Psychopharmacology (2002) 159:351–360
`DOI 10.1007/s002130100909
`
`O R I G I N A L I N V E S T I G AT I O N
`
`Sandra D. Comer · Eric D. Collins
`Herbert D. Kleber · Elie S. Nuwayser
`James H. Kerrigan · Marian W. Fischman
`Depot naltrexone: long-lasting antagonism of the effects
`of heroin in humans
`
`Received: 28 November 2000 / Accepted: 2 August 2001 / Published online: 1 November 2001
`© Springer-Verlag 2001
`
`Abstract Rationale: Naltrexone, an opioid antagonist, is
`currently approved as a treatment for heroin dependence.
`However, naltrexone is generally not well accepted by
`patients, and medication non-compliance is a difficult
`obstacle to treatment. A sustained-release form of nal-
`trexone may improve compliance. Objective: The pres-
`ent study was designed to evaluate the time course, safe-
`ty, and effectiveness of a depot formulation of naltrexone
`(Depotrex®). Methods: Twelve heroin-dependent indi-
`viduals participated in an 8-week inpatient study. After a
`1-week detoxification period, six participants received
`192 mg naltrexone base and six participants received
`384 mg naltrexone base. For safety, the low dose of de-
`pot naltrexone was tested before the high dose. The ef-
`fects of heroin (0, 6.25, 12.5, 18.75, 25 mg, IV) were
`evaluated for the next 6 weeks. One dose of heroin was
`tested per day on Mondays through Fridays, and the en-
`tire dose range was tested each week. Active heroin dos-
`es were administered in ascending order during the
`week, while placebo could be administered on any day.
`Subjective, performance, and physiological effects were
`measured both before and after heroin administration.
`The hypotheses were that depot naltrexone would antag-
`onize the effects of heroin, and that the high dose of de-
`pot naltrexone would produce a more effective and lon-
`ger-lasting antagonism than the low dose. Results: The
`low and high doses of depot naltrexone antagonized her-
`oin-induced subjective ratings for 3 and 5 weeks, respec-
`tively. Plasma levels of naltrexone remained above
`1 ng/ml for approximately 3 and 4 weeks after adminis-
`tration of 192 mg and 384 mg naltrexone. Other than the
`initial discomfort associated with the injection of depot
`
`S.D. Comer (✉
`) · E.D. Collins · H.D. Kleber · M.W. Fischman
`Division on Substance Abuse,
`New York State Psychiatric Institute and Department of Psychiatry,
`College of Physicians and Surgeons of Columbia University,
`1051 Riverside Drive, Unit 120, New York, NY 10032, USA
`e-mail: sdc10@columbia.edu
`Tel.: +1-212-5435981, Fax: +1-212-5435991
`E.S. Nuwayser · J.H. Kerrigan
`Biotek Inc., 21-C Olympia Avenue, Woburn, MA 01801, USA
`
`naltrexone, there were no untoward side-effects. Conclu-
`sions: These results suggest that this depot formulation
`of naltrexone provides a safe, effective, long-lasting an-
`tagonism of the effects of heroin.
`
`Keywords Heroin · Human · Naltrexone · Opioid ·
`Subjective effect · Sustained-release · Depotrex
`
`Introduction
`
`Naltrexone, an orally effective opioid antagonist, was
`approved in 1984 by the Food and Drug Administration
`as a maintenance medication for the treatment of heroin
`dependence. Naltrexone potently antagonizes the effects
`of opioid agonists, while producing no agonist effects of
`its own (Jaffe and Martin 1990). Tolerance does not de-
`velop to naltrexone’s antagonist effects and the drug has
`few side effects, even after chronic administration of
`over 1 year (Kleber et al. 1985). Because of its ability to
`antagonize the effects of mu opioid agonists, its long du-
`ration of action, and its favorable pharmacokinetic and
`metabolic characteristics (Martin et al. 1966, 1973), nal-
`trexone initially held great promise as a treatment for
`opioid dependence. The early rationale for using a pure
`antagonist was that once the individual was maintained
`on naltrexone, subsequent attempts to self-administer the
`illicit opioid would not produce euphoria (Wikler 1965;
`Martin et al. 1966) and the user would eventually discon-
`tinue opioid use altogether.
`Although the use of naltrexone as a maintenance ther-
`apy for opioid abuse can be effective (Martin et al. 1973;
`O’Brien et al. 1975; Judson et al. 1981), it has been used
`most successfully with only a select subpopulation of
`highly motivated individuals. Because of the problems
`with medication non-compliance, naltrexone therapy has
`not lived up to its initial promise. This may be in part be-
`cause opioid users are accustomed to self-administering
`potent reinforcers, and, by contrast, the complete ab-
`sence of opioid-induced reinforcing effects may be unac-
`ceptable. Another factor that may contribute to noncom-
`
`APOTEX EXHIBIT 1004
`Apotex v. Alkermes
`IPR2025-00514
`
`

`

`352
`
`Table 1 Participant demo-
`graphics. Numbers in parenthe-
`ses represent+1 SEM
`
`192 mg naltrexone
`
`384 mg naltrexone
`
`Age (average; years)
`Years of heroin use (average)
`Amount spent for heroin (average; $/day)
`Tobacco cigarette use (range; no. per day)
`Cocaine use (range; occasions/week)
`Amphetamine use (range; occasions/week)
`Marijuana use (range; occasions/week)
`Alcohol use (range; occasions/week)
`Sedative use (range; occasions/week)
`
`33.8 (2.5)
`10.7 (2.5)
`$39 (4)
`8–20
`0–1
`0–1
`0–1
`0–1
`0–1
`
`29.2 (3.2)
`9.1 (3.5)
`$55 (12)
`10–20
`0–3
`0
`0–3
`0–3
`0–1
`
`pliance is that, unlike methadone, discontinuation of nal-
`trexone maintenance has no adverse consequences (e.g.
`withdrawal effects). Furthermore, naltrexone itself may
`induce adverse neuropsychiatric and gastrointestinal ef-
`fects, such as dysphoria, nausea, and abdominal pain
`(Hollister et al. 1981; Crowley et al. 1985; Oncken et al.
`2001).
`Sustained-release forms of naltrexone could increase
`compliance and ultimately improve treatment effective-
`ness (Martin and Sandquist 1974; Abrahams and Ronel
`1975; Chiang et al. 1985a, 1985b). Chiang et al. (1985a,
`1985b), for example, administered biodegradable beads
`containing a dose of 63 mg naltrexone to normal, healthy
`volunteers. Following an initial burst of release, this for-
`mulation yielded relatively constant plasma levels of nal-
`trexone (0.3–0.5 ng/ml) for up to 1 month. However,
`when these investigators administered challenge doses of
`morphine (15 mg IM), the results were variable. In some
`participants, morphine was completely ineffective, while
`in others, morphine-like effects were observed. In addi-
`tion, three of the five participants who completed the
`study developed tissue inflammation near the site of
`bead implantation (Chiang et al. 1985b). Although the
`adverse tissue reaction and the variable antagonist effec-
`tiveness of the naltrexone beads limited its clinical utili-
`ty, the rationale behind the development of a sustained-
`release form of naltrexone was sound.
`A new depot formulation of naltrexone (Depotrex®)
`has been developed that provides a stable, long-lasting
`elevation in plasma naltrexone levels with either no or
`minimal side-effects (Heishman et al. 1994; Alim et al.
`1995; Kranzler et al. 1998). In an early tolerability study,
`Alim and colleagues (1995) reported blockade of the
`physiological and subjective effects of 10 mg intrave-
`nous (IV) morphine in cocaine-dependent participants
`who received 206 mg depot naltrexone; side-effects as-
`sociated with naltrexone were minimal in these partici-
`pants. Kranzler and colleagues (1998) further showed
`that 206 mg depot naltrexone significantly reduced the
`percentage of heavy drinking days in alcoholics. Adverse
`effects reported after depot naltrexone were comparable
`to those reported after oral naltrexone administration.
`Although this formulation of depot naltrexone appears to
`be safe and effective in treating alcohol dependence, it
`has not yet been tested with heroin. The purpose of the
`current study was 1) to determine whether the new for-
`mulation of depot naltrexone will antagonize the effects
`
`of heroin at doses comparable to those used on the
`streets today, and 2) to assess the duration of antagonist
`effect of 192 mg and 384 mg depot naltrexone. The hy-
`pothesis was that depot naltrexone would dose-depen-
`dently antagonize the effects of heroin.
`
`Materials and methods
`
`Participants
`
`Fifteen heroin-dependent men, who were not seeking treatment for
`their drug use, began the 8-week protocol. Three participants left
`the study prior to depot naltrexone administration: one was dis-
`charged for aggressive behavior toward the staff, and two left for
`personal reasons. Twelve participants (eight non-Hispanic Cauca-
`sian, three Hispanic, and one African American) completed the
`study: six received 192 mg depot naltrexone, and six received
`384 mg depot naltrexone (Table 1). The low dose of depot naltrex-
`one was tested in the first six participants. The groups did not dif-
`fer in age, years of heroin use, and amount of money spent on her-
`oin per day. All participants had experience using heroin IV. One
`participant in the low-dose group and two in the high-dose group
`preferred to use heroin intranasally; all other participants preferred
`to use heroin IV. All participants were dependent on heroin at the
`start of the study, as verified by a naloxone challenge test (Wang
`1974).
`After an initial telephone interview, eligible participants com-
`pleted detailed questionnaires on drug use, general health and
`medical history, and a medical and psychological evaluation in the
`laboratory. An electrocardiogram and Mantoux test or chest X-ray
`were also performed. Routine laboratory analyses included a
`blood chemistry panel, thyroid function test, syphilis and hepatitis
`(A, B, and C) screening, and urinalysis. Urine drug toxicologies
`(opioids, cocaine, benzodiazepines, cannabinoids, and ampheta-
`mines) were also performed using a radiative energy attenuation
`and fluorescence polarization immunoassay system (ADx System;
`Abbott Laboratories, Abbott Park, Ill., USA). Participants were
`told that they would be detoxified from heroin during the first
`week of the study, that they would receive one of two doses of a
`depot formulation of naltrexone, and that a range of IV heroin
`doses would be tested each week for the 6 weeks following depot
`naltrexone administration.
`Participants were excluded from the study if they were seeking
`drug treatment, dependent on alcohol or illicit drugs other than
`opioids, or had a major Axis I psychiatric diagnosis other than
`opioid dependence. Those who had recent histories of violence or
`who were on parole/probation were excluded from the study. Par-
`ticipants were required to be physically healthy, and fully able to
`perform all study procedures. Although both men and women
`were screened for the study, none of the women met the eligibility
`requirements. Prior to admission, participants completed a training
`session, during which the study procedures were explained to
`them in detail. Volunteers were paid $25 per inpatient day and an
`additional $25 per day bonus if they completed the study. Partici-
`pants signed consent forms describing the aims of the study, and
`
`

`

`the potential risks and benefits of participation. Free HIV testing
`and education were offered, and during the last week of the study,
`participants were offered referrals for treatment. This study was
`approved by the Institutional Review Board of the New York State
`Psychiatric Institute (NYSPI).
`
`Apparatus
`
`During experimental sessions, participants were seated in a room
`equipped with Macintosh computers. All computer activities, vital
`signs and behaviors were continuously monitored by the experi-
`menters in an adjacent control room via a continuous on-line com-
`puter network, video cameras, and vital signs monitors (cardiovas-
`cular function was measured using a Sentry II Vital Signs Monitor,
`NBS Medical, Costa Mesa, Calif., USA; arterial oxygen saturation
`was measured using a pulse oximeter Model 400, Palco Laborato-
`ries, Santa Cruz, Calif., USA). Communication between the staff
`and participants was kept to a minimum during experimental ses-
`sions.
`
`Detoxification procedures
`
`Participants were admitted into the hospital, and detoxified during
`the first week after admission. Buprenorphine (8 mg sublingual
`tablet; National Institute on Drug Abuse, Rockville, Md., USA)
`was administered on the first 1–2 days after admission. Two days
`after the last buprenorphine dose, oral naltrexone (DuPont
`Pharma, Wilmington, Del., USA) was administered for 3 con-
`secutive days (25, 50, and 50 mg per day) to ensure that partici-
`pants were willing and able to tolerate its effects. Clonidine HCl
`(0.2 mg PO, every 6 h; Boehringer Ingelheim Pharmaceuticals,
`Inc., Ridgefield, Conn., USA), ketorolac tromethamine (30 mg
`IM, every 6 h; Roche Laboratories, Nutley, N.J., USA), prochlor-
`perazine (10 mg PO or IM, every 8 h; SmithKline Beecham Con-
`sumer Healthcare, Pittsburgh, Penn., USA) and clonazepam (2 mg
`PO, every 8 h; Roche Laboratories) were available, as needed,
`during the detoxification week. Thereafter, trazodone (50–100 mg
`PO, at bedtime; Warner Chilcott, Morris Plains, N.J., USA) was
`available if participants reported having trouble sleeping. Depot
`naltrexone was administered on a Monday morning, 2 days after
`the last oral naltrexone dose.
