compliance
`Naltrexone appears to be especially effective for patients who
`stay in treatment and comply with medication regimens (Chick et al.
`2000; Monti et al. 2001; O’Brien et al. 1996; O’Malley et al. 1992;
`Volpicelli et al. 1997). As Table 2 shows, naltrexone was associated
`with slightly greater retention and compliance than placebo,
`although this trend was not statistically significant and there was a
`wide range across studies.
`Most RCTs reported “intention-to-treat” (ITT) analyses that
`included data from all patients, whether or not they remained in the
`study or took their medication. This tends to understate medication
`efficacy and might have occurred, for example, in the Oslin et al.
`(1997) trial. There was very low treatment compliance (less than a
`third of patients in either group) and consequently few significant
`benefits of naltrexone were reported in the ITT analysis. (Oslin and
`colleagues also used an unusual dosing schedule: every other day –
`100, 100, 150 mg – considered equivalent to 50 mg/day).
`Four of the naltrexone RCTs – Chick et al. 2000; Morris et al.
`2001; O’Malley et al. 1992; Volpicelli et al. 1997 – reported analyses
`focusing on patients who completed the trials and were compliant
`with medication regimens. These analyses, known as “per protocol,”
`demonstrated significant effects of naltrexone and are reflected in
`Table 1.
`This apparently did not slant the summarization of outcomes in
`this report, since a recent meta-analysis by Streeton and Whelan
`(2001) using only ITT data reached the same conclusions as present-
`ed above in figure 1. That is, naltrexone significantly improves out-
`comes in terms of alcohol consumption, relapse to heavy drinking,
`
`*Number of studies reporting the measure. **Based on averages across
`studies. ***Compliance is variously defined across studies.
`
`12
`
`10
`
`72%
`
`70%
`
`66%
`
`64%
`
`41% - 91%
`
`42% - 91%
`
`32% - 98%
`
`31% - 98%
`
`Long-Term Efficacy
`Six of 14 RCTs examined
`long-term effects of naltrexone
`during followup periods ranging
`from 14 to 40 weeks after the
`end of drug treatment (ie, off-
`treatment). Results suggest that
`naltrexone is effective as long as
`it is taken, but benefits begin
`fading once the medication is
`terminated (see Table 1 “Notes”
`– Anton et al. 1999; Heinala
`2001; Krystal et al. 2001; Monti et al. 2001; O’Malley et al. 1996a;
`Mansson et al. 1999).
`Some