1.
`
`Introduction
`
`2. Addiction and the
`µ-opioid receptor
`
`3. Pharmacologic treatment
`strategies in opioid addiction
`
`4. Pharmacology of naloxone
`
`5. Naloxone in the treatment of
`opioid addiction
`
`6. Summary and conclusions
`
`7. Expert opinion
`
`For reprint orders,
`please contact:
`ben.fisher@informa.com
`
`Review
`
`Central & Peripheral Nervous Systems
`
`Naloxone treatment in opioid
`addiction: the risks and benefits
`
`Eveline LA van Dorp, Ashraf Yassen & Albert Dahan†
`Leiden University Medical Center, Department of Anesthesiology, P5-Q, PO Box 9600, 2300 RC
`Leiden, The Netherlands
`
`Naloxone is a non-selective, short-acting opioid receptor antagonist that has
`a long clinical history of successful use and is presently considered a safe drug
`over a wide dose range (up to 10 mg). In opioid-dependent patients,
`naloxone is used in the treatment of opioid-overdose-induced respiratory
`depression, in (ultra)rapid detoxification and in combination with buprenor-
`phine for maintenance therapy (to prevent intravenous abuse). Risks related
`to naloxone use in opioid-dependent patients are: i) the induction of an
`acute withdrawal syndrome (the occurrence of vomiting and aspiration is
`potentially life threatening); ii) the effect of naloxone may wear off prema-
`turely when used for treatment of opioid-induced respiratory depression;
`and iii) in patients treated for severe pain with an opioid, high-dose naloxone
`and/or rapidly infused naloxone may cause catecholamine release and conse-
`quently pulmonary edema and cardiac arrhythmias. These risks warrant the
`cautious use of naloxone and adequate monitoring of the cardiorespiratory
`status of the patient after naloxone administration where indicated.
`
`Keywords: µ-opioid-receptor, µ-opioid-receptor antagonist, addiction, naloxone, opioids
`
`Expert Opin. Drug Saf. (2007) 6(2):125-132
`
`1. Introduction
`
`Although opium has been in use for many centuries, opioid addiction only
`became a major global problem since the mid 1800s [1]. In the US alone, almost
`3 million people aged > 12 years have used heroin, of which 326,000 people
`received treatment for heroin abuse [101]. In Europe, 1.2 – 2.1 million people are
`known to be problematic drug users, most of whom use opioids (often in combi-
`nation with other [illicit] drugs) [102,103]. Of these drug abusers, 450,000 people
`receive treatment for their addiction. Besides the fact that addicts are more likely
`to develop mental illness or exhibit criminal behavior, they are also at risk for
`fatal overdose and various infectious diseases, such as hepatitis B and C and HIV.
`The number of drug-related deaths in EU member states is estimated to be in the
`range of 7000 – 9000 per year [103]. Opioid addiction can, therefore, be viewed as
`a major medical and social problem.
`The recent advancements in the understanding of the neurobiology underlying
`addiction-related behavior contributed to the recognition that opioid addiction is a
`serious complication of chronic opioid intake in some individuals (note that patients
`receiving opioids for chronic pain do not necessarily develop addiction). Addiction
`is nowadays considered a chronic disease of the brain rather than a mental illness
`carrying a social stigma [2]. New perspectives in the neurobiology of opioid addic-
`tion offer unique opportunities for the development of novel treatment strategies.
`However, as the disease has a multifactorial etiology, treatment must always be
`multidisciplinal, combining both pharmacologic and psychologic interventions.
`The pharmacologic interventions are either aimed at detoxification and permanent
`abstinence from illicit drugs, or at the attenuation of (often protracted) withdrawal
`
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`
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`

`Naloxone treatment in opioid addiction: the risks and benefits
`
`symptoms using opioid replacement therapy. Although some-
`times complete abstinence is achieved, often lifelong substitu-
`tion is the chosen therapy mode. Methadone substitution
`therapy is the main cornerstone in the treatment of opioid
`addiction, although in some countries a clear shift is seen in
`treatment approach with buprenorphine
`rather
`than
`methadone being the first-choice substitution therapeutic [3].
`This short review discusses some of the pharmacologic
`strategies of opioid addiction treatment with special focus on
`the benefits and risks of the non-selective opioid-receptor
`antagonist, naloxone.
`
`2. Addiction and the µ-opioid receptor
`
`Opioids exert their effects through specific opioid receptors.
`The existence of three subtypes (µ, κ and δ) is accepted. The
`µ-opioid receptor subtype, especially, mediates the positive
`reinforcing effects of heroin and other illicit opioids. This
`receptor subtype is, therefore, considered crucial in the deve-
`lopment of opioid addiction [4]. Dedicated in vivo studies
`have shown that mice lacking the µ-opioid receptor (exon 2
`µ-opioid
`receptor gene knockout mice) display
`less
`self-administration of morphine and reduced conditioned
`place preference [5], underlining the importance of the
`µ-opioid receptor in the development of opioid addiction.