`
`General procedures
`
`The effects of IV heroin (placebo, 6.25, 12.5, 18.75, and 25 mg)
`were evaluated each week for 6 weeks following depot naltrexone
`administration. The entire dose range was tested each week, and
`one dose of heroin was tested each day on weekdays. For safety,
`active heroin doses were administered in ascending order within
`each week, with the exception that the day of placebo injection
`was varied across weeks. On the day that depot naltrexone was ad-
`ministered, placebo was tested during the experimental session.
`
`Experimental sessions
`
`During all sessions, participants completed computerized tasks
`and subjective-effects questionnaires. Heart rate and blood pres-
`sure were measured every 2 min, and blood oxygen saturation
`was monitored continuously with a pulse oximeter and recorded
`every minute during experimental sessions. Participants received
`breakfast between 0800 and 0900 and lunch between 1230 and
`1330 hours. Experimental sessions occurred between 0930 and
`1130 hours. Participants were not allowed to smoke tobacco ciga-
`rettes during experimental sessions.
`Physiologic, subjective and performance effects were mea-
`sured both before and after drug administration (see descriptions
`below). Heroin or placebo was administered only if vital signs
`were within safe limits (SpO2 >93%). A photograph was taken of
`the right pupil before and 4, 10, 20, 40 and 60 min after drug ad-
`
`353
`
`ministration. The subjective-effects battery (see description be-
`low) was administered before and 4, 40 and 90 min after drug ad-
`ministration. The performance battery (see description below) was
`administered before and 10 and 60 min after drug administration.
`The Subjective Opioid Withdrawal Scale was administered before
`drug administration. The Drug Effects Questionnaire was adminis-
`tered 90 min after drug administration.
`
`Subjective measures
`
`Four questionnaires were used to assess subjective effects
`throughout the experimental sessions. The first questionnaire was
`a 26-item visual analog scale (VAS) designed to assess subjective
`and physiological effects (modified from Foltin and Fischman
`1995). The first 18 lines were labeled with adjectives describing
`mood states (e.g., “I feel...:” “high”) and four additional lines, la-
`beled with questions about the dose just received (i.e. “I liked the
`dose,” “For this dose, I would pay”). Participants also indicated,
`by making a mark along a 100 mm line, how much they “wanted”
`each of the following drugs: heroin, cocaine, alcohol, and tobacco.
`Participants rated each item on the VAS from “Not at all” (0 mm)
`to “Extremely” (100 mm), except for the “For this dose, I would
`pay” question, which ranged between $0 (0 mm) to $20 (100 mm).
`The second questionnaire was a 13-item opioid symptom checklist
`consisting of true/false questions designed to measure opioid ef-
`fects (e.g. “My skin is itchy,” etc.; Fraser et al. 1961; Foltin and
`Fischman 1992). The VAS and opioid symptom checklist together
`constituted the subjective-effects battery. The third questionnaire
`was the 16-item Subjective Opioid Withdrawal Scale (SOWS;
`Handelsman et al. 1987). Participants rated each item on a scale
`from 0 to 4, with 0 being “Not at all” and 4 being “Extremely”
`(e.g. “I have gooseflesh,” etc.). The fourth questionnaire was a
`6-item Drug Effects Questionnaire (DEQ; Evans et al. 1995). Par-
`ticipants described drug effects by selecting among a series of
`possible answers ranging from 0 (“No effects at all”) to 4 (“Very
`strong (good, bad, etc.) effects”). Ratings of drug liking ranged
`between –4 (“Dislike very much”) to 4 (“Like very much”).
