66 BIOL PSYCHIATRY
`1985;20:66-72
`
`Nontolerance to the Opioid Antagonism
`
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`of N altrexone
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`
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`Herbert D. Kleber, Thomas R. Kosten, Joseph Gaspari,
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`
`and Mark Topazian
`
`Controlled opiate challenges of naltrexone-pretreated human subjects have established
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`that naltrexone is an effective opioid antagonist. However, these challenges have been
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`and tolerance to this antagonism acute dosing with naltrexone, conducted after relatively
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`after chronic treatment is possible. We therefore administered morphine challenges in a
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`double-blind, placebo-controlled design to nine ex-addicts who had been taking naltrexone
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`for a mean of 9.4 months. None of the ex-addicts experienced euphoria; instead, most
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`of these blockaded ex-addicts had a dysphoric histaminelike response to the intravenous
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`morphine. The only physiological change was a slight increase in heart rate. We conclude
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`that tolerance does not develop to the opioid antagonist properties of naltrexone up to
`as long as 21 months of treatment.
`
`Introduction
`
`Opioid antagonists have been explored as possible treatment alternatives to methadone
`
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`maintenance or residential treatment. Because of problems with treatment using cycla­
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`zocine and naloxone, most recent studies have used naltrexone, a long-acting, orally
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`effective opioid antagonist (National Research Council on Clinical Evaluation of Narcotic
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`Antagonists 1978). Initial studies of naltrexone established it as an effective opioid
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`antagonist by using controlled morphine challenges in naltrexone-pretreated subjects (Ver­
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`ebey et al., 1976). Former addicts pretreated with naltrexone reported no euphoria and
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`showed no evidence of intoxication when given substantial intravenous doses of heroin
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`(25 mg) or morphine (25-100 mg). These were acute studies and did not involve chronic
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`treatment with naltrexone followed by quantitated morphine challenge. In the phase III
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`clinical testing of naltrexone, former addicts were maintained on naltrexone for several
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`months and reported not getting any euphoria or "high" when they used heroin (Table
`5
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`as an opioid of naltrexone suggested that the efficacy in Hurzler et al. 1976). This finding
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`Treatment Unit, New Haven, Connecticut 06510.
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`Support for this work was provided by a grant from the DuPont Pharmaceutical Company.
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`Address reprint requests to: Dr. H.D. Kleber, Connecticut Mental Health Center, 34 Park Street, New Haven, Connecticut
`06510.
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`
`
`From the Department of Psychiatry, Yale University School of Medicine Connecticut Mental Health Center, Substance Abuse
`
`Received May 24, 1984; revised July 6, 1984.
`
`
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`Cl 1985 Society of Biological Psychiatry
`
`0006-3223/85/$03. 30
`
`ALKERMES EXHIBIT 2024
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
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`Nontolerance to Naltrexone
`
`BIOL PSYCHIATRY
`67
`1985;20:66-72
`
`antagonist was sustained and that subjects did not develop tolerance to this antagonism.
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`In contrast, with narcotic agonists, tolerance develops to the euphoria produced by mor­
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`phine after even a few days of regular dosing.
`Although during these phase III trials no systematic studies were conducted on the
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`continued efficacy of naltrexone as an antagonist, two studies have provided some in­
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`dication that tolerance does not develop to the drug's opioid blockade. In rhesus monkeys,
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`continuous intravenous infusions of naltrexone produced stable suppression of morphine
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`self-administration over 4-week periods when the dose of morphine was held constant at
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`8 µg/kg/injection (Harrigan and Downs, 1978). The single human study by Martin et al.
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`(1973) demonstrated that after 16 days of naltrexone at either 30 mg or 50 mg daily, no
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`tolerance to its ability to block morphine euphoria at doses up to 240 mg/day occurred.
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`In summary, several studies have suggested that tolerance does not develop. However,
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`if tolerance to the opioid antagonism of naltrexone were to develop, a patient who is
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`chronically taking naltrexone might run the risk of heroin overdose by overriding the
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`opioid blockade of naltrexone. We therefore designed a double-blind, placebo-controlled
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`study to test the efficacy of the opioid blockade of naltrexone after several months of
`maintenance.