`Drugs of abuse, in general, overstimulate those neural sys-
`tems in the brain that are normally reserved for the response
`to natural reward systems. In this respect, the mesolimbic
`dopamine system, as well as the nucleus accumbens, is con-
`sidered a relevant part of the ventral tegmental area in the
`midbrain [6,7]. Acute administration of drugs of abuse induces
`high levels of dopamine being released in the nucleus
`accumbens, resulting in an increased feeling of reward. Opio-
`ids cause dopamine release by inhibiting the γ-aminobutyric
`acid-ergic inhibition of dopamine release in the ventral teg-
`mental area, a typical part of the midbrain with a high density
`of µ-opioid receptors [8]. Overstimulation of dopamine results
`in stronger deregulations of the natural reward pathways (sen-
`sitization and tolerance) and learning processes in the brain
`(reinforcement) [5].
`Abrupt abstinence from opioids or the administration of
`µ-opioid-receptor antagonists in opioid-dependent persons
`will produce the opioid withdrawal syndrome. Signs and
`symptoms of this syndrome include negative moods, irritabi-
`lity, muscular and abdominal pains, gastrointestinal com-
`plaints (nausea, diarrhea), sweating, lacrimation, malaise and
`insomnia [9]. Symptoms usually start 6 – 12 h after the last
`dose of a short-acting opioid and 36 – 48 h after the last dose
`of a long-acting opioid, such as methadone. The duration of
`the syndrome is variable. Some studies report a duration of no
`more than 7 – 14 days, whereas others also describe a more
`prolonged withdrawal syndrome lasting from several weeks to
`a few months. Although the syndrome is not life threatening,
`many patients experience difficulties completing this initial
`phase of the therapy [10].
`
`3. Pharmacologic treatment strategies in
`opioid addiction
`
`Treatment of opioid addiction should primarily be aimed at
`reduction of illicit drug use (next to stabilizing the social func-
`tioning of the patient and improving his or her quality of life).
`This can be done by either gaining control of the patient’s
`drug use by drug replacement therapy or by withdrawing the
`patient from all opioids (detoxification). It is, however, insuf-
`ficient to regard complete withdrawal as the ultimate therapy;
`addiction is a chronic disease (reflected in long-term changes
`in the brain) and should, therefore, be treated as such.
`Nowadays, most patients receive maintenance therapy con-
`sisting of µ-opioid receptor agonists or a combination of
`µ-opioid-receptor agonists and antagonists.
`Potent and long-acting opioid agonists with low-intrinsic
`efficacy are considered good candidates for opioid replacement
`therapy. Examples of such opioids are methadone and
`buprenorphine. Methadone is a full agonist at the µ-opioid
`receptor, buprenorphine a partial µ-opioid-receptor agonist.
`This characteristic makes buprenorphine an attractive alterna-
`tive for methadone, because low-efficacy agonists, are associ-
`ated with a lower abuse potential compared with relatively
`higher efficacy agonists such as methadone. Furthermore, the
`partial agonist, buprenorphine, has a better safety profile than
`full µ-opioid-receptor agonists, indicating that it can be more
`easily titrated to the desired effect even at high doses [11]. In
`addition, its unique slow receptor association/dissociation char-
`acteristic at the µ-opioid receptor contributes to the extended
`duration of action following single-dose administration [12].
`Opioid antagonists, such as naloxone and naltrexone,
`reverse and prevent opioid effects by blocking the µ-opioid
`receptor. As discussed in Section 2, µ-opioid-receptor block-
`ade causes the occurrence of acute withdrawal symptoms in
`opioid-dependent individuals. µ-Opioid-receptor antagonists
`are widely used in rapid and ultra-rapid detoxification to facil-
`itate the transition from dependence to abstinence. Antago-
`nists can also be used to prevent relapse, as µ-opioid-receptor
`occupancy by opioid antagonists results in a decreased effec-
`tiveness of administered opioids. This diminishes the reinforc-
`ing effects of heroin and potentially the association between
`opioid use and conditioned stimuli [9].
`
`4. Pharmacology of naloxone
`
`For many years, the development of non-addictive opioids,
`with the beneficial analgesic action of morphine but devoid of
`any addictive properties, has been considered an important
`objective. During the twentieth century, various mor-
`phine-like substances were synthesized and tested for their
`non-addictive properties. Nalorphine, a derivative of mor-
`phine, was shown to reverse most of morphine’s typical effects
`at relatively low dose (while inducing analgesia at high dose).
`In addition, nalorphine precipitates the abstinence syndrome
`in opioid addicts. Although nalorphine showed promