Naltrexone long-acting formulation
`in the treatment of alcohol dependence
`
`R E V I E W
`
`Bankole A Johnson
`Department of Psychiatry and
`Neurobehavioral Sciences, University
`of Virginia, Charlottesville, VA, USA
`
`Correspondence: Bankole A Johnson
`Alumni Professor and Chairman,
`Department of Psychiatry and
`Neurobehavioral Sciences,
`University of Virginia, PO Box 800623,
`Charlottesville, VA 22908-0623, USA
`Tel +1 434 924 5457
`Fax +1 434 244 7565
`Email bankolejohnson@virginia.edu
`
`Abstract: While oral naltrexone has a demonstrated ability to decrease alcohol reinforcement,
`it also has pharmacotherapeutic limitations, such as a small treatment effect size, adverse events,
`and plasma level fl uctuations. The pharmacokinetic profi le of naltrexone could be enhanced
`by intramuscular administration, which would sustain its release over several weeks and keep
`plasma levels relatively constant, ie, low enough to minimize side effects but high enough to
`reduce drinking. Vivitrex®/Vivitrol® and Naltrel® are injectable naltrexone depot formulations
`that have been tested as possible medications for treating alcohol dependence. Their adverse-
`event profi les appear to be less severe than that of oral naltrexone. Vivitrex®/Vivitrol® has
`demonstrated effi cacy at decreasing heavy drinking among alcohol-dependent males. Naltrel®
`helped to promote abstinence and decrease the incidence of relapse in two samples of alco-
`hol-dependent subjects. The data on a third formulation, Depotrex®, are still limited. All three
`formulations require further study of their effi cacy.
`Keywords: alcohol dependence, depot, Depotrex®, Naltrel®, naltrexone, Vivitrex®, Vivitrol®
`
`Introduction
`The reinforcing effects of alcohol associated with its abuse liability are mediated
`by dopaminergic pathways that originate in the ventral tegmental area, relay to the
`nucleus accumbens with neuronal inputs from other limbic regions, and progress to
`the cortex (Wise and Bozarth 1987; Weiss and Porrino 2002; Koob 2003). Naltrexone,
`a mu-opioid receptor antagonist, decreases alcohol reinforcement via two mecha-
`nisms: (1) suppression of alcohol-mediated beta-endorphin stimulation of dopamine
`neurons directly in the nucleus accumbens, and (2) reduction of beta-endorphin
`disinhibition of the tonic inhibition of dopamine cells by gamma-aminobutyric acid
`neurons in the ventral tegmental area (Spanagel and Zieglgansberger 1997; Johnson
`and Ait-Daoud 2000).
`Srisurapanont and Jarusuraisin (2005), in a review of 27 randomized controlled
`clinical trials, reported that oral naltrexone was effi cacious at decreasing relapse and
`a return to heavy drinking among recently abstinent alcohol-dependent individuals,
`which is consistent with the above hypothesis. Yet, since the pharmacokinetic proper-
`ties of oral naltrexone lead to signifi cant fl uctuations in plasma levels with oral daily
`dosing, its general effectiveness has been limited by two consequential factors. First,
`the low plasma trough level of oral naltrexone diminishes its effi cacy, which could
`explain why medication adherence above 85% is required in order for there to be a
`therapeutic response (Volpicelli et al 1997). Second, high peak levels are deemed
`responsible for adverse events (Croop et al 1997; King et al 1997), and up to 15% of
`oral naltrexone recipients drop out of treatment because of adverse events, especially
`nausea (Croop et al 1997).
`The effectiveness of naltrexone also is limited by its small treatment effect
`size (Johnson and Ait-Daoud 2000; Feinn and Kranzler 2005), especially in newer
`
`Therapeutics and Clinical Risk Management 2007:3(5) 741–749
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`and multi-site trials; the number needed to treat (ie, to see
`a difference from placebo) is 7 for decreasing the likelihood
`of relapse and 12 for decreasing the likelihood of returning
`to drinking (Srisurapanont and Jarusuraisin 2005). Never-
`theless, subjects with the Asp40 allele of the mu-opioid
`receptor, as opposed to those with the Asn40 allelic type,
`might derive greater therapeutic benefi t than is seen in
`the averaged response (Oslin et al 2003). Further study is
`needed to confi rm these results.
`Optimizing the pharmacokinetic profi le of naltrexone by
`developing a deep intramuscular injection that would release
`naltrexone over several weeks would, therefore, enhance its
`overall effectiveness. Consequently, plasma levels would
`remain relatively constant and low enough to reduce the
`incidence of adverse events yet high enough for the desired
`anti-drinking effects (Bartus et al 2003). In other words,
`while the effect size of naltrexone’s long-acting, intramus-
`cular formulation would not be expected to exceed the effect
`size of oral naltrexone, the overall outcome would probably
`be enhanced by the increased compliance and longer exposure
`to a therapeutic dose. This review focuses on the therapeutic
`effects and pharmacological properties of two long-acting,
`injectable depot preparations of naltrexone – Vivitrex®,
`recently renamed Vivitrol® (Alkermes, Inc., Cambridge,
`MA, USA), and Naltrel® (DrugAbuse Sciences, Inc., Paris,
`France) – for treating alcohol dependence. Another depot
`formulation, Depotrex® (Biotek, Inc., Woburn, MA, USA),
`for which published data are limited, is also mentioned.
`Table 1 provides a summary of the advantages and dis-
`advantages of depot naltrexone preparations compared with
`oral naltrexone in alcohol-dependent individuals.
`
`Currently available preparations
`Properly formulated depot preparations can maintain
`relatively constant plasma levels for days or weeks because
`of the slow, timed release of the compound. Long-acting
`naltrexone depot formulations also are designed to minimize
`the high plasma peaks and exposure of the gastrointestinal
`tract to naltrexone that occur with the oral formulation.
`Thus, there is a reduction in nausea, the main adverse event
`associated with discontinuation of naltrexone treatment.
`Also, the relatively stable plasma levels of a naltrexone depot
`formulation help to maintain constant levels of mu-opioid
`receptor occupancy, and, importantly, this facilitates a
`linear pharmacodynamic response. Since alcohol-dependent
`individuals often are relatively non-compliant with regard to
`medication taking (Rohsenow et al 2000), spacing naltrexone
`injections at intervals of up to 4 weeks, thereby keeping
`plasma levels constant, should enhance compliance and
`promote greater effi cacy.
`Vivitrex®/Vivitrol® is naltrexone formulated into
`poly-(lactide-co-glycolide) (Shive and Anderson 1997),
`small-diameter (⬍100 µm), injectable microspheres, which
`contain other proprietary active moieties that lead to its
`extended-release properties lasting for several weeks (Lewis
`1990). In animal studies, these microspheres were suspended
`in 1 mL of an aqueous solution (3.0% low-viscosity
`carboxymethylcellulose, 0.9% saline, and 0.1% Tween-20),
`enabling injection of a 50 mg/kg dose of naltrexone (Bartus
`et al 2003). The plasma naltrexone level reached its peak
`at approximately 15 ng/mL by the third day post-injection,
`was sustained at approximately 12 ng/mL for another
`18 days, and then tapered off until it dipped below 1 ng/mL
`
`Table 1 Advantages and disadvantages of depot naltrexone preparations compared with oral naltrexone in alcohol-dependent
`individuals
`Advantages of depot naltrexone preparations compared with
`oral naltrexone
`• Effi cacy is not compromised since there are
`
`not signifi cant fl uctuations in plasma levels
`
`causing low trough levels
`• Adverse events, particularly nausea, are not
`
`increased by high peak levels that would result from the
`
`plasma level fl uctuations
`•
`Since injections are spaced 4-weeks apart,
`
`problems with compliance are minimized
`• The simplicity of supervision and administration
` might make the depot formulations suitable for
`
`forensic settings
`• Patients who will be in situations where oral
`
`naltrexone is unavailable can receive treatment
`
`
`
`
`Disadvantages of depot naltrexone preparations compared
`with oral naltrexone
`• An apparent gender disparity in effi cacy
`
`(with men receiving the greater benefi t)
`
`requires further exploration
`• Certain adverse events, such as erythema,
`
`induration, and injection site reactions, are unique to
`
`the depot formulations
`• Vivitrol® is contraindicated in patients
`
`receiving opioid analgesics
`• More health care providers must be involved to
`
`ensure proper administration
`• Depot formulations could be cost prohibitive for many
`
`patients
`• Delivery of psychosocial support might be
`
`needed more often than the monthly injections
`
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`14 days after that (Bartus et al 2003). Vivitrex® resulted in
`an approximate 70% reduction, compared with placebo, of
`morphine-induced analgesia in the hot-plate test for approxi-
`mately 3 weeks – an effect that disappeared by 4 weeks after
`injection. The expected rise in mu-receptor density, caused by
`Vivitrex®-induced antagonist blockade, was evaluated using
`[D-ala2, N-methyl-phe4, glycol5] enkephalin ([3H]DAMGO).
`This revealed that there was a 110% increase, compared with
`placebo, in mu-receptor density, from 5 days after the injec-
`tion until 33 days later, most prominently in the thalamus,
`nucleus accumbens, dorsal raphe nucleus, and striatum.
`Vivitrex®, therefore, appears to block effectively the central
`mu-opioid receptors for a period of approximately 4 weeks
`after the injection (Bartus et al 2003).
`Fewer data on Naltrel® than on Vivitrex®/Vivitrol® exist
`in the public domain. Naltrel® consists of naltrexone incor-
`porated within microspheres of poly-(DL-lactide) polymer.
`These microspheres are contained in single-dose vials and
`suspended in a diluent comprising mannitol, carboxymeth-
`ylcellulose, polysorbate 80, and water for injection. When
`metabolized, the polylactide polymer produces water and
`carbon dioxide. Degradation of the microspheres causes
`naltrexone to be released (Kranzler et al 2004).
`A lesser-known third formulation, Depotrex®, is dis-
`cussed briefl y in the Clinical Results section below.
`
`Pharmacodynamics
`and pharmacokinetics
`The marked analgesic response to morphine in the hot-plate
`paradigm in rats was blocked by Vivitrex® (50 mg/kg) from
`the fi rst day of injection until 4 weeks later. An injection
`of Vivitrex® 5 weeks after the fi rst injection led to suppres-
`sion of morphine analgesia for another 4 weeks (Bartus
`et al 2003). When Vivitrex® was injected subcutaneously,
`plasma naltrexone peaked at approximately 15 ng/mL after
`approximately 3 days; following intramuscular injection, it
`peaked at 19 ng/mL, also after approximately 3 days. Mean
`plasma naltrexone levels were 12 to 14 ng/mL for the next
`3 weeks regardless of the route of administration, and they
`were detectable until 5 weeks after the injection. After the
`administration of a competitive mu-receptor antagonist, there
`usually is a neuroadaptive upregulation of these receptors
`(Lahti and Collins 1978; Zukin et al 1982). This pharmacody-
`namic response was quantifi ed by measuring the mu-receptor
`density with [3H]DAMGO radioligand autoradiography fol-
`lowing the administration of Vivitrex®. After a single injec-
`tion, signifi cant increases in mu-receptor density occurred,
`especially in the midbrain and striatum a week later and in the
`
`Naltrexone long-acting formulation for alcohol dependence
`
`neocortex a month later; these were sustained for 2–4 weeks.
`Similar results were seen in immunochemistry studies, but
`with relatively smaller increases, which ranged from 10%
`to 40% (Bartus et al 2003). Importantly, the amount of mu-
`receptor upregulation after injection of Vivitrex® appears
`similar to the amount after at least 4 weeks of oral naltrexone
`administration (Giordano et al 1990). In view of the fact
`that suppression of morphine analgesia also occurred in the
`hot-plate paradigm for 5 weeks after the administration of
`a single Vivitrex® injection, it is reasonable to suggest that
`a pharmacologically relevant dose of Vivitrex®/Vivitrol®
`continues its pharmacodynamic effect of blocking central
`mu-receptors for up to 1 month post-injection.
