British Journal of Clinical
`Pharmacology
`
`Injectable and implantable
`sustained release naltrexone
`in the treatment of opioid
`addiction
`
`Nikolaj Kunøe,1,2 Philipp Lobmaier,1,2 Hanh Ngo3 & Gary Hulse3
`
`1The Norwegian Centre for Addiction Research, University of Oslo, Oslo, Norway, 2Oslo University
`Hospital, Oslo, Norway and 3Unit for Research and Education in Drugs and Alcohol, School of
`Psychiatry & Clinical Neurosciences, University of Western Australia, Perth, Western Australia, Australia
`
`DOI:10.1111/bcp.12011
`
`Correspondence
`Dr Nikolaj Kunøe PhD, The Norwegian
`Centre for Addiction Research, the
`Medical Faculty, the University of Oslo, P.O.
`Box 1039 Blindern, N-0315 Oslo, Norway
`Tel.: +47 23 36 89 00
`Fax: +47 23 36 89 86
`E-mail: nikolaj.kunoe@medisin.uio.no
`-----------------------------------------------------------------------
`Keywords
`drug addiction, drug dependence,
`naltrexone, opioids, substance-related
`disorders, sustained release
`-----------------------------------------------------------------------
`Received
`31 May 2012
`Accepted
`16 October 2012
`Accepted Article
`Published Online
`22 October 2012
`
`Sustained release technologies for administering the opioid antagonist naltrexone (SRX) have the potential to assist opioid-addicted
`patients in their efforts to maintain abstinence from heroin and other opioid agonists. Recently, reliable SRX formulations in
`intramuscular or implantable polymers that release naltrexone for 1–7 months have become available for clinical use and research. This
`qualitative review of the literature provides an overview of the technologies currently available for SRX and their effectiveness in
`reducing opioid use and other relevant outcomes. The majority of studies indicate that SRX is effective in reducing heroin use, and the
`most frequently studied SRX formulations have acceptable adverse events profiles. Registry data indicate a protective effect of SRX on
`mortality and morbidity. In some studies, SRX also seems to affect other outcomes, such as concomitant substance use, vocational
`training attendance, needle use, and risk behaviour for blood-borne diseases such as hepatitis or human immunodeficiency virus. There
`is a general need for more controlled studies, in particular to compare SRX with agonist maintenance treatment, to study combinations
`of SRX with behavioural interventions, and to study at-risk groups such as prison inmates or opioid-addicted pregnant patients. The
`literature suggests that sustained release naltrexone is a feasible, safe and effective option for assisting abstinence efforts in opioid
`addiction.
`
`Introduction
`
`Heroin is used by an estimated 0.4% of the world’s popula-
`tion,but heroin-related problems account for nearly 60% of
`the treatment demand in Europe and Asia [1]. The best
`candidate explanation for this lies in the comprehensive
`nature of heroin addiction;the sedative effects of the opioid
`agonist heroin greatly increase the risk of fatal or near-
`fatal overdose, while a high incidence of injecting use
`greatly increases the risk of introducing bacterial, viral or
`fungal agents due to nonsterile injecting practices.
`Regular heroin users also have an increased occurrence of
`mental health disorders, and often engage in the regular
`use of at least two other illicit drugs [2].In the USA,diversion
`and misuse of prescription opioids is an increasing problem
`[3]. There are environmental factors associated with illicit
`opioid use, such as engagement in criminal activities, poor
`living standards and‘less stable environments’(i.e.exposure
`to violence, accidents, injury and suicide) [4]. All these
`
`factors contribute to increase the risk of death from regular
`illicit opioids to a rate of about 8.6 deaths per 1000 person-
`years [5]. This risk is heightened following detoxification
`and discharge from a controlled environment, because
`opioid receptors are thought to readjust to function
`without exogenous opioid intake. For example, one study
`found that the risk of overdose death was 12 times that of
`the pre-admission risk following discharge from inpatient
`treatment such as detoxification [6]. Another study found
`that the risk of mortality was up to 34 times elevated during
`the first 2 weeks following release from a prison setting [7].
`Recovery from heroin addiction often takes several years,
`with at least occasional relapse and setbacks;it is thus often
`understood as a chronically relapsing disease [8]. While
`most of our present knowledge on opioid addiction comes
`from experience with illicit heroin users, all types of opioid
`agonists share the same basic neurophysiological path-
`ways and thus the risk of dependence, tolerance, with-
`drawal, intoxication and abuse.
`
`264 / Br J Clin Pharmacol
`
`/ 77:2 / 264–271
`
`© 2012 The Authors
`British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
`
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`Sustained release naltrexone in the treatment of opioid addiction
`
`Present treatment alternatives
`
`Until recently, treatment options for heroin addiction were
`limited to the following three main alternatives: detoxifica-
`tion followed by long-term residential treatment; opioid
`maintenance treatment (OMT); and oral naltrexone.
`Detoxification followed by long-term residential treat-
`ment has been found to result in some reduction in drug
`use for a large minority of patients, but suffers from prob-
`lems with retention in treatment and risk of overdose upon
`discharge [9]. Opioid maintenance treatment maintains or
`substitutes dependence on heroin via the supervised
`administration of opioid agonist medications including
`methadone, buprenorphine or medically dispensed
`heroin [10]. While OMT is effective in reducing mortality,
`morbidity and drug-related criminal activity, chief con-
`cerns are dropout during the initial months of treatment
`and that only a minority of patients are able to achieve
`normal vocational and social functioning. For those who
`do achieve such integration, there is currently no validated
`alternative to life-long dependence on the opioid agonists
`administered daily in OMT.
`
`Naltrexone – an opioid antagonist
`
`Naltrexone induces a competitive antagonism at all the
`main types of opioid receptors, with some preference for
`the m receptor. Although both naltrexone and naloxone
`were developed based on modifications of oximorphan,
`the overall affinity of naltrexone for opioid receptors is
`higher and its half-life significantly longer than that of
`naloxone. Thus, naloxone is better suited for acute pur-
`poses, such as reversing the effects of opioid-induced
`sedation, while naltrexone is better for scenarios that
`require prolonged antagonism, e.g. assisting abstinence
`from opioid agonists following detoxification and/or
`reducing addiction-related craving. While a full review of
`these latter types of effects is beyond the scope of this
`article, the high prevalence of comorbid substance use
`problems makes them relevant to the overall therapeutic
`effect, especially for heroin users.
`Naltrexone has long been known to cause a reduction
`in craving sensation for many types of addictive sub-
`stances, including alcohol [11] and amphetamine [12].
`There have also been reports of a similar effect on certain
`types of compulsive behaviours, such as bodily self-harm
`[13] and gambling addiction [14]. The precise mechanism
`for craving reduction has not been determined, but the
`most likely is that naltrexone causes antagonism of opioid
`pathways to the nucleus accumbens, reducing the total
`amount of dopamine released. Naltrexone at very low
`doses (0.25 mg day-1) seems to reduce the severity and/or
`longevity of opioid withdrawal during detoxification [15],
`possibly assisting a restoration of normal opioid receptor
`functioning [16] and attenuating noradrenergic with-
`
`drawal systems [17]. In addition, opioid antagonists like
`naltrexone affect other biological systems, such as
`G-protein second messenger systems [18], the immune
`system [19] and the hypothalamic–pituitary–adrenal axis
`[20].
`
`Compliance problems with oral
`naltrexone
`
`Studies of oral naltrexone tablets taken daily or bidaily
`have generally failed to show superiority over placebo,
`mostly due to rapid dropout in the active naltrexone
`group. However, modestly improved results can be
`achieved when oral naltrexone is taken as part of a
`compliance-reinforcing scheme, such as contingency
`management [21]. The lack of clinical success with oral
`naltrexone was recognized in the first clinical studies of
`oral naltrexone [22, 23]. Consequently, research efforts
`were started in order to develop sustained release tech-
`nologies that would decrease compliance problems by
`reducing the number of dropout opportunities. As part of
`development efforts for a sustained release formulation,
`the following two central characteristics for sustained
`release naltrexone (SRX) were formulated: (i) for blocking
`street heroin doses, the minimal plasma level of naltrexone
`was estimated to be about 1 ng ml-1, although some of this
`blockade is also provided by the metabolite 6b-naltrexol
`[24]; and (ii) a clinically useful SRX formulation was thus
`considered to release naltrexone at levels of 1 ng (ml
`plasma)-1 or above for the duration of at least 4 weeks, with
`an acceptable rate of
`tissue-related adverse events.
`Following more than 30 years of development efforts, this
`goal has recently been achieved.
`
`Sustained release naltrexone (SRX)
`formulations
`
`Currently, two main types of sustained release technolo-
`gies are used to release naltrexone: injectable intramuscu-
`lar suspension and surgically implantable pellets. This
`section provides a summary of the data from the literature
`on the currently available SRX technologies, and their
`ability to block opioid agonists, such as heroin or mor-
`phine. While there are other sustained release technolo-
`gies available, e.g. for buprenorphine [25], these have not
`been developed for naltrexone.
`
`Polylactide suspension
`The naltrexone release of this class of SRX medications is
`based on the slow biodegrading of a 380 mg polylactide
`and naltrexone suspension, providing therapeutic blood
`levels of naltrexone over a period of 28 days. An intramus-
`cular SRX suspension of this type was recently approved by
`the US Food and Drug Administration for prescription for
`
`Br J Clin Pharmacol
`
`/ 77:2 / 265
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`N. Kunøe et al.
`
`opioid dependence in the USA, after being approved for
`the treatment of alcohol dependence in 2006. The intra-
`muscular suspension is administered via injection into the
`gluteus muscle, alternating sides every 4 weeks. A
`research-only formulation can be injected subcutaneously.
`With the latter formulation, a heroin challenge study was
`conducted where participants were administered a
`380 mg dose subcutaneously and then received intrave-
`nous heroin at dosages of 0, 6.25, 12.5 or 25 mg in a
`double-blind design. The suspension provided satisfac-
`tory blockade of both self-rated and objective measures
`(e.g. pupillary diameter) of heroin for between 4 and 5
`weeks [26]. Recently, a similar experiment was conducted
`using the Food and Drug Administration-approved intra-
`muscular suspension at reduced dosages of 75, 150 or
`300 mg of naltrexone and using hydromorphone instead
`of heroin for the challenge tests; 3 mg of hydromorphone
`was blocked by the 300 mg SRX formulation for 28 days,
`whereas the lower SRX dosages blocked this challenge for
`a correspondingly shorter duration [27].
`
`Surgically implanted capsules
`The other main type of SRX technology consists of pellets
`with biodegradable solid polymer surgically inserted or
`implanted under the skin or fatty tissue with the use of
`local anaesthetic. The wound is then sealed with one to
`three sutures, with the wound being inspected after about
`1 week. The two formulations of surgically implanted nal-
`trexone that have been used in the majority of controlled
`studies are an Australian type with release periods as long
`as 7 months when 30 pellets are inserted [28] and a
`Russian type with a release period of 2–3 months [29].
`Other manufacturers of naltrexone implants exist, but little
`research has been published on their reliability or produc-
`tion methods (see [30] for an exception to this). Case data
`support the view that SRX implants releasing naltrexone at
`or above 1 ng (ml blood)-1 will block normal dosages of
`laboratory-administered heroin, as well as high dosages of
`illicit heroin [24, 31, 32].
`
`Effect on opioid use
`
`The majority of randomized controlled trials (RCTs) on SRX
`have shown promising increases in heroin abstinence in
`the SRX group relative to control subjects, despite diversity
`in sample composition, study design and cultural settings.
`Two studies have been conducted of 4 week intramuscular
`SRX suspensions: an 8 week double-blind study from the
`USA of a selected sample divided into a high-dosage, low-
`dosage and placebo [33]; and a 24 week double-blind trial
`of SRX vs. placebo in a sample of Russian heroin users [34].
`Both studies found significant increases in the proportion
`of urine samples negative for heroin use.
`On implantable naltrexone, five RCTs will be reviewed
`here. Three RCTs utilized a 6 month version of the Austral-
`
`266 / 77:2 / Br J Clin Pharmacol
`
`ian implant. One open-label study randomized to treat-
`ment as usual in a Norwegian treatment setting [35], and
`there was a placebo-controlled, double-dummy design
`with oral naltrexone in Western Australia [36]; both found
`significant decreases in heroin use. A Norwegian open-
`label study randomizing to methadone OMT or naltrexone
`implant in probationer settings experienced dropout
`problems, and found similar reductions in opioid use
`among the patients who remained [37]. Two randomized
`studies have been conducted in Russia using a Russian
`naltrexone implant. A 10 week study of n = 100 patients (n
`= 50 in the SRX and placebo groups, respectively) who
`were both amphetamine and heroin dependent found sig-
`nificant reductions in heroin use [29]. A larger study that
`followed n = 306 opioid-dependent patients over 6
`months in a three-group, double-dummy design found
`that a significantly larger proportion of urine samples were
`opioid negative in the active SRX group compared with
`both oral naltrexone and placebo [38].
`The magnitude of the reduction in opioid use with SRX
`is typically about 50% at a group level when compared
`with oral naltrexone or usual-treatment control subjects,
`although there is considerable individual variation among
`patients. In summary, sustained release naltrexone seems
`to succeed in assisting patients in achieving abstinence
`from opioids. The consistency of this finding despite diver-
`sity in study designs, cultural setting and SRX formulation
`reinforces the impression that the effect of SRXs on heroin
`use is a clinically robust finding. There are few data regard-
`ing the effectiveness of SRX in the treatment of addiction
`to prescription opioids.
`
`Sustained release naltrexone and
`heroin-related overdose
`
`The ability of naltrexone to compete against heroin for
`opioid receptors means that it should provide protection
`against overdose and death. The RCTs thus far completed
`have an insufficient number of participants to permit
`meaningful analyses of mortality rates. A series of registry
`cohort studies from Western Australia have used samples
`of several thousand patients; these studies suggest that
`SRX reduces the number of deaths among heroin users
`compared with methadone users and oral naltrexone
`[39–41]. The same open cohort was used for the SRX
`implant patients in two of these studies. Case reports that
`have been published of patients ‘breaking the naltrexone
`blockade’ with large doses of opioids (e.g. [42]), as well as
`postmortem cases [43], often do not account for potential
`confounding factors. Data from Norwegian SRX patients
`confirm that a minority of patients report ‘breakthrough’-
`like experiences, but that the use of non-opioid illicit drugs
`makes it difficult to verify which substance induced the
`experience [32]. The concept of true receptor agonism or
`‘breakthrough’ in the presence of naltrexone also appears
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`Sustained release naltrexone in the treatment of opioid addiction
`
`to be inconsistent with case stories of naltrexone blocking
`large quantities of heroin [24, 32].
`An extension of this question is whether death from an
`overdose of heroin can occur in active SRX patients. Like
`any pharmacotherapy, the binding of naltrexone at the
`receptor site is of a competitive type that it is technically
`possible to outperform using extreme quantities of
`normal-affinity opioids or high-affinity synthetic opioids,
`such as fentanyl. In clinical settings, obtaining and self-
`administering agonists of the right type or quantity would
`be very difficult; deaths in patients treated with a reliable
`SRX formulation are thus more likely to be caused by expo-
`sure to the many non-opioid mortality sources common in
`the heroin demographic.
`
`Retention in SRX for heroin users
`
`Ambivalence between remaining in treatment and recom-
`mencing heroin use means that heroin users are often
`tempted to drop out from treatment. Thus, retention in
`treatment is considered to be a highly important measure
`of the clinical feasibility of any treatment for heroin addic-
`tion, including OMT and SRX. For naltrexone treatment, the
`inability to retain patients in oral naltrexone regimens has
`strongly contributed to the reason that oral naltrexone
`treatment has seen minimal adoption in clinical settings
`with heroin users [21]. A central clinical advantage of sus-
`tained release over oral naltrexone is the reduction in
`dropout opportunities, e.g. one intramuscular injection
`every 28th day instead of a tablet every day. In one RCT
`[33], retention was 62% between the first and second 28
`day intramuscular SRX administration. In the Russian study
`of intramuscular SRX (28 days of naltrexone release), attri-
`tion at the end of 6 months of administration of intramus-
`cular SRX administrations was about 50% [34]. This is
`similar to retention between the first and second adminis-
`tration of 6 month implantable SRX [44]. For patients
`receiving the 10 week Russian implant, retention was 63%
`over 6 months among Russian heroin users [38] and 52% in
`the study of patients with both opioid and amphetamine
`dependence [29]. Differences in study design and setting,
`as well as differences in re-administration frequencies and
`adverse event profile make it difficult to infer beyond the
`finding that retention rates for SRX are within a clinically
`acceptable range and tend to be better than their com-
`parison group. Thus, in this respect SRX seems to confirm
`hopes that it would constitute an improvement over oral
`naltrexone [21].
