01 45-000819812205- 1074$03.00/0
`AI ('01101.ISM: CUNI(.AL AN11 E X P ~ K I M I . N I A ~ RI.SEAKCII
`
`Vol. 22, No. 5
`August 1998
`
`RAPID COMMUNICATION
`
`Sus tained-Release Naltrexone for Alcoholism
`Treatment: A Preliminary Study
`
`Henry R. Kranzler, Vania Modesto-Lowe, and Elie S. Nuwayser
`
`This 12-week study examined the bioavailability, tolerability, and po-
`tential efficacy of an injectable sustained-release preparation (SRP)
`of naltrexone (NTX). Twenty alcohol-dependent subjects took NTX
`50 mg PO daily for 2 weeks, followed by a 2-week, no-medication
`Washout Period, a 4-week Injection Period, and a 4-week Follow-up
`Period. Fifteen subjects (75%) received a single subcutaneous injec-
`tion of 206 mg of sustained-release NTX, and five subjects (25%)
`received a placebo injection. All subjects also received eight weekly
`coping skills sessions during the Oral NTX, and the Washout and
`Injection Periods. Results: After injection, NTX plasma concentra-
`tions exceeded a mean of 1 ng/ml for 21 days. Adverse effects pro-
`duced by the SRP of NTX were comparable with those resulting from
`oral NTX therapy. Compared with placebo, the SRP of NTX signifi-
`cantly reduced the frequency of heavy drinking days during the In-
`jection and Follow-up Periods. Conclusions: The results of this pre-
`liminary study support the potential clinical utility of the SRP of NTX
`for treatment of alcohol dependence.
`Key Words: Naltrexone, Sustained-Release Preparation, Alcohol-
`ism, Alcohol Dependence, Pharmacotherapy.
`
`N alcohol consumption
`ALTREXONE (NTX), an opioid antagonist, reduces
`in alcohol-dependent pa-
`tients. ',' Despite these early results, more recent findings
`indicate that, as in opioid addicts,3 the effectiveness of
`NTX in alcoholics is limited by problems with compliance.
`Recent studies by Chick4 and Volpicelli et al.' failed to
`show an overall advantage for NTX. In these studies, the
`active medication was superior to placebo (PLA) in reduc-
`ing alcohol consumption only among highly compliant sub-
`jects. Although compliance with a variety of medications is
`often problematic,'
`the importance of these findings is
`underscored by the fact that alcoholics show particularly
`low rates of medication ~ompliance.'~~
`One approach to ensuring medication compliance is the
`
`Frotn the Alcohol Research Center, Department of Psychiatry (H. R. K.,
`V. M. -L), Uriiversi!y of Conncc~ticut Health Ccnter, Furmington, Connecticut;
`und BIOTEK, Iric. (E.S. N.), Wohiirn, Mussuchwetts.
`Receivcd for pi~hlicution Junuury 28. I99X; accepted April 6. 1998
`This sludy was siipported by the Nationul Institures of Health Grants
`AA03510. AAORQO, AA00239, utzd RRV6192 (General Clinical Research
`Center).
`Reprint requests: Hetvy R. Krunzler, M. D., Department of Psychiatry,
`MC2103, University of Connecticut fleullh Center, Farnington, CT 06030-
`2103.
`Copyright 0 I998 by The Reseurch Society on Alcoholism.
`
`1074
`
`use of a sustained-release preparation (SRP), which may
`also increase the likelihood of a therapeutic response by
`yielding a more predictable and constant plasma concen-
`tration than oral drug administration.' A parenterally ad-
`ministered SRP may also result in a higher brain concen-
`tration of the parent compound by bypassing hepatic
`metabolism.'
`Chiang et al. ' O administered a 63-mg, sustained-release
`NTX bead preparation to three healthy male volunteers.
`Concentrations of NTX were highest on the first day after
`subcutaneous administration and then fell to 0.2 to 0.4
`ng/ml from day 2 until the end of the experiment (23 to 32
`days after implantation). Local irritation occurred in two of
`the subjects. In a subsequent study, Chiang et al." found
`relatively constant plasma concentrations of NTX (0.30 to
`0.46 ng/ml) and 6-p-naltrexol (0.64 to 1.07 ng/ml) for 2 to 4
`weeks after implantation, concentrations that partially or
`completely blocked the effects of intravenous challenges
`with 15 mg of morphine.
`More recently, an SRP of NTX that uses biodegradable,
`injectable microcapsules was administered to four healthy
`volunteers with no reported adverse effects.'* Alim et al.13
`administered the same microcapsule preparation subcuta-
`neously to 8 cocaine-dependent subjects: 2 received a PLA
`injection, 3 received 103 mg of NTX, and 3 received 206 mg
`of NTX. Patients in the NTX and PLA groups reported
`mild pain during the first few days after injection, with
`erythema and induration occurring commonly. The present
`study examined the bioavailability, tolerability, and poten-
`tial efficacy of this microcapsule SRP of NTX (produced by
`BIOTEK, Inc., Woburn, MA) in alcohol-dependent sub-
`jects.
`
`METHODS
`
`Procedures
`Twenty alcohol-dependent subjects participated in this 12-week study.
`After a minimum of 3 days of abstinence from alcohol, all subjects
`underwent 2 weeks of treatmcnt with 50 mg/day of oral NTX (Oral NTX
`Period) to identify those individuals who could not tolerate the medica-
`tion. Subjects then entered a 2-week, medication-free Washout Period,
`followed by random assignment to receive one injection of either depot
`NTX (15 subjects, 75%) or placebo (5 subjects, 25%), which was expected
`Alcohol Clin Exp Res, Val 22, No 5, 1998: pp 1074-1079
`APOTEX EXHIBIT 1008
`Apotex v. Alkermes
`IPR2025-00514
`
`

`

`SUSTAINED-RELEASE NTX FOR ALCOHOLISM TREATMENT
`
`Week 0
`I Oral
`: NTX
`: Period
`
`2
`
`4
`
`I Washout 1
`Period
`
`8
`
`Injection Period
`
`Followup Period
`
`12
`
`I
`
`Weekly Coping Skills Sessions
`(Treatment Phase)
`Fig. 1. Timeline of study periods.
`
`* ’
`
`to dclivcr medication for 4 weeks (Injection Period). The first 8 weeks of
`thc study (which included the 2-week Oral NTX Period, the 2-week
`Washout Period, and the 4-week Injection Pcriod) were designated as the
`Treatment Phase, hecausc during this time all subjects also received
`weekly, individual coping skills psychotherapy.14.15 After the 8-week
`Trcatmcnt Phase, all subjects underwcnt two research assessments over a
`4-wcek Follow-up Period. Figure 1 shows a timeline of each subject’s
`participation.
`
`Assessments
`The Michigan Alcoholism Screening Test,I6 Addiction Severity In-
`dex,” and Alcohol Dcpcndence Scale’x werc administered at study entry
`to evaluate alcoholism severity and alcohol treatment history. The Time-
`Line Follow-Back Assessment method” was used to quantify drinking
`days, heavy drinking days ( 2 4 drinks in a day for females and 2 5 drinks
`in a day for males), and total alcohol consumption during the 4-week
`Prctreatment Period and for each period of
`the 12-week study.
`y-Glutamyltranspeptidasc (GGTP) levels were obtained at the same in-
`tervals to validate reported alcohol consumption.
`Three assessments werc repeated weekly during the 8-week Treatment
`Phase: breath alcohol testing, the Systcmatic Assessment for Treatment
`Emergent Events’” to monitor adverse events, and the Beck Depression
`Inventory“ to measure recent depressive symptoms.
`
`Subjects
`Subjects werc recruited through advertisements. All subjects gave writ-
`ten, informed consent to participate. After screening, subjects were eval-
`uated using the Structured Clinical Interview for DSM-IV,22 clinical lab-
`oratory tcsts (CBC, urinalysis, blood chemistries, and, for women, a serum
`pregnancy test), and a physical examination. Inclusion criteria were age 18
`to 60 years, ability to read English, and a current DSM-IV diagnosis of
`Alcohol Dcpendencc.23 Exclusion criteria were a current DSM-IV diag-
`nosis of drug dependcnce (other than nicotine), a lifetime diagnosis of
`opioid dependence, psychoactive drug use in the preceding month, no
`stable residence, evidence of a major psychiatric or medical illness, preg-
`nancy, or lack of birth control. As shown in Table 1, there were no
`significant between-group differences on any demographic or clinical
`variables. All subjects werc Caucasian.
`
`Treatment
`Prior to injection, the microcapsule preparation was reconstituted in a
`suspending medium, to a total volume of 2.4 ml. The preparation was
`administered subcutaneously as a single injection in the gluteal region.
`Thc active SRP contained 206 mg of NTX, the maximal dose previously
`administered to humans.” The PLA preparation contained vehicle and
`microcapwles, but no NTX. A research pharmacist randomly assigned
`subjects to a mcdication group, with double-blind conditions maintained
`throughout thc study.