`
`Methods
`
`
`
`Setting and Sample
`
`Nine former heroin addicts in the Connecticut Mental Health Center Drug Dependence
`
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`Unit took naltrexone for a mean of 9.4 months (range: 4.5-21 months) after giving written
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`informed consent. The subjects were part of a comprehensive outpatient treatment program
`
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`that has been previously described and had regular medical evaluations and biweekly
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`urine toxicology screens for illicit drug use (Kosten and Kleber, 1984; Kosten et al.,
`
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`
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`1983). Program participants took naltrexone three times per week, i.e. , l 00 mg on Monday
`
`and Wednesday and 150 mg on Friday.
`The former addicts had a mean age of 33 (range: 27--48) years; six were male and
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`eight were white. They had been using primarily heroin for a mean of 10.4 (range: 1-21)
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`years, and three had been on methadone maintenance in the past. Although no concurrent
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`substance abuse was detected in the urine toxicology screens, only three participants
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`reported never having tested the opioid blockade of naltrexone on their own. None of
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`the participants had abused alcohol in the previous month, and none was taking any
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`concurrent medications. Medical evaluations had excluded any potential subjects with
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`
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`significant hepatic, cardiovascular, or renal disease.
`
`Study Design
`
`The study design was a double-blind, placebo-controlled trial involving intravenous bol­
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`uses of either morphine or placebo on different days. On the basis of previous acute
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`
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`studies of naltrexone (Verebey et al. 1976; Martin et al. 1973; Meyer and Mirin, 1979),
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`a single 60-mg dose of morphine was considered the upper limit for a challenge dose,
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`and the initial two participants were given doses of 20 mg followed by the next two
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`
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`participants receiving 40 mg. The last five participants received 60 mg. The challenge
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`was given as a bolus through an intravenous line maintained for at least 60 min postin­
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`jection with 5% dextrose solution. To prevent participants from knowing when the in-
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`Page 2 of 7
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`68
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`BIOL PSYCHIATRY
`
`I 985;20:66--72
`
`H.D. Kleber et al.
`
`jection was given, subjects were placed in an isolation room and the intravenous tubing
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`was run through an opening in the wall to the observation room. The experimenter could
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`view the subject through a video monitor and give the intravenous challenge through the
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`line without the subject knowing when the injection was given. The order of placebo and
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`morphine injections was randomized. The challenge testing occurred in the afternoon, 4
`hr after a 100-mg dose of naltrexone.
`After obtaining written informed consent, the participant was asked to give a urine
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`sample for toxicology, and a brief psychiatric interview and physical examination were
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`conducted. Several standard outcome measures were also administered before the chal­
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`lenge testing began, and these outcome measures were repeated at intervals of 2 min
`
`after the injection, then at every 20 min for l hr, and then at 2 hr after the injection.
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`The initial four subjects were also assessed at 3 hr after injection.
`
`Outcome Measures
`
`Both physiological and psychological assessments of the participants were made. Phys­
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`
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`iological assessments included blood pressure, heart rate, respiratory rate, and pupillo­
`
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`metry. Blood pressure was assessed with an AMR Dinamap Automated Noninvasive
`
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`
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`monitor using the oscillometric method. These readings were checked with manually
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`
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`obtained blood pressures and were found to correspond well. Heart rate was monitored
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`using a three-lead electrocardiogram connected to a Gould brush 480 amplifier and chart
`
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`recorder. Respiratory rate was measured using changes in the electrical impedance of the
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`chest wall. The impedance change was processed by a Hewlett-Packard respiration monitor
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`and was written on the chart recorder. Pupillometry was performed using a Polaroid CU-
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`was then filter. The pupil size in the photographs with polarizing 5 closeup 3 : l camera
`measured.
`Psychological assessments included both self-reports and observer ratings. The self­
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`reports were six analog scales ranging from Oto 10 for feeling "high," feeling a "rush,"
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`feeling sleepy, feeling pleasant, craving, and dollar value of the injection. From the
`
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`Addiction Research Center Inventory (ARCI) (Hill et al. 1963) the 45 items known to
`
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`detect a weak opioid response were also administered. Observer ratings were completed
`
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`at the baseline and at five subsequent time intervals using 10-point analog
`that
`scales
`
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`included "nodding," sedation, dysphoria, withdrawal, and intoxication.
`
`Data Analysis
`This experiment had a balanced repeated-measures design, with nine subjects having
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`measurements repeated six times under the two challenge conditions of morphine and
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`placebo. For statistical analysis, a two-way repeated-measures analysis of variance (AN­
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`OV A) was used to determine any differences between the two challenge conditions.
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`Interaction effects were important, because they indicated a difference between the mor­
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`phine and placebo challenges. This difference was related to the pattern of change over
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`time in the physiological (i.e., heart rate) or psychological (i.e., dysphoria) measure. If
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`a significant interaction effect was demonstrated, the pattern of change over time was
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`vi:mally examined to determine at which time points the major differences occurred (i.e.,
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`at 2 min after the injection). To assess the significance of these differences, matched
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`sample Student's t-tests were used.
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`Page 3 of 7
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`
`Nontolerance to Naltrexone
`
`BIOL PSYCHIATRY
`1985;20:66--72 69
`
`
`
`Table I. Physiological Measures During the Baseline and After Placebo and Morphine Challenges
`
`
`
`
`
`
`
`
`(n = 9)
`
`Placebo
`
`Morphine
`
`Significance•
`
`Measure Base Post" Base Post" Chai. Rep. Inter.
`
`Systolic BP
`
`
`Diastolic BP
`76
`Respiration
`17
`Pupil size (mm)'
`5.0 5.0 5.3 5.1
`Heart rate
`
`125 123 124
`77
`
`76
`
`17
`
`18
`
`73
`
`71
`
`70
`
`74
`
`124
`
`78
`
`17
`
`*
`
`*
`
`** **
`
`
`
`"Base: 20-min baseline assessment of physiological measures; Post: average of five postinjection assessments at 2, 20, 40, 60, and 120
`
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`
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`
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`min.
`'Significance determined using two-way repeated-measures ANOV A for six sampling times. Chai: challenge effect overall for morphine
`
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`
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`vs. placebo; Rep: repeated measure, i.e .. change in response measure over time for both challenges combined; Inter: interaction term for
`
`
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`
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`difference between morphine and placebo challenge in pattern of response measure change over time. • = p < 0.05, •• = p < 0.01.
`
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`with F( 1,80) for challenge effect and F(5,80) for repeated-measures and interaction effects.
`
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`,·For pupil size, assessments were made only at 2, 20, 40, and 60 min postinjection for the last six participants.
`
`Results
`
`
`
`Physiological Responses
`
`the between a significant difference The only physiological outcome to demonstrate
`
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`morphine and placebo injection was heart rate, but no other physiological index suggested
`
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`that morphine intoxication had occurred. For heart rate, the repeated measure [F(5,80) = 5.8,
`
`
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`were both significant. Upon p < 0.01] and interaction [F(5,80) = 6.2, p < 0.01] effects
`
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`visual examination of the change in heart rate over time, the largest difference between
`
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`
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`At that time, at 2 min after the injection. occurred the morphine and placebo challenges
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`the placebo rate remained the morphine rate rose to 88.4 beats/min, while at 70 beats/min
`
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`the challenge condition, rise during the morphine (t = 2.2, p < 0.05). After this initial
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`For the other heart rate fell to the same rate as the placebo condition and remained stable.
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`physiological outcomes, the two challenge conditions did not differ. Table l compares
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`and the morphine the placebo the blood pressure, respiratory rate, and pupil size during
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`challenge conditions for the baseline and for the postinjection times. The values for the
`
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`five postinjection ratings were averaged, as no significant differences were demonstrated
`
`
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`effect was sig­using the repeated-measures ANOV A. Although the repeated-measures
`
`
`
`for diastolic blood pressure and pupil size, the direction of the change in these
`nificant
`
`
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`was the opposite of what would be expected from an opioid response.