`Johnson et al (2004) showed, in a double-blind,
`placebo-controlled, randomized, multi-site, 16 week study
`of 30 alcohol-dependent individuals, that the 25 subjects
`receiving an intramuscular injection of Vivitrex® (400 mg)
`every 4 weeks for 4 months had a mean plasma 6-beta-
`naltrexol (naltrexone’s major metabolite) trough level of
`3.0 ng/mL and a mean naltrexone trough level of 1.3 ng/mL.
`In contrast, an earlier study found that – 16 hours after
`administration of oral naltrexone (50 mg) – subjects had a
`mean serum 6-beta-naltrexol level of 24.9 ng/mL (McCaul
`et al 2000). The fi ndings of King et al (1997) showed mean
`urinary concentrations of 29.0 µg/mg for 6-beta-naltrexol
`and 2.9 µg/mg for naltrexone, 3 hours after oral administra-
`tion of naltrexone (50 mg) in 24 male moderate-to-heavy
`social drinkers.
`Galloway et al (2005) demonstrated, in an open-label,
`single-site, 6 week study of 16 alcohol-dependent indi-
`viduals receiving just one intramuscular injection of Naltrel®
`(300 mg), that serum naltrexone levels increased to a peak of
`approximately 2.04 ng/mL at 2 weeks and dissipated slowly
`to 0.58 ng/mL over the next 4 weeks. Plasma naltrexone and
`6-beta-naltrexol levels at week 4 were approximately 0.75
`and 2.2 ng/mL, respectively. These levels were proportion-
`ately (ie, to dose) less than those found in the Vivitrex® study
`by Johnson et al (2004).
`In humans, the peak plasma concentration of long-acting
`naltrexone depot formulations is greater than that of oral nal-
`trexone during the days immediately after the injection. The
`advantage of these formulations with respect to tolerability,
`therefore, may be that such peaks just occur early in treatment
`with the depot preparations whereas they occur daily with
`oral naltrexone. The lack of fi rst-pass metabolism with the
`long-acting preparations, with diminished 6-beta-naltrexol
`levels, also might lead to an improved adverse-event profi le
`as increased levels of beta-naltrexol have been associated
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`with a greater severity and frequency of naltrexone-related
`adverse events (King et al 1997).
`Thus, preclinical and human studies provide a phar-
`macodynamic and pharmacokinetic basis for the monthly
`injection of a long-acting naltrexone depot formulation as
`treatment for alcohol dependence through the blockade of
`mu-opioid receptors.
`
`Clinical results
`Clinical trials involving alcohol-dependent individuals have
`examined the effi cacy, safety, and tolerability of Naltrel® and
`Vivitrex®/Vivitrol®.
`
`Naltrel®
`The fi rst published study on the effi cacy, safety, and toler-
`ability of Naltrel® for treating alcohol dependence comprised
`a multi-site, double-blind, 12 week clinical trial. One hun-
`dred fi fty-eight alcohol-dependent men and women were
`assigned to receive Naltrel® and 157 received placebo, both
`accompanied by motivation enhancement-based psycho-
`social support, every 4 weeks (Kranzler et al 2004). The
`fi rst Naltrel® dose consisted of one injection of 150 mg in
`each buttock, and each dose thereafter was just 150 mg.