`
`Task battery
`
`The task battery consisted of four tasks: the first task was a 3-min
`digit-symbol substitution task, during which participants were
`required to emulate a series of patterns on a keypad (McLeod
`et al. 1982). The second task was a 10-min divided attention task,
`which consisted of concurrent pursuit-tracking and vigilance tasks
`(Miller et al. 1988). The third task was a 10-min rapid information
`processing task, during which a series of digits was displayed rap-
`idly on the computer screen (100 digits/min), and participants
`were instructed to press a key as quickly as possible after three
`consecutive odd or even digits (Wesnes and Warburton 1983). The
`fourth task was a 3-min repeated acquisition of response sequenc-
`es task, during which four buttons were illuminated, and partici-
`pants were instructed to learn a ten-response sequence of button
`presses (Kelly et al. 1993).
`
`Physiological measures
`
`A blood pressure cuff was attached to the non-dominant arm,
`which recorded automatically every 2 min. Participants were also
`connected to a pulse oximeter via a soft sensor on a finger of the
`dominant hand, which monitored arterial blood oxygen saturation
`(%SpO2). For safety, supplemental oxygen (2 l/min) was provided
`via a nasal cannula during all experimental sessions. A specially
`modified Polaroid camera with a close-up lens (×2 magnification)
`was used to take pupil photographs. All photographs were taken
`under ambient lighting conditions. Horizontal and vertical mea-
`surements of pupil diameter were made using calipers, and then
`these two measurements were averaged and divided by 2 to cor-
`rect for the ×2 magnification.
`
`

`

`354
`
`Fig. 1 Mean plasma levels of
`naltrexone (left panel) and
`6-β-naltrexol (right panel) as
`a function of depot naltrexone
`dose and days after administra-
`tion of depot naltrexone. Data
`points represent the mean
`across 6 participants per group.
`Error bars represent±1 SEM
`
`Blood was drawn 2 h, 1, 2, 3, 4, 5, 6, 8, 11, 15, 18, 22, 25, 29,
`32, 36, and 39 days after administration of depot naltrexone, and
`immediately centrifuged at 3000 rpm for 15 min. Plasma was
`drawn off and stored at –20°C until it was shipped by overnight
`mail on dry ice for analyses of naltrexone and 6-β-naltrexol (Cen-
`ter for Human Toxicology, University of Utah, Salt Lake City,
`Utah, USA). Analyses were performed by solid phase extraction
`and negative ion chemical ionization gas chromatography/mass
`spectrometry, as described by Huang and colleagues (1997). The
`lower limit of detectability for both analytes was 0.1 ng/ml.
`Blood was also drawn prior to, and at weekly intervals after
`administration of depot naltrexone for analyses of liver enzymes
`(AST, ALT, GGT).
`
`Drugs
`
`Depot naltrexone (Depotrex®) was manufactured by Biotek Inc.
`(Woburn, Mass., USA) and provided by the National Institute on
`Drug Abuse. Depotrex is a registered trademark of Biotek, Inc.
`Naltrexone microcapsules and placebo microspheres were pack-
`aged in sterile single-dose vials. After reconstituting in suspending
`medium, 2.4 ml of the suspension was injected. The active formu-
`lation contained drug equivalent to 192 mg naltrexone base. The
`placebo formulation contained the equivalent weight in polymer
`microspheres. Injections were administered subcutaneously into
`the buttocks (one injection per buttock), using an 18 gauge needle.
`For the low dose, participants received one placebo and one nal-
`trexone injection (192 mg naltrexone base), and for the high dose,
`participants received two naltrexone injections (394 mg naltrexone
`base). For safety, the low dose of Depotrex was tested in the first
`six participants, and the high dose of Depotrex was tested in the
`next six participants.
`Heroin HCl was provided by the National Institutes on Drug
`Abuse and prepared by the Columbia-Presbyterian Medical Center
`research pharmacy. A 25 mg/ml heroin concentration was pre-
`pared in a 5% dextrose solution to enhance stability. Dose calcula-
`tions were based on the hydrochloride salt form. Heroin was
`stored in a freezer and used within 3 months of preparation. The
`stock solution was diluted in 5% dextrose to produce each dose.
`Placebo (5% dextrose solution) or heroin (6.25, 12.5, 18.75, and
`25 mg) was administered intravenously over a 30-s period in a
`total volume of 2 ml. Heroin doses were administered in a double-
`blind fashion. Physiological saline solution was infused continu-
`ously during experimental sessions, except during drug adminis-
`tration. Between 1 and 2 ml heparinized saline (10 IU/ml) was
`flushed into the catheter four to eight times each day. All venous
`catheters were maintained as heplocks and were removed within
`72 h of insertion.