`
`Integration with other behavioural
`interventions
`
`A study from the Johns Hopkins behavioural laboratory
`found that when entry into a voucher-based workplace
`
`system was contingent on acceptance of a monthly intra-
`muscular SRX, compliance and retention were improved
`when patients could enter the workplace freely vs. those
`who were simply prescribed SRX monthly; 74% of contin-
`gency patients accepted all six injections, whereas only
`26% of prescription patients did the same [45]. This is con-
`sistent with previous findings from contingency manage-
`ment with oral naltrexone [46]. This suggests that the
`retention in SRX can be greatly improved when combined
`with behavioural interventions in order to maximize its
`clinical usefulness.
`Sustained release naltrexone administered as part of a
`planned release from prison is another area of consider-
`able interest, in particular due to the increase in overdose
`mortality reported in several studies (e.g. [7, 47]). Given
`that heroin is less available in prison, inmates are more
`likely to maintain abstinence from heroin, which greatly
`facilitates naltrexone induction [48]. Several studies on
`oral naltrexone for opioid-dependent inmate populations
`concluded with beneficial outcomes when naltrexone
`was integrated with psychosocial support to enhance
`external motivation, e.g. work-release programmes and
`parole including follow-up by criminal
`justice staff
`[49–52]. Although treatment attrition was still high in
`these trials, those who stayed on oral naltrexone were less
`likely to relapse to heroin and less likely to engage in
`criminal activity than comparison groups not receiving
`naltrexone. A recent pilot study suggests that intramus-
`cular SRX is feasible in probationers, with participants dis-
`playing reductions in opioid use [53]. This is consistent
`with findings from a Norwegian OMT–SRX randomized
`study [37], where heroin abstinence rates were equivalent
`between the two groups 6 months after release. There is
`debate regarding the ethical aspects of mandating SRX
`for heroin users as part of sentencing or parole conditions
`(e.g. [54]).
`
`Concomitant substance use
`
`Several studies have examined whether SRX also reduces
`concomitant use of non-opioid illicit drugs. Naltrexone
`has been known to reduce craving for a number of addic-
`tive substances (see elsewhere in this issue), often result-
`ing in a subsequent reduction in substance use. Of the
`available studies, RCTs with stricter inclusion criteria seem
`to confirm a change in non-opioid drug use [33, 34]; this
`effect does not reach significance in studies with less
`strict inclusion criteria [28, 34, 35]. This indicates that SRX
`may have an effect on concomitant drug use in heroin
`users, but less dramatic than the effect seen on heroin
`consumption; the division along inclusion criteria may
`also indicate that a reduction in concomitant substance
`use is more likely to occur in subgroups of heroin users
`that are prescreened to reduce the incidence of potential
`confounders.
`
`Br J Clin Pharmacol
`
`/ 77:2 / 267
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`N. Kunøe et al.
`
`Somatic and mental health
`outcomes
`
`A registry cohort study in Australia followed cohorts of
`both SRX and methadone patients, and found that their
`rate of mental health-related hospitalization reduced to a
`similar extent [55]. In a similar study, SRX patients pre-
`sented with fewer psychiatric hospital admissions after
`entering SRX [56]. For somatic hospitalizations, overdose
`admissions were reduced to zero among SRX implant
`patients in a registry linkage study, and continued to be
`reduced compared with pre-admission levels for an addi-
`tional 6 months following the expiry of naltrexone from
`the SRX implant [39].
`
`Adverse events
`
`Moderate adverse effects, such as nausea, vomiting and
`muscle twitches, are experienced by heroin users in both
`SRX and oral naltrexone treatment [22, 57].The majority of
`adverse effects are described as mild to moderate [35], and
`are more likely to occur in active SRX groups than in
`placebo patients [29, 33, 34]. As SRX releases naltrexone
`into the bloodstream gradually at concentrations typically
`in the 1–5 ng ml-1 range, the intensity of adverse effects is
`much reduced compared with oral naltrexone, where
`blood naltrexone levels can remain at 10–30 ng ml-1 for
`several hours every day following tablet intake. The block-
`ade of endogenous opioids thought to result from treat-
`ment with SRX has not been reported to have
`consequences for the occurrence of mood disorders in any
`of the RCTs thus far published, even though the majority of
`them administered instruments to measure depression.
`While there have been reports of depression in users of
`oral naltrexone [58, 59], subsequent investigations failed to
`confirm any effects on mood [60, 61]. Clinicians should
`perhaps be more concerned that naltrexone blocks the
`effects of opioid agonist-based analgesics in an accident-
`prone population,although increasing the dosage or using
`other types of analgesics will often resolve the problem. It
`has also been suggested that naltrexone increases the sen-
`sitivity of the opioid receptor system, making patients
`more vulnerable than usual to heroin overdose once SRX is
`concluded [62]. However, findings from toxicological
`examinations of heroin-related deaths comparing patients
`with or without prior naltrexone exposure do not support
`this hypothesis [63]. In addition, a recent database study
`found a reduction in deaths among SRX patients during
`the first months following treatment when compared with
`oral naltrexone patients [41].
`An important difference between SRX and oral naltrex-
`one is the occurrence of site-related adverse events [64].
`For implantable SRX, these may appear as mild allergic
`itching or redness around the implantation site, or infec-
`tion of the skin, stitching or underlying tissue [65]. These
`
`268 / 77:2 / Br J Clin Pharmacol
`
`events are reported to occur in 2–5% of patients (e.g. [29,
`35]) and usually resolve with symptomatic treatment, but
`in extreme cases may require removal of the implant.
`Some patients have cosmetic concerns with the fact that
`some implantable SRX formulations may take months or
`years to biodegrade completely [66]. Likewise, recipients of
`SRX with intramuscular suspension can often experience
`some site pain, while a few per cent experience more
`serious site reactions, such as induration and infection.
`Hepatic health is sometimes a concern with heroin
`users, especially for patients recently infected with hepati-
`tis C.There is little evidence that SRX in ordinarily adminis-
`tered doses is hepatotoxic. Intramuscular SRX has been
`found to be well tolerated in alcohol-dependent patients
`with hepatic impairment, requiring no dose adjustments
`[67, 68]. A pilot study of implantable SRX in heroin users
`found key hepatic indicators such as ALT to improve over
`the course of treatment [31], and the influence of SRX on
`indicators in other studies has generally been below levels
`of clinical significance. A clinical study of 50 SRX implant
`patients undergoing antiviral therapy for hepatitis C found
`that 62% were hepatitis C virus negative following comple-
`tion of hepatitis C virus treatment and 6 months of SRX
`[69]. Still, caution may be warranted in administering SRX
`to patients who present with severely reduced hepatic
`functioning, e.g. those who qualify for an impairment clas-
`sification corresponding to Child–Pugh grade C.
`Pregnancy is a debated topic in SRX research, as with
`heroin users in general [70–72]. Sustained release naltrex-
`one medication is now available for regular prescription in
`the USA, and there is an interest among pregnant drug
`users despite a general
`lack of knowledge about the
`effects of SRX on fetal health. While this lack of knowledge
`is unfortunate from a medical point of view, the risk of
`return to heroin use upon discontinuation of SRX may be
`considered an even worse outcome. Historically, the solu-
`tion most often adopted has been to continue the phar-
`macotherapies for pregnant heroin users and initiate
`short- and long-term studies on adverse effects following
`delivery of the child [73]. Only one case has been reported
`following this approach, with no adverse effects detected
`in mother or child [74].
`
`Conclusions
`
`Since a Cochrane review in 2008 [75] concluded that there
`were too few studies to conduct any meaningful assess-
`ment of SRX in the opioid addicted, the amount of
`research published on SRX has accumulated to the point
`where this conclusion seems gradually less valid.Sustained
`release naltrexone is showing promising, consistent effects
`in supporting the efforts of opioid users to achieve absti-
`nence across different clinical study design and treatment
`settings. The SRX formulations that have been the subject
`of the majority of research articles appear to have a
`
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`Sustained release naltrexone in the treatment of opioid addiction
`
`satisfactory rate of consistency in naltrexone release and
`an acceptable adverse effects profile. The literature on SRX
`for opioid addiction still requires more studies in order to
`confirm initial findings on effects. There is a particular
`need for more knowledge on SRX compared with current
`standard treatments, the impact on poly-drug depend-
`ence, the use of SRX during pregnancy and the combina-
`tion of SRX with other interventions in order to maximize
`the impact on recovery.
`
`Competing Interests
`
`The authors have completed the Unified Competing Inter-
`est form at http://www.icmje.org/coi_disclosure.pdf (avail-
`able on request) and declare: no support from any
`organization for the submitted work; G.K.H. had entered
`into a contractual arrangement (via the University of
`Western Australia) with Go Medical Industries (who manu-
`facture the Australian naltrexone implant) to conduct a
`number of research studies in the previous 3 years; G.K.H.
`had co-authored with Dr George O’Neil
`(Director, Go
`Medical Industries) on a number of previous publications.
`
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