`Placebo was identical in number and volume of injections
`but did not contain the active compound. Generally, Naltrel®
`appeared to be well tolerated and safe. Side effects that were
`reported signifi cantly more frequently in the Naltrel® group
`than in the placebo group included injection site reactions,
`chest pain, and upper abdominal pain. Irritability, however,
`was more common after placebo than after injection of
`Naltrel®. There were 13 dropouts (8.2%) in the Naltrel®
`group and only 6 dropouts (3.8%) in the placebo group;
`the subjects’ reasons for discontinuing treatment, however,
`were similar between the groups. Naltrel® recipients were
`more likely than placebo recipients to have a higher mean
`number of cumulative abstinent days (52.8 days, 95%
`CI 48.5–57.2 days, vs 45.6 days, 95% CI 41.1–50.0 days,
`respectively; p = 0.018) and a longer median time to fi rst
`drink (5 days, 95% CI 3–9 days, vs 3 days, 95% CI 2–4
`days, respectively; p = 0.003). The effects of gender on treat-
`ment outcome were not examined, probably because of the
`relatively small sample size (Kranzler et al 2004).
`A single-site, 6 week, open-label trial studied 16 alcohol-
`dependent individuals who were given a single intramuscular
`dose of Naltrel® (300 mg) (Galloway et al 2005). Of the
`198 adverse events that were reported, 17 were rated as
`severe, including fatigue, gastrointestinal pain, irritability,
`nausea, somnolence (2 reports), headache (4 reports from
`
`3 subjects), injection site pain, injection site mass, lethargy,
`depression, increased gamma-glutamyl transferase (GGT)
`level (an index of heavy drinking) (Conigrave et al 2002),
`back pain, and fl atulence. There were no serious adverse
`events. Also, the trend was for participants’ drinking out-
`comes to improve between enrollment and the end of the
`trial (Galloway et al 2005).
`Since the Naltrel® formulation has shown promise as an
`effi cacious medication for treating alcohol dependence, it
`deserves further study. Early fi ndings indicate that Naltrel® is
`safe and well tolerated, and its adverse-event profi le appears
`to be milder than that reported for oral naltrexone. Additional
`data are needed regarding the effects of gender on treatment
`outcome. Future studies also should show whether Naltrel® is
`likely to cause injection site-related allergic-type reactions.
`
`Vivitrex®/Vivitrol®
`The fi rst published study on the initial effi cacy, safety, and
`tolerability of Vivitrex® for treating alcohol dependence was
`a double-blind, placebo-controlled, randomized, multi-site,
`16 week clinical trial (Johnson et al 2004). Twenty-fi ve
`alcohol-dependent individuals were assigned to receive intra-
`muscular injections of Vivitrex® (400 mg) every 4 weeks,
`while fi ve participants received placebo via the same route
`of administration every 4 weeks. Vivitrex® appeared to be
`relatively safe and well tolerated; the most common adverse
`events were non-specifi c abdominal pain, nausea, pain at
`the injection site, and headaches. Two Vivitrex® recipients
`and zero placebo recipients discontinued treatment because
`of side effects. One participant dropped out due to indura-
`tion at the injection site, and one was discontinued by the
`research staff because of an allergic reaction that resulted
`in angioedema, which resolved soon after the participant
`stopped taking the medication. Even though any conclu-
`sions regarding effi cacy must take into consideration the
`study’s unbalanced cell design, it did appear that Vivitrex®
`was more likely than placebo to lead to a lower percentage
`of heavy drinking days (ie, 11.7% vs 25.3%, respectively).
`In the exercise of scientifi c caution, no inferential statistical
`testing was conducted on these descriptive values. Addition-
`ally, participants in both the Vivitrex® and placebo groups
`demonstrated improved drinking outcomes between enroll-
`ment and study end (Johnson et al 2004).
`The effi cacy, safety, and tolerability of Vivitrex® were
`later studied in a placebo-controlled, double-blind, ran-
`domized, multi-site, 24 week clinical trial (Garbutt et al
`2005). Intramuscular injections of high-dose Vivitrex®
`(380 mg) (n = 205), low-dose Vivitrex® (190 mg) (n = 210),
`
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`or matching placebo (n = 209), along with low-intensity
`psychosocial support, were administered to alcohol-
`dependent men and women every 4 weeks. Participants
`who received high-dose Vivitrex® were signifi cantly more
`likely than placebo recipients to report the adverse events of
`decreased appetite, nausea, pain at the injection site, dizzi-
`ness, and fatigue. The low-dose Vivitrex® and placebo groups
`experienced adverse events at a similar frequency. Although
`14.1% of the high-dose Vivitrex® recipients dropped out of
`treatment, only 6.7% of the low-dose Vivitrex® and placebo
`groups did so. Injection site reactions, headaches, and nausea
`were the most common reasons given for discontinuing treat-
`ment. Two high-dose Vivitrex® recipients had serious adverse
`events caused by an interstitial pneumonia and allergic-type
`eosinophilic pneumonia, both of which resolved after medical
`treatment. The high-dose Vivitrex® group, averaged between
`men and women, had a signifi cantly lower percentage of
`heavy drinking days than did placebo recipients (hazard
`ratio [HR] 0.75, 95% CI 0.60–0.94; p = 0.02). An analysis
`by gender, however, demonstrated that the only improvement
`in drinking outcomes among high-dose Vivitrex® recipients
`was in men (HR 0.56, 95% CI 0.41–0.77; p ⬍ 0.001) and
`not women (HR 1.23, 95% CI 0.85–1.78; p = 0.28). These
`fi ndings demonstrate that although women in the high-dose
`Vivitrex® group versus the placebo group reported a 23%
`relative increase in percentage of heavy drinking, men in
`the high-dose Vivitrex® group reported a relative decrease of
`44% in the same variable. High-dose Vivitrex® and placebo
`recipients did not differ signifi cantly in GGT level, and low-
`dose Vivitrex® and placebo recipients did not experience a
`signifi cant difference in GGT level or drinking outcomes
`(Garbutt et al 2005).
`At least four points need to be made concerning the evi-
`dence that Vivitrex®/Vivitrol® can decrease heavy drinking in
`men but not women (Johnson 2006). First, since individuals
`with alcohol dependence in their family history have reportedly
`experienced the best results with oral naltrexone (Monterosso
`et al 2001), it is tempting to speculate that male subjects in the
`Garbutt et al (2005) trial may have responded to Vivitrex® for
`the same reason. Comparative rates of family history of alco-
`holism between men and women, however, were not given.
`Hence, future studies testing the effi cacy of Vivitrex®/Vivitrol®
`should investigate any potential interaction between familial
`alcoholism (or related variables including age of alcoholism
`onset) and treatment outcome.
`Second, Vivitrex® injections might have been more likely
`in women than in men to be delivered subcutaneously instead
`of intramuscularly, thereby slowing absorption, since women
`
`Naltrexone long-acting formulation for alcohol dependence
`
`tend to have a relatively higher percentage of body fat (Blaak
`2001). Indeed, in a study by Kiefer et al (2005), drinking
`outcomes appeared to be better for women than for men
`receiving oral naltrexone. Since Garbutt et al (2005) did not
`study pharmacokinetic data, a report comparing the kinetic
`profi le of Vivitrex®/Vivitrol® between women and men
`would be required to exclude this possibility.
`Third, alcohol-dependent men and women enrolled
`in clinical trials perhaps cannot be compared directly as
`they might differ on non-drinking outcomes, including
`familial pressure to change, rates of affective disorder,
`or individual motivation to achieve treatment objectives.
`There is no evidence, however, to suggest that the women
`enrolled in this trial were atypical of women participat-
`ing in pharmacotherapy trials for the treatment of alcohol
`dependence. Moreover, among the enrolled men, there was
`probably heterogeneity on these same factors. Attempts
`to match women and men who are enrolled in pharmaco-
`therapy trials for treating alcohol dependence on multiple
`non-drinking-related factors would not be practical and
`would lead to the same conclusion, ie, that the therapeutic
`effect of Vivitrex®/Vivitrol® to diminish heavy drinking
`among alcohol-dependent men does not translate to alcohol-
`dependent women. Subjects who participate in pharmaco-
`therapy trials for treating alcohol dependence are mostly
`men, and the relatively small sample sizes of single-site
`studies do not allow meaningful statistical comparisons of
`drinking outcomes between women and men. Of the two
`important trials that resulted in US Food and Drug Admin-
`istration approval of oral naltrexone for treating alcohol
`dependence (O’Malley et al 1992; Volpicelli et al 1992),
`only the O’Malley et al (1992) study included women, but
`not in large enough numbers to permit gender comparisons.
`Given the multitude of published studies testing oral naltrex-
`one for the treatment of alcohol dependence (Srisurapanont
`and Jarusuraisin 2005), a meta-analytic approach to
`examining for a gender effect on treatment outcome would
`be of scientifi c interest. If oral naltrexone has demonstrated
`similar effi cacy between women and men, then the absence
`of an effect for Vivitrex® in women might be a result of
`the fact that oral naltrexone and Vivitrex®/Vivitrol® are
`prepared and administered differently. If, on the other
`hand, meta-analytic studies reveal that oral naltrexone, like
`Vivitrex®/Vivitrol®, exhibits greater effi cacy for men than
`for women, then it is plausible that such fi ndings would be
`related to common pharmacodynamic interaction factors.
`A greater understanding of such factors is necessary for
`optimization of treatment delivery.
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`Fourth, pharmacotherapy studies of naltrexone or its
`analogues for treatment of alcohol dependence usually
`reveal a small to medium effect size. Thus, the differential
`effi cacy for Vivitrex® between men and women might have
`happened by chance.
`The importance of the fi ndings of allergic-type interactions
`with Vivitrex® is uncertain. Based upon the two cases of
`pneumonia reported by Garbutt et al (2005) and the one case
`of angioedema reported by Johnson et al (2004), the allergic-
`type reaction rate for Vivitrex®/Vivitrol® would be 1 per 218
`study subjects. Additional investigation of oral naltrexone
`and naloxone (a structurally similar medication designed for
`intravenous injection) is needed to determine their allergic-
`type reaction rates. Comparing the Vivitrex®/Vivitrol®
`fi ndings directly with any such results, however, would be
`complicated by differences in study population size, disease
`states, and length of exposure, among other factors. A prudent
`analysis would require extensive monitoring of the potential
`for allergic-type reactions after Vivitrex®/Vivitrol® admin-
`istration in future clinical trials. Since Vivitrex®/Vivitrol®
`cannot be removed from a subject’s body after it is injected,
`and any allergic-type reactions would be prolonged as a
`result of the formulation’s long duration of action, a practical
`approach to naltrexone treatment might (depending upon the
`allergic-type reaction rates for oral naltrexone and naloxone)
`be to use a small “test dose” of Vivitrex®/Vivitrol® before
`delivering the full therapeutic dose a few days later.
`Clinical evidence suggests that Vivitrex®/Vivitrol® can
`diminish heavy drinking among men but not women. The
`reason for this difference in effi cacy is still unclear, as is the
`pathophysiological signifi cance of the potential for allergic-
`type reactions with Vivitrex®/Vivitrol®; thus, further investi-
`gation is warranted. Overall, Vivitrex®/Vivitrol® appears to
`be safe and well tolerated, with a milder adverse-event profi le
`than oral naltrexone. Future studies should compare directly
`the side-effect profi les of Vivitrex®/Vivitrol® and Naltrel®.
`
`Depotrex®
`Published data on another depot naltrexone formulation,
`Depotrex®, are limited. Depotrex® appears to cause a
`stable and sustained increase in plasma naltrexone levels.
`It antagonizes mu-opioid receptors with few side effects
`(Heishman et al 1994; Alim et al 1995). Comparative dose-
`ranging pharmacokinetic data on Depotrex® have been
`reported in a study of 12 heroin-dependent individuals
`(Comer et al 2002). Depotrex® (low and high doses of 192
`and 384 mg, respectively) kept plasma naltrexone levels
`above 1 ng/mL for 3 and 4 weeks, respectively. Mean peak
`
`levels for the low and high Depotrex® doses were 3.8 and
`8.9 ng/mL, respectively. Plasma beta-naltrexol levels were
`proportionately higher but were undetectable 5 weeks
`following administration. Both the low and high doses
`antagonized heroin-induced positive subjective effects. The
`primary adverse event reported was mild discomfort at the
`injection site, with no irritation or erythema (Comer et al
`2002). Previously, Kranzler et al (1998) reported promis-
`ing fi ndings showing that the administration of Depotrex®
`(206 mg) was associated with a prolonged increase in plasma
`naltrexone, similar to the Comer et al (2002) study in heroin
`addicts. Moreover, their study highlighted the effi cacy of
`Depotrex®, compared with placebo, at reducing heavy drink-
`ing among alcohol-dependent individuals; nevertheless,
`injection site reactions including induration were observed
`in some participants (Kranzler et al 1998). Additional studies
`on this promising formulation are needed.
`
`Discussion
`While the naltrexone long-acting formulations discussed
`herein have the benefi t of lower adverse-event profi les and
`necessitate fewer visits to a treatment center than would be
`needed for the administration of oral naltrexone, their use
`does require that more health care providers be trained. For
`instance, injections must be administered properly to decrease
`the possibility of local site reactions, which could, in turn,
`diminish compliance. Moreover, the number of physicians
`or nurses might have to be increased so that providers are on
`hand to administer the injections and to assess and triage any
`medical complications that may occur (Johnson 2006).
`Although depression and other psychiatric problems are
`not listed among the contraindications for injectable naltrex-
`one in the Vivitrol® package insert (Alkermes, Inc. 2005),
`adverse events of a suicidal nature were reported infrequently
`in controlled trials among Vivitrol®-treated patients (1% vs 0
`in the placebo group), and depressed mood was twice as likely
`(10% vs 5%) for Vivitrol® (380 mg) recipients vs placebo
`recipients in a 24 week controlled trial. Hence, alcohol-
`dependent patients taking Vivitrol® should be monitored for
`depression or suicidal ideation (Alkermes, Inc. 2005).
`Vivitrol® is contraindicated in patients who are receiving
`opioid analgesics. If pain management becomes necessary
`in an emergency situation, Vivitrol® recipients should be
`given regional analgesia, conscious sedation with a benzo-
`diazepine, and non-opioid analgesics or general anesthesia.
`In situations requiring opioid analgesia, administration of a
`rapidly acting opioid analgesic that minimizes the duration
`of respiratory depression is recommended, with the amount
`
`746
`
`Therapeutics and Clinical Risk Management 2007:3(5)
`
`AMN1050
`IPR of Patent No. 7,919,499
`
`

`

`of analgesic titrated to the patient’s needs. These patients
`should be closely monitored by personnel who are trained in
`cardiopulmonary resuscitation (Alkermes, Inc. 2005).
`Thus far, no precedent exists in the psychiatric fi eld for
`administering a medication intramuscularly instead of orally.
`Practitioners, therefore, might use these long-acting depot
`preparations only if a “trial” of oral naltrexone has failed
`because of low compliance. Furthermore, it also is possible
`that, in real-world generic clinics as opposed to clinical trial
`settings in a research facility, patients might be less likely to
`consent to injections for the treatment of alcohol dependence
`due to injection phobia, relatively less individual attention
`paid by medical staff, or a lower intensity of psychosocial
`support provided by health professionals. Providers might
`also consider a “trial” of oral naltrexone to guarantee early
`detection of any adverse events (Johnson 2006).
`If long-acting depot formulations of naltrexone are
`approved by the US Food and Drug Administration, their
`widespread use might be limited because of cost. Uneven
`insurance coverage has hampered the use of oral naltrexone
`in many parts of the US. While the prices of the depot formu-
`lations have not yet been announced, their daily cost might
`exceed that of oral naltrexone. Hence, these preparations
`might be less accessible to uninsured patients who cannot
`pay on their own (Johnson 2006).
`Treatment providers should not avoid delivering regular,
`adequate psychosocia