`
`Laborat09 Analysis
`Blood was collected nine times over the course of the 8 weeks after
`injection (i.c., during the Injection and Follow-up Periods). Solid-phase
`
`Table 1. Pretreatment Demographic and Clinical Features by
`Medication Group
`NTX
`(n = 15)
`
`PLA
`(n = 5)
`
`Test
`
`1075
`
`p
`
`73.3
`66.7
`80.0
`47.0 (9.0)
`14.9 (2.8)
`
`80.0
`80.0
`40.0
`48.2 (4.3)
`15.0 (4.1)
`
`1.7 (2.5)
`4.9 (1.0)
`21.9 (8.4)
`13.1 (3.1)
`19.8
`(10.6)
`0.47 (0.64)
`
`1.0 (1.7)
`5.2 (1.3)
`24.0 (14.0)
`15.2 (8.2)
`23.2 (7.2)
`0.80 (0.45)
`
`Demographics
`Gender (% male)
`Employment (% full time)
`Marital status (% married)
`Age (years)
`Education (years)
`Clinical Features
`BDI’ score
`DSM-IVt criteria
`MASTS score
`ADS§ score
`Years of heavy drinking#
`Prior treatments for
`alcoholism#
`* BDI, Beck Depression Inventory (Beck et al., 1961).
`* MAST, Michigan Alcohol Screening Test (Selzer, 1971).
`t Alcohol Dependence Criteria (American Psychiatric Association, 1994).
`5 ADS, Alcohol Dependence Scale (Skinner and Allen, 1982).
`# From the Addiction Severity index (McLellan et al.. 1988).
`
`FET
`FET
`FET
`F = 0.08
`F = 0.00
`
`F = 0.24
`F = 0.24
`F = 0.17
`F = 0.49
`F = 0.44
`F = 1.15
`
`1 .oo
`1 .oo
`0.13
`0.77
`0.96
`
`0.63
`0.63
`0.69
`0.49
`0.51
`0.30
`
`extraction and derivitization, followed by gas chromatography-negative
`ion chemical ionization-mass spectrometry, were used to measure plasma
`concentrations of NTX and 6-p-naltre~ol.~~ The precision and accuracy of
`this procedure have previously been demonstrated.”
`
`Data Analysis
`A two-tailed criterion of p < 0.05 was used to define statistical signif-
`icance. One-way analysis of variance (ANOVA) was used to compare
`groups on continuous measures and Fisher’s Exact Test (FET) was used
`for categorical measures. Paired t tests were used to compare mean weekly
`adverse effects during the Oral NTX Period with those occurring during
`the Injection and Follow-up Periods. The Pearson correlation coefficient
`was used to examine the degree of association between changes in GGTP
`level and changes in total alcohol consumption during the OralWashout,
`Injection, and Follow-up Periods and to examine the association between
`adverse effects and changes in alcohol consumption.
`Hierarchical multiple regression was used to examine the effect of the
`SRP (i.e., NTX versus PLA) on adverse effects and drinking outcomes,
`after controlling for the respective measures during the Oral NTX and
`Washout Periods. Measures from these periods were entered into the
`analyses prior to medication group to examine change from the time of
`random assignment through the end of the study (i.e., the only time over
`which the injection could have exerted its effects). Because drinking
`measures from the Pretreatment Period did not contribute significantly to
`the variance in drinking outcomes during the study, they were not included
`in the regression equations. Regression analyses were conducted sepa-
`rately for the Injection and Follow-up Periods. Based on prior reports,’.’
`we hypothesized that the SRP of NTX would exert its greatest effects on
`the percentage of heavy drinking days.
`
`RESULTS
`
`Plasma Concentrations
`Plasma concentrations of NTX and 6-P-naltrexol were
`obtained after the Washout Period (i.e., immediately prior
`to the depot injection), and then a mean of 1, 3, 8, 13, 20,
`27,34,42, and 64 days after the injection. As can be seen in
`Fig. 2, the mean plasma NTX concentration exceeded 1
`ng/ml, the concentration thought to produce opioid antag-
`
` 15300277, 1998, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1530-0277.1998.tb03703.x by Pennsylvania State University, Wiley Online Library on [22/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
`
`

`

`1076
`
`KRANZLER ET AL.
`
`Table 2. Means for Drinking Measures by Study Period and Medication Group
`Prior to Depot Injection
`NTX
`(n = 15)
`
`PIA
`(n = 5)
`
`p Value’
`
`Pretreatment Period (4 weeks)
`% drinking days
`YO heavy drinking days
`Average drinkdday
`Oral NTX Period (2 weeks)
`% drinking days
`% heavy drinking days
`Average drinkgday
`Washout period (2 weeks)
`% drinking days
`YD heavy drinking days
`Average
`
`* Using ANOVA.
`
`68.1 (19.1)
`50.2 (30.0)
`4.9 (3.6)
`
`11.4 (14.9)
`2.9 (9.3)
`0.3 (0.5)
`
`21.0 (24.3)
`7.3(13.6)
`0.8 (1.1)
`
`71.3 (16.1)
`64.7 (29.0)
`6.1 (4.0)
`
`5.8 (7.4)
`0
`0.1 (0.2)
`
`19.1 (19.4)
`0
`0.5 (0.6)
`
`0.73
`0.36
`0.61
`
`0.44
`0.51
`0.37
`
`0.88
`0.26
`0.57
`
`45
`
`5o
`
`55
`
`0
`
`5
`
`10
`
`15
`
`4o
`
`s5
`30
`25
`20
`Days Following Injection
`Fig. 2. Naltrexone and 6-p-naltrexol plasma concentrations after a single
`depot injection in 15 alcoholics. Values are mean (SEM) for days on which multiple
`.
`.
`
`measurements were taken.
`
`onist effects,”’25 for 21 days after the active SRP was
`administered.
`
`Medication Tolerance
`Seven subjects [5 NTX (33.3%) and 2 PLA (40%)] com-
`plained of a burning sensation at the time of the injection
`(FET = 0.59). In three of these cases (2 NTX and 1 PLA),
`soreness at the injection site persisted over the week after
`injection. An area of induration was evident at the injection
`site among 13 subjects [ l l NTX (73%) and 2 PLA (40%)
`(FET = 0.29)], with the size of the induration ranging from
`0.5 cm (NTX subject) to 4.0 cm (PLA subject) in diameter.
`The induration resolved completely to palpation over a
`period of 2.8 (SD = 1.3) weeks (range = 1 to 5 weeks).
`Nine subjects [2 PLA (40%) and 7 NTX (46.7%)] re-
`ported other adverse effects during the Injection Period
`(FET = 0.60). The mean number of weekly complaints
`during this period was 0.40 (SD = 0.54) for the PLA group
`and 1.33 (SD = 1.95) for the NTX group. Adverse effects
`reported after depot NTX were comparable in frequency to
`those reported during the Oral NTX Period (mean = 1.80,
`SD = 1.82, paired t , , = 1.07, p = 0.30). Although the
`number of adverse effects during the Oral NTX Period
`predicted the number of adverse effects during the Injec-
`tion Period [ p = 0.457, F(1,18) = 4.74, p = 0.0431, the
`depot NTX and PLA groups did not differ significantly on
`this measure [ p = 0.257, F(1,16) = 1.59, p = 0.231.
`Of the adverse effects reported during the Injection Pe-
`riod, fatigue was most common (n = 3: no PLA subjects
`and 20% of NTX subjects), followed by complaints of
`mood changes (n = 2: no PLA subjects and 13.3% of NTX
`subjects). Rash, palpitations, headache, nausea, vertigo,
`and insomnia were each reported by one NTX subject. No
`complaints of a severe nature were reported during the
`Injection Period. All adverse effects resolved spontane-
`ously.
`During the Follow-up Period, eight NTX subjects (40%)
`and no PLA subjects reported adverse effects (FET =
`0.051). The mean number of weekly complaints by NTX
`subjects during this period was 1.27 (SD = 1.67), which
`
`does not differ statistically from the comparable measure
`during the Oral NTX Period (paired t,, = 0 . 8 1 , ~ = 0.43).
`There was a trend for the number of complaints reported
`during the Follow-up Period to be correlated with both the
`number of complaints during the Oral NTX Period [ p =
`0.455, F(1,18) = 4 . 2 2 , ~ = 0.0551 and with the medication
`group [ p = 0.402, F(1,16) = 4.16, p = 0.0591. During the
`Follow-up Period, 1 NTX subject reported severe vomiting,
`which resolved spontaneously.