`Supplemental medications available to all participants for the
`duration of the study included: Mylanta, acetaminophen, ibupro-
`fen, Colace, Milk of Magnesia and multi-vitamins with iron.
`
`Morning urine samples were collected daily and one random
`sample per week was screened for the presence of other illicit sub-
`stances. No illicit substances were found in the participants’ urine
`samples.
`
`Statistical analyses
`
`Repeated-measures analyses of variance (ANOVA) with planned
`comparisons were used to address the following questions:
`1) What was the duration of antagonism of heroin’s effects?
`2) Did the low and high doses of depot naltrexone differ in ability
`to antagonize the effects of heroin? In order to address the first
`question, the data for each group were analyzed separately as a
`function of week (1–6) and heroin dose (0, 6.25, 12.5, 18.75,
`25 mg). Twenty-five planned comparisons were made: each week
`(2–6) was compared to week 1 for each dose (e.g. placebo-week 2
`versus placebo-week 1, placebo-week 3 versus placebo-week 1,
`placebo-week 4 versus placebo-week 1, etc.) because it was likely
`that virtually complete antagonism would occur during week 1. In
`order to address the second question, an overall analysis was per-
`formed with one between-group factor (group) and two within-
`group factors (week, heroin dose): the main effect of group, and
`the week×group and dose×group effects were evaluated. Interac-
`tion effects were examined using post-hoc comparisons. Peak sub-
`jective ratings, peak performance effects, trough pupil diameter,
`liver enzyme levels, average arterial oxygen saturation, and plas-
`ma levels of naltrexone and 6-β-naltrexol were analyzed. Liver
`enzymes (AST, ALT, GGT) were also analyzed: each week post-
`depot naltrexone was compared to a pre-depot naltrexone baseline.
`Due to an excessive number of missing data points, the cardiovas-
`cular data were not analyzed. To control for type I errors, a modi-
`fied Bonferroni test was used in that only those comparisons with
`P<0.01 were considered statistically significant.
`
`Results
`
`Plasma drug levels
`
`Figure 1 shows mean plasma levels of naltrexone (left
`panel) and 6-β-naltrexol (right panel) for each group as a
`function of time since the depot naltrexone injection.
`Two hours after administration of 192 mg and 384 mg
`depot naltrexone, plasma levels of naltrexone were 3.8
`(±0.2) and 8.9 (±1.4) ng/ml. Plasma levels of 6-β-naltr-
`exol were 8.5 (±0.3) and 17.4 (±1.3) ng/ml, respectively,
`24 h after administration of 192 mg and 384 mg depot
`naltrexone. Across individual participants, plasma levels
`
`

`

`Fig. 2 Mean peak VAS ratings
`of “Good Drug Effect” after
`administration of heroin
`(0–25 mg) as a function of
`depot naltrexone dose and
`study week (week 1: left panel;
`week 6: right panel). Maxi-
`mum rating=100 mm. Data
`points represent mean peak
`ratings (n=6 per group). Error
`bars represent±1 SEM.
`* Indicates significant differ-
`ences from week 1
`
`355
`
`of naltrexone ranged between 3.1 and 4.5 ng/ml after
`administration of 192 mg depot naltrexone, and 5.6 and
`14.2 ng/ml after administration of 384 mg depot naltrex-
`one. After administration of 192 mg and 384 mg of
`depot naltrexone, plasma levels of naltrexone were less
`than 1 ng/ml on day 22 and 29, respectively. The group
`and group×day effects for naltrexone [group: F(1,10)=
`48.5, P<0.0001; group×day: F(1,10)=8.6, P<0.0001] and
`6-β-naltrexol [group: F(1,10)=33.8, P<0.0002; group×
`day: F(1,10)=8.3, P<0.0001] were significant.
`
`Subjective effects
`
`Figure 2 shows mean peak visual analog scale ratings of
`“Good Drug Effect” for each group as a function of her-
`oin dose and week. After low-dose depot naltrexone, rat-
`ings of “Good Drug Effect” significantly increased by
`week 4, relative to week 1, after administration of
`18.75 mg [F(1,100)=6.4, P<0.01] and 25 mg heroin
`[F(1,100)=7.9, P<0.006]; ratings of “Good Drug Effect”
`significantly increased by week 5 after administration of
`12.5 mg heroin [F(1,100)=8.4, P<0.004]. In the high-
`dose group, ratings of “Good Drug Effect” did not
`significantly increase until week 6, after 18.75 mg
`[F(1,100)=7.5, P<0.007] and 25 mg heroin [F(1,100)=
`47.3, P<0.0001]. Both the week×group [F(5,50)=4.8,
`P<0.001] and dose×group [F(4,40)=4.4, P<0.005] ef-
`fects were significant for ratings of “Good Drug Effect.”