`
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`
`Psychological Responses
`
`The psychological ratings did not demonstrate the expected effects of morphine intoxi­
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`cation; instead, a significant dysphoric response was found during the morphine challenge.
`
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`Among the subjective responses, the ARCI scale indicated a slight morphine effect
`
`
`
`beginning at 2 min after the injection, as shown in Table 2. Three of the analog scales
`
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`
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`also indicated a subjective response to the morphine. The rush scale rose from a baseline
`
`
`of O to 5.4 at 2 min after the morphine injection [F(l ,80) = 11.5, p < 0.01, for the
`
`
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`
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`The "high" scale challenge effect, and F(5,80) = 13.9, p < 0.01, for the interaction].
`
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`rose from 0.1 to 2.2 at 2 min [F(l ,80) = 6. 7, p < 0.05, for the challenge effect, and
`
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`from = 4.8, p < 0.05, for the interaction]. The feeling-pleasant scale dropped
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`F(5,80)
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`Page 4 of 7
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`70
`
`BIOL PSYCHIATRY
`1985;20:66--72
`
`H.D. Kleber et al.
`
`Table 2.
`
`(n = 9)
`
`
`
`
`
`
`
`Psychological Measures During the Baseline and After Placebo and Morphine Challenges
`
`
`
`Placebo
`
`Morphine
`
`Significance
`
`b
`
`Measure
`Base
`
`Post" Base
`
`Post" Chai. Rep. Inter.
`
`*
`
`ARCI'
`3.7 3.8 3.3 3.6 6.6 5.0
`0
`Feel high
`0.1 .02 0.1 2.2 0.5 *
`** **
`Feel rush
`0
`0.1 .07 0
`5.4 I. I ** ** **
`
`Dollar value 0
`0
`0 0.9 0.8 0.8
`Pleasant 4.8 4.6 4.4 5.4 2.8 4.1
`Dysphoric 0.6 0.1 .o7 0.1 2.8 0.8
`Sedated 0.7 1.3 1.3 I. I 1.0 0.7
`
`*
`
`*
`
`** **
`
`"Base: 20-min baseline assessment of physiological measures; Post the 2-min postinjection rating (see Table I). It is given in addition
`
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`
`
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`to the average of the postinjection ratings because these ratings were often markedly different from the other four postinjection ratings.
`
`
`
`
`
`
`
`
`•significance determined using two-way repeated-measures ANOV A for six sampling times. Chai: challenge effect overall for morphine
`
`
`
`
`
`
`term for interaction combined; Inter: measure, i.e., change in response measure over time for both challenges vs. placebo; Rep: repeated
`
`
`
`
`
`difference between morphine and placebo challenge in pattern of response measure change over time. • = p < 0.05, •• = p < 0.01,
`
`
`
`
`
`with F( 1,80) for challenge effect and F(5,80) for repeated-measures and interaction effects.
`
`
`
`
`
`
`
`
`
`''ARC!: Addiction Research Center Inventory, consisting of weak opioid response scale of 45 true/false items.
`
`5.4 to 2.8 at 2 min and had a significant interaction effect [F(5,80) = 2.44, p < 0.05].
`
`
`
`
`
`
`
`Thus, the rise in ARCI score and the "rush" and "high" analogs were associated with an
`
`unpleasant response.
`This unpleasant response was corroborated by observer ratings. Among the observer
`
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`ratings, only the dysphoria rating demonstrated a significant interaction effect using
`
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`
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`ANOVA (F(5,80) = 8.4, p < 0.01]. When the dysphoria rating during the morphine
`
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`
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`challenge was compared with this rating during the placebo challenge, a major difference
`
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`
`
`was apparent at 2 min after the injection. The ARCI weak opioid response occurred at
`
`
`
`
`
`
`
`the same time as the peak dysphoria rating. The values at the baseline and at 2 min after
`
`
`
`injection and the average of the other four ratings are shown in Table 2 for all the scales
`
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`
`
`except craving, "nodding," withdrawal, and intoxication. These four scales are not in­
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`
`
`
`cluded in the analysis because they never demonstrated any change during either challenge
`condition.
`
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`
`
`Clinical Responses to Morphine Challenge
`
`Below 60 mg of morphine, only two of the four participants reported any response to
`
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`morphine. At 20 mg of morphine, one participant felt a "buzz in his head" for about I
`
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`min after the injection, and at 40 mg another participant said he was "getting a rush"
`
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`
`
`followed by paresthesia, nausea, and a pounding bitemporal headache for 20 min. At 60
`
`
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`mg, every participant easily identified the morphine injection by a feeling of "pins and
`
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`
`
`needles" in the injected arm, and the observer noted diffuse erythema in all five partic­
`
`
`
`
`
`ipants. These symptoms cleared within 20-30 min. Other symptoms described by some
`
`
`
`
`participants included pruritis, feeling warm all over, a "po unding
`heart, puffy face" and
`
`
`
`
`
`
`a metallic taste. No respiratory distress or major allergic-type responses occurred.
`
`Discussion
`
`The present study with former addicts maintained on naltrexone for a mean of 9.4 months
`
`
`
`
`
`
`
`
`
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`indicates that subjects do not become tolerant to its opioid antagonism, but may become
`
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`dysphoric when challenged by intravenous morphine. The only physiological assessment
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`Nontolerance to Naltrexone
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`BIOL PSYCHIATRY
`71
`1985;20:66-72
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`to show some response to the opioid challenge in this study was heart rate. This mild
`
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`
`
`response to the morphine may have been mediated through a release of histamine (Douglas,
`
`
`
`
`
`1980). A short-term heart rate increase has been reported after 25 mg of heroin in humans
`
`
`
`
`(Volavka et al. 1974), which could suggest that some partial tolerance to the opioid
`
`
`
`
`blockade may have developed. It is more likely that this increase in heart rate represented
`
`
`
`
`
`a histamine response, since the other usual physiological responses to morphine involving
`
`
`
`
`blood pressure, pupil size, and respiration did not change. Similarly, the participants'
`
`
`experience of feeling high and a "rush" did not appear to be a weak opioid response,
`
`
`
`
`
`
`because this experience was not pleasurable, but dysphoric. The "rush" appeared to be
`
`
`
`
`
`
`a conditioned response to feeling the histamine release that accompanies the intravenous
`
`
`
`use of heroin or morphine (Hill et al. 1963; Meyer and Mirin 1979). A brief clinical
`
`
`
`
`
`
`summary of the morphine challenge responses illustrated that the dysphoric feelings that
`
`
`
`
`the study participants described as a "rush" or feeling "high" were clearly not euphoric
`
`
`
`
`
`experiences. Thus, former addicts maintained on naltrexone had physiological and psy­
`
`
`
`
`
`
`chological responses to a double-blind placebo-controlled morphine challenge that sug­
`
`
`
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`
`
`gested a sustained opioid blockade and an aversive response to morphine.
`
`
`
`In the practical therapeutic use of naltrexone, the dysphoria that every participant
`
`
`
`
`
`described at 60 mg of morphine might be the most important finding. Instead of reinforcing
`
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`properties, certain opioid drugs may be associated with an aversive quality after naltrexone
`
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`
`
`treatment. According to the conditioning theory of opioid antagonist treatment, the aver­
`
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`
`
`sive quality of these morphine challenges could actually be therapeutic (Wilder 1976).