`
`Validation of Selj-Reported Drinking
`NTX subjects’ GGTP levels (n = 15) declined from 40.9
`unitsfliter (SD = 28.9) at baseline to 29.4 unitsfliter (SD =
`21.3) for the Injection Period and 30.1 unitsfliter (SD =
`21.4) for the Follow-up Period. PLA subjects’ levels (n = 4;
`one subject failed to provide one specimen) declined from
`43.0 unitsfliter (SD = 19.9) at baseline to 33.5 unitsfliter
`(SD = 16.4) for the Injection Period and 38.5 unitsfliter
`(SD = 7.1) for the Follow-up Period. Between-group com-
`parisons of GGTP levels were nonsignificant (p’s all >
`0.10). However, change in GGTP level was significantly
`correlated with change in total alcohol consumption during
`the Oral and Washout Periods combined [r = 0.48, p =
`0.0171 and during the Injection Period [r = 0 . 4 7 , ~ = 0.0211.
`There was also a trend for an association between the
`change in these measures during the Follow-up Period [r =
`0 . 3 3 , ~ = 0.0841.
`
`Drinking Measures
`Table 2 shows drinking measures for the three study
`periods preceding the depot injection. ANOVA revealed
`no between-group differences on these measures (p’s all
`BO.10).
`Table 3 shows drinking measures for the Injection and
`Follow-up Periods. These comparisons control for the cor-
`responding measures during the Oral NTX and Washout
`Periods.
`Injection Period. During the Injection Period, the per-
`centage of drinking days was predicted by the comparable
`
` 15300277, 1998, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1530-0277.1998.tb03703.x by Pennsylvania State University, Wiley Online Library on [22/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
`
`

`

`SUSTAINED-RELEASE NTX FOR ALCOHOLISM TREATMENT
`
`Table 3. Means for Drinking Measures by Study Period and Medication Group
`after Depot Injection
`NTX
`(n = 15)
`
`PLA
`(n = 5)
`
`p Value’
`
`Injection Period (4 weeks)
`% drinking days
`% heavy drinking days
`Average drinkslday
`Follow-up Period (4 weeks)
`% drinking days
`% heavy drinking days
`Average drinkslday
`
`21 .O (25.5)
`3.7 (10.7)
`0.7 (0.6)
`
`28.2 (35.8)
`7.8 (18.2)
`1.1 (1.7)
`
`28.4 (34.5)
`5.3 (8.4)
`0.9 (1 -2)
`
`44.6 (31.4)
`23.0 (32.8)
`1.9 (1.7)
`
`0.42
`0.03
`0.08
`
`0.58
`0.04
`0.04
`
`* Using linear regression, controlling for the corresponding measures during
`the Oral NTX and Washout Periods.
`
`measure during the Oral NTX [ p = 0.72, F(1,18) = 19.25,
`p < 0.0011 and Washout [ p = 1.31, F(1,17) = 2 7 . 8 0 , ~ <
`0.0011 Periods. The medication group did not affect this
`measure [ p = -0.09, F(1,16) = 0 . 7 0 , ~ = 0.421.
`The percentage of heavy drinking days during the Injec-
`tion Period was predicted by the comparable measure dur-
`ing the Oral NTX Period [ p = 0.84, F( 1,18) = 40.54, p <
`0.0011, but not by heavy drinking days during the Washout
`Period [ p = 0.47, F(1,17) = 3 . 8 5 , ~ = 0.0671. However, as
`hypothesized, the SRP of NTX produced a significantly
`lower percentage of heavy drinking days during the Injec-
`tion Period [ p = -0.26, F(1,16) = 5.46, p = 0.0341, an
`effect @) = 0.269.26
`Mean drinks/day during the Injection Period was pre-
`dicted by the comparable measure during both the Oral
`NTX Period [ p = 0.70, F(1,18) = 1 7 . 6 3 , ~ = 0.0011 and the
`Washout Period [ p = 0.74, F(1,17) = 13.45, p = 0.0021.
`There was a trend [ p = -0.23, F(1,16) = 3 . 4 , ~ < 0.0831 for
`the SRP of NTX to reduce the mean number of drinks/day
`during the Injection Period.
`Follow-up Period. During the Follow-up Period, there
`was a trend for the percentage of drinking days to be
`predicted by the comparable measure during the Oral NTX
`Period [ p = 0.45, F(1,18) = 4.45, p = 0.051. The compa-
`rable measure during the Washout Period was a significant
`predictor [ p = 1.65, F(1,17) = 2 4 . 7 2 , ~ < 0.0011. However,
`there was no effect of the SRP of NTX on the percentage
`of drinking days during the Follow-up Period [ p = -0.09,
`F(1,16) = 0 . 3 2 , ~ = 0.581.
`The percentage of heavy drinking days during the
`Follow-up Period was predicted by the comparable mea-
`sure during the Oral NTX Period [ p = 0.56,F(1,18) = 8.25,
`p = 0.0101, but not by heavy drinking days during the
`Washout Period [ p = 0.05, F(1,17) = 0.02, p = 0.881.
`Again, as hypothesized, individuals receiving the SRP of
`NTX had significantly fewer heavy drinking days during the
`Follow-up Period [ p = -0.43, F(1,16) = 5 . 1 8 , ~ = 0.0371,
`an effect (f) = 0.245.26
`The mean number of drinkdday during the Follow-up
`Period was predicted by the comparable measure during
`both the Oral NTX Period [ p = 0.55, F(1,18) = 7 . 7 1 , ~ =
`0.0121 and the Washout Period [ p = 0.71, F(1,17) = 7.12,
`p = 0.0161. A significant advantage for the SRP of NTX on
`
`0 Depot Naltrexone (N=15)
`
`1077
`
`*
`
`80
`
`70
`
`60
`
`50 -
`
`$40
`al a
`30
`
`20
`
`10
`
`0
`Pretreatment Oral NTX
`Follow-up
`Injection
`Washout
`Fig. 3. Percent (mean + SEM) heavy drinking days by medication group and
`study period ‘ p < 0 05, after controlling for heavy drinking days during the Oral
`NTX and Washout Periods. aNo heavy drinking by placebo subjects during the
`Oral NTX and Washout Periods
`
`this outcome measure emerged during the Follow-up Pe-
`riod [p = -0.35, F(1,16) = 5 . 0 1 , ~ = 0.0401, an effect (f)
`= 0.239.26
`
`Relations Between Adverse Events and Changes in
`Alcohol Consumption
`When correlations between the number of adverse
`events reported and the change in each of the three drink-
`ing measures were examined separately for the Injection
`and Follow-up Periods, all were found to be nonsignificant
`(r’s all <0.34, p’s all >0.10).
`
`Integn’ty of the Double Blind
`When subjects were asked to judge which medication
`they received, the majority (12, or 60%) guessed incor-
`rectly. One PLA subject (20%) and 7 NTX subjects
`(46.7%) correctly identified their medication assignment
`(FET = 0.60).
`
`DISCUSSION
`This study provides preliminary evidence for the bio-
`availability, tolerability, and efficacy of an SRP of NTX for
`the treatment of alcohol dependence. A clinically signifi-
`cant effect of NTX on the frequency of heavy drinking was
`evident during the 4-week Injection Period. This effect
`persisted during the 4-week Follow-up Period (Fig. 3). An
`effect of similar magnitude was observed on the mean
`number of drinks per day, but only during the Follow-up
`Period. GGTP level did not differ by treatment group,
`which may be due to the fact that GGTP levels are a
`relatively insensitive measure of alcohol c o n s ~ m p t i o n , ~ ~
`and they were only modestly elevated in this subject sample
`at baseline. However, correlations with GGTP level ob-
`served herein support the validity of self-reported alcohol
`consumption. Because participants were no better able to
`
` 15300277, 1998, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1530-0277.1998.tb03703.x by Pennsylvania State University, Wiley Online Library on [22/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
`
`

`

`1078
`
`KRANZLER ET AL.
`
`identify the medication they received and there was no
`correlation between adverse events and changes in self-
`reported drinking, it appears that there was a direct phar-
`macological effect of the SRP of NTX on alcohol consump-
`tion.
`Olsen and Kinc12* listed the following criteria for an ideal
`NTX sustained-delivery system: ease of administration, ab-
`sence of an adverse tissue reaction, a relatively constant
`release of the drug for at least 30 days, and biodegradation
`within a short time after that. Using these criteria, the
`microcapsule formulation described herein, although
`promising, is not ideal. The volume of fluid that was in-
`jected produced discomfort. Although the induration lasted
`beyond the immediate Injection Period, in all cases it re-
`solved spontaneously within 5 weeks of injection. Because
`an NTX concentration in excess of 1 ng/ml was maintained
`for 21 days, this preparation can be expected to block
`opioid agonist effects for at least that long.’0225 Further-
`more, NTX was detectable in plasma, and clinical effects
`were present for >30 days after injection.