`Several other VAS ratings showed a similar pattern in-
`cluding ratings of “High,” “Liking,” drug “Potency,”
`drug “Quality,” and how much they would be willing
`to pay for the dose (data not shown). The dose×group
`
`effect was significant [F(4,40)=4.2, P<0.006], and the
`week×group effect approached statistical significance
`[F(5,50)=2.9, P<0.02] for ratings of “High.” Although
`ratings tended to be higher in the low-dose group for
`VAS ratings of “Liking,” drug “Potency,” and drug
`“Quality,” the week×group and dose×group effects were
`not statistically significant for these items.
`VAS ratings of “I feel...” “Gooseflesh,” “Depressed,”
`“Muscle Pain,” “Anxious,” and “Restless” were elevated
`in both groups during the first week after receiving depot
`naltrexone, and were higher in the high-dose group (data
`not shown). The week×group effect was statistically
`significant for ratings of “Gooseflesh” [F(5,50)=3.4,
`P<0.01] and “Depressed” [F(5,50)=3.5, P<0.009], while
`the week×group effect for ratings of “Muscle Pain”
`(P<0.03), “Anxious” (P<0.04), and “Restless” (P<0.04)
`approached statistical significance. Ratings of “I Want
`Heroin,” which did not vary across study weeks or hero-
`in doses, were significantly elevated in the high-dose
`group [main effect of group: F(1,10)=26.3, P<0.0004].
`Ratings of “I Want Heroin” ranged between 26 and 37 in
`the low-dose group, and 86 and 95 in the high-dose
`group.
`The pattern of results obtained from the opioid symp-
`tom checklist and DEQ (data not shown) were similar to
`the VAS ratings of “Good Drug Effect” (Fig. 2) in that
`total scores on the opioid symptom checklist and DEQ
`ratings of drug “Liking,” “Good Drug Effect,” strength
`of drug effect, and desire to take the drug again in-
`creased as a function of heroin dose and across study
`weeks. The week×group effect was statistically signifi-
`cant for the opioid symptom checklist [F(5,50)=3.2,
`P<0.01]. Although ratings tended to be higher in the
`
`

`

`356
`
`Fig. 3 Mean total scores on
`the Subjective Opioid With-
`drawal Scale (SOWS) after
`administration of heroin as a
`function of depot naltrexone
`dose and study week. Maxi-
`mum score=64. All other
`details are as in Fig. 2
`
`low-dose group compared to the high-dose group, the
`week×group and dose×group effects were not statistical-
`ly significant for any of the items on the DEQ.
`Subjective ratings of opioid withdrawal, as measured
`by total scores on the SOWS, did not significantly differ
`between groups during detoxification, prior to adminis-
`tration of depot naltrexone. SOWS scores peaked on day
`4 after admission: total SOWS scores on day 4 of with-
`drawal were 22.5 (±11.2) and 26.3 (±7.3), out of a maxi-
`mum possible score of 64, after administration of 192 and
`384 mg depot naltrexone, respectively. On the day prior
`to administration of depot naltrexone, SOWS scores were
`11.0 (±8.2) and 18.7 (±9.0) in the low- and high-dose
`groups, respectively. Figure 3 shows total SOWS scores
`after administration of depot naltrexone for each group as
`a function of heroin dose and week. Total SOWS scores
`were significantly elevated during the first week in the
`high-dose group, but not in the low-dose group. By the
`second week after administration of depot naltrexone,
`SOWS scores did not differ between groups. The week×
`group interaction for total SOWS scores approached sta-
`tistical significance [F(5,50)=2.5, P<0.04].