`
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`By repeating the connection between the morphine injection and dysphoria, the former
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`addict may be conditioned to avoid further use of opioid drugs. The pharmacological
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`basis for this dysphoria seemed to be related to a typical histamine response (Douglas
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`1980). The response seemed unusually severe after an injection of morphine, but this
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`probably resulted from the relatively large dose of morphine used and the blockade of
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`any euphoria or calming effect by the opioid antagonism of naltrexone. The "rush" and
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`also a of morphine were probably rise in heart rate at 2 min following the injection
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`reflection of this histamine response. Importantly, no one developed histamine shock or
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`any severe allergic responses after morphine, but if the competitive blockade ofnaltrexone
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`needed to be overridden for medical reasons, opioid drugs with less tendency to release
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`should be considered. Such an attempt to override should clearly be done only
`histamine
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`in a hospital setting to avoid the risk of respiratory depression.
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`This is the first demonstration of the long-term pharmacological efficacy of naltrexone.
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`However, two studies have tested the drug's opioid blockade after 2-4 weeks of main­
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`tenance. Both studies supported the current findings that tolerance does not develop to
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`naltrexone over 4 treated with the opioid antagonism of naltrexone. Rhesus monkeys
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`that the reinforcing opioid drugs, suggesting weeks had no tendency to self-administer
`the 4 weeks of continuous
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`properties of these drugs was blocked by naltrexone during
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`dosing with naltrexone (Martin et al. 1973). In a study on human volunteers conducted
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`for a period of 16 days, naltrexone induced a sustained blockade of morphine euphoria
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`(Meyer and Mirin 1979). During those 16 days, a daily dose of 50 mg ofnaltrexone was
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`Because we also used able to block euphoria effectively from 240 mg/day of morphine.
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`might suggest that naltrexone daily, their results the equivalent of 50 mg of naltrexone
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`have been able to antagonize more opioid drug than our single 60-mg dose of
`actually
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`morphine. As the opioid antagonism ofnaltrexone is competitive, it is possible to overdose
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`by taking a very large dose of narcotics, but it is important to emphasize that 60 mg is
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`pain relief. to achieve clinical four to five times larger than the usual dose administered
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`Page 6 of 7
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`72 BIOL PSYCHIATRY
`1985;20:66--72
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`H.D. Kleber et al.
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`Therefore, former addicts who are taking naltrexone chronically and challenge its opioid
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`blockade on their own do not appear to be at any greater risk of heroin overdose at 9
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`months than when they initially began taking naltrexone.
`In summary, no significant physiological or psychological tolerance has developed to
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`the opioid antagonism of naltrexone, and it is pharmacologically effective for up to 21
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`months of sustained maintenance in former heroin addicts. The opiate blockade of nal­
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`trexone is effective in inhibiting euphoria and intoxication as well as in preventing possible
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`drug overdose in a former addict who challenges the naltrexone blockade on his or her
`own.
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`Patient support and help with the ratings were provided by Dr. Clyde Swift, Dr. G. Baily, S. Nelson, Izola
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`Hogan, and c: O'Connor.
`
`References
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`Harrigan SE, Downs DA (1978): Continuous intravenous naltrexone effects on morphine self­
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`Douglas WT (1980): Histamine and 5-hydroxytryptamine (serotonin) and their antagonists. In The
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`Gilman AG, Goodman LS, Gilman A (eds). New York:
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`PIUJrmacological Basis of Therapeutics,
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`J PIUJrmacol administration in rhesus monkeys. Exp Ther 204:481-486.
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`Hill HE, Haertzen CA, Wolbach AB, et al (1963): The Addiction Research Center Inventory:
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`Hurzler M, Gerwitz D, Kleber HD (1976): Varying clinical contexts for administering naltrexone,
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`after acute and chronic dosing. Clin PIUJrmacol Ther 20:315-328.
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`Volavka J, Levine R, Feldstein S, et al (1974): Short-term effects of heroin in man. Arch Gen
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`Wikler A (1976): The theoretical basis of narcotic addiction treatment with narcotic antagonists.
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`Washington DC: National In Julius D, Renault P (eds), Narcotic Antagonists: Naltrexone.
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`Kosten TR, Jalali B, Hogan I, et al (1983): Family denial as a prognostic factor in opiate addict
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`Martin WR, Jasinski DR, Mansky PA (1973): Naltrexone, an antagonist for the treatment of heroin
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