`Although during the Follow-up Period, there was a trend
`toward a greater number of adverse effects among subjects
`receiving the active injection, the frequency of adverse
`effects of the SRP of NTX was comparable with that of oral
`NTX. Furthermore, the lack of association between ad-
`verse and therapeutic effects suggests that it may feasible to
`increase tolerability without reducing the efficacy of the
`preparation. For example, by reducing the total dose of
`NTX in each injection, the volume injected and the peak
`plasma concentration would be reduced, which could re-
`duce adverse effects. However, more frequent injections
`would be required to sustain the therapeutic effects.
`Given the small number of subjects included and the fact
`that each subject received only one dose of the SRP, this
`study provides only preliminary data on this formulation of
`NTX. Nonetheless, a number of clinically significant ther-
`apeutic effects were observed. These were demonstrable
`despite the low level of drinking that was evident during the
`Oral NTX and Washout Periods, which served as the base-
`line against which the effects of the injection were evalu-
`ated. A larger study of this SRP should include patients
`with a wide range of alcohol dependence severity. Further-
`more, because the medication effects were obtained in the
`context of weekly, individual psychotherapy, it may also be
`useful to evaluate the SRP in conjunction with a less inten-
`sive psychosocial intervention.
`Based on the findings reported herein, an SRP of NTX
`may have an important place in the treatment of alcohol
`dependence, particularly in light of variable compliance
`with the oral medication in this patient pop~lation.4.~ Ad-
`ditional study of this formulation appears warranted. Ulti-
`mately, comparison with oral NTX therapy should help to
`determine which individuals might be most likely to benefit
`from the SRP of NTX.
`
`ACKNOWLEDGMENTS
`The authors thank the staff of the Clinical Research and Eval-
`uation Unit, Alcohol Research Center, University of Connecticut
`School of Medicine, for their assistance in the conduct of this
`study. Special thanks go to Roberta Gline for help in conducting
`the clinical trial and Jeffrey Van Kirk, J.D., M.S., for help with
`data analysis. Joseph Burleson, Ph.D., Nancy Petry, Ph.D., and
`Cheryl Oncken, M.D., provided helpful comments on the manu-
`script.
`
`REFERENCES
`1. Volpicelli JR, Alterman AI, Hayashida M, O’Brien C Naltrexone
`and the treatment of alcohol dependence. Arch Gen Psychiatry 49:876-
`880, 1992
`2. O’Malley SS, Jaffe AJ, Chang G, Schottenfeld RS, Meyer RE,
`Rounsaville B: Naltrexone and coping skills therapy for alcohol depen-
`dence: A controlled study. Arch Gen Psychiatry 49:894-898, 1992
`3. Kosten TR: Current pharmacotherapies of opioid dependence.
`Psychopharmacol Bull 26:69-74, 1990
`4. Chick J: New insights in alcoholism treatment: The UK naltrexone
`study results. Presented at the Annual Meeting of the American Psychi-
`atric Association, New York, May 5-9, 1996
`5. Volpicelli J, Rhines KC, Rhines JS, Volpicelli LA, Alterman AI,
`O’Brien CP: Naltrexone and alcohol dependence: Role of subject com-
`pliance. Arch Gen Psychiatry 54737-742, 1997
`6. Greenberg RN: Overview of patient compliance with medication
`dosing: A literature review. Clin Ther 6:592-599, 1984
`7. Fuller RK, Branchey L, Brightwell DR, Derman RM, Emrick CD,
`Iber FL, James KE, Lacoursiere RB, Lee KK, Lowenstam I, Maany I,
`Neiderhiser D, Nocks JJ, Shaw S. Disulfiram treatment of alcoholism: A
`Veteran’s Administration Cooperative Study. JAMA 256:1449-1455,1986
`8. Cox WM, Blount JP, Crowe PA, Singh SP: Diabetic patients’
`alcohol use and quality of life: Relationships with prescribed treatment
`compliance among older males. Alcohol Clin Exp Res 20:327-331, 1996
`9. Johnson DAW: Observations on the use of long-acting depot neu-
`roleptic injections in the maintenance therapy of schizophrenia. J Clin
`Psychiatry 5:13-21, 1984
`10. Chiang CN, Hollister LE, Kishimoto A, Barnett G: Kinetics of
`naltrexone sustained-release preparation. Clin Pharmacol Ther 36:704-
`708, 1984
`11. Chiang CN, Hollister LE, Gillespie HK, Foltz R L Clinical evalu-
`ation of a naltrexone sustained-release preparation. Drug Alcohol De-
`pend 16:l-8, 1985
`12. Heishman SJ, Francis-Wood A, Keenan RM, Chiang CN, Terrill
`JB, Tai B, et al.: Safety and pharmacokinetics of a new formulation of
`naltrexone, in Harris LS (ed): Problems of Drug Dependence 1993, vol2,
`NIDA Research Monograph No. 141 (NIH Publ. No. 94-3749). Washing-
`ton, D.C., US. Government Printing Office, 1994, p 82
`13. Alim TN, Tai B, Chiang CN, Green T, Rosse RB, Lindquist T, et
`al.: Tolerability study of a depot form of naltrexone in substance abusers,
`in Harris LS (ed): Problems of Drug Dependence 1994, vol 2, NIDA
`Research Monograph No. 153 (NIH Publ. No. 95-3883). Washington,
`D.C., US. Government Printing Office, 1995, p 253
`14. Marlatt GA, Gordon J R Relapse Prevention. New York, Guilford,
`1985
`15. Chaney EF: Social skills training, in Hester RK, Miller WR (eds):
`Handbook of Alcoholism Treatment Approaches: Effective Alternatives.