`
`Performance tasks
`
`Heroin minimally affected task performance, with the
`exception that performance of the divided attention task
`was significantly impaired: in the low-dose group, the
`latency to identify a target significantly increased by
`1.7 s during week 5, relative to week 1, after administra-
`tion of 25 mg heroin [F(1,100)=8.3, P<0.005]. In the
`high-dose group, the latency to identify a target signifi-
`
`cantly increased by 1.3 s during week 6, relative to week
`1, after administration of 25 mg heroin [F(1,100)=30.9,
`P<0.0001]. Latency to identify a target did not signifi-
`cantly change across weeks after administration of place-
`bo in either group. The week×group and dose×group
`effects were not statistically significant for latency to
`identify a target during the divided attention task.
`
`Physiological effects
`
`Figure 4 shows the effects of heroin on pupil diameter
`for each group as a function of heroin dose and week.
`During week 1, pupil diameter was large in both groups,
`consistent with the possibility that both groups were in
`mild withdrawal. After placebo administration during
`week 1, pupil diameter was 5.3 (±0.3) and 5.6 (±0.6) mm
`in the low- and high-dose groups, respectively. Pupil
`diameter was relatively stable under the placebo condi-
`tion in both groups from weeks 2–6 (Fig. 4), although
`pupil diameter consistently remained larger in the high-
`dose group throughout the study. After administration of
`active doses of heroin, pupil diameter progressively de-
`creased across study weeks in both groups. The week×
`group and dose×group effects were not significant for
`pupil diameter.
`The average arterial oxygen saturation significantly de-
`creased by 0.9% in both groups from week 1 to week 6,
`after administration of 25 mg heroin [low-dose group:
`F(1,100)=17.2, P<0.0001; high-dose group: F(1,100)=7.8,
`P<0.006]. However, these changes in oxygen saturation
`occurred in the presence of supplemental oxygen, and
`were not clinically significant.
`
`

`

`Fig. 4 Mean trough pupil
`diameter after administration
`of heroin as a function of depot
`naltrexone dose and study
`week. All other details are as in
`Fig. 2
`
`357
`
`Table 2 ALT, AST, and GGT values (IU/l) at baseline and for 6 weeks following administration of 192 mg or 384 mg depot naltrexone.
`Numbers in parentheses represent+1 SEM. Asterisks represent significant differences from baseline (P<0.01)
`
`Baseline
`
`Week 1
`
`Week 2
`
`Week 3
`
`Week 4
`
`Week 5
`
`Week 6
`
`192 mg
`ALT
`AST
`GGT
`384 mg
`ALT
`AST
`GGT
`
`29.2 (7.2)
`19.7 (2.3)
`42.3 (17.5)
`
`54.7 (22.2)
`27.8 (6.9)
`39.7 (14.6)
`
`24.3 (7.2)
`21.5 (3.7)
`28.7 (9.7)
`
`132.3 (99.8)
`31.8 (5.9)
`55.0 (24.0)
`
`63.3 (26.5)
`31.2 (7.4)
`46.8 (14.6)
`
`51.8 (17.4)
`22.8 (4.8)
`47.5 (16.4)
`
`65.3 (25.8)
`26.8 (6.2)
`55.0 (18.4)*
`
`75.2 (31.0)*
`34.7 (8.9)*
`62.3 (20.7)*
`
`60.7 (21.4)
`31.5 (7.8)
`56.7 (18.0)*
`
`34.3 (6.3)
`22.5 (3.1)
`45.7 (16.1)
`
`45.5 (16.0)
`24.7 (5.5)
`40.0 (11.7)
`
`50.0 (20.0)
`29.5 (6.5)
`40.2 (12.1)
`
`53.3 (24.2)
`36.2 (11.8)
`39.0 (11.3)
`
`49.0 (21.6)
`31.0 (6.8)
`36.0 (11.3)
`
`Liver enzyme (ALT, AST, GGT) values at baseline
`were within the normal range for all participants, with the
`exception of one individual in the low-dose group whose
`GGT value (128 IU/l) slightly exceeded the normal range
`of 5–80 IU/l. Three individuals in the low-dose group
`tested positive for hepatitis, and four individuals in the
`high-dose group tested positive for hepatitis. In the low-
`dose group, average GGT levels significantly increased
`during weeks 3, 4, and 5, relative to baseline [Tables 2;
`week 3: F(1,30)=7.5, P<0.01; week 4: F(1,30)=18.6,
`P<0.0002; week 5: F(1,30)=9.6, P<0.004]. Both ALT
`[F(1,30)=7.5, P<0.01] and AST [F(1,30)=8.5, P<0.007]
`values in the low-dose gro