`New York, Pergamon Press, 1989
`16. Selzer M L The Michigan Alcoholism Screening Test: The quest
`for a new diagnostic instrument. Am J Psychiatry 127:1653-1658, 1971
`17. McLellan AT, Luborsky L, Cacciola J, Griffith J, McGahan P,
`O’Brien CP: Guide to the Addiction Severity Index: Background, Admin-
`istration, and Field Testing Results. U.S. DHHS Publication No. (ADM)
`88-1419. Washington, D.C., U.S. Government Printing Office, 1988
`18. Skinner H, Allen B A Alcohol dependence syndrome: Measure-
`ment and validation. J Abnorm Psycho1 91:199-209, 1982
`
` 15300277, 1998, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1530-0277.1998.tb03703.x by Pennsylvania State University, Wiley Online Library on [22/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
`
`

`

`SUSTAINED-RELEASE NTX FOR ALCOHOLISM TREATMENT
`
`1079
`
`19. Sobell MB, Maisto SA, Sobell LC, Cooper AM, Cooper TC, Sand-
`ers TB: Developing a prototype for evaluating alcohol treatment effec-
`tiveness, in Sobell LC, Sobell MB, Ward E (eds): Evaluating Alcohol and
`Drug Ahuse Treatment Effectiveness: Recent Advances. New York, Per-
`gamon Press, 1980
`20. Levine J, Schooler NR: S A F E E : A technique for the systematic
`assessment of side effects in clinical trials. Psychopharmacol Bull 22:343-
`381, 1986
`21. Beck AT, Ward CH, Mendelson M, Mock J, Erhaugh J: An inven-
`tory for measuring depression. Arch Gen Psychiatry 4:461-471, 1961
`22. Biometrics Research Department, NY State Psychiatric Institute:
`Structured Clinical Interview for DSM-IV (SCID-I). New York, NY State
`Psychiatric Institute, 1995
`23. American Psychiatric Association: Diagnostic and Statistical Man-
`ual of Mental Disorders, ed 4. Washington, D.C., American Psychiatric
`Press, 1994
`24. Huang W, Moody DE, Foltz RL, Walsh S L Determination of
`
`naltrexone and 6-P-naltrexol in plasma by solid-phase extraction and gas
`chromatography-negative ion chemical ionization-mass spectrometry.
`J Anal Toxic01 21:252-257, 1997
`25. Verebey K, Volavka J, Mule SJ, Resnick RB: Naltrexone: Dispo-
`sition, metabolism, and effects after acute and chronic dosing. Clin Phar-
`macol Ther 20:315-328, 1976
`26. Cohen J: Statistical Power for the Behavioral Sciences, ed 2. Hill-
`sdale, NJ, Lawrence Erlhaum Associates, Inc., 1988
`27. Kranzler HR, Mason BJ, Pettinati HM, Anton RF: Methodological
`issues in pharmacotherapy trials with alcoholics, in Hertzman M, Feltner
`D (eds): The Handbook of Psychopharmacology Trials. New York, New
`York University Press, 1997, pp 213-245
`28. Olsen JL, Kincl F A A review of parenteral sustained-release nal-
`trexone systems, in Narcotic Antagonists: Naltrexone Pharmacochemistry
`and Sustained-Release Preparations, NIDA Monograph Series #28.
`DHHS Publ. No. (ADM) 81-102. Washington, D.C., U.S. Government
`Printing Office, 1981, pp 187-193
`
` 15300277, 1998, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1530-0277.1998.tb03703.x by Pennsylvania State University, Wiley Online Library on [22/01/2025]. See the Terms and Conditions (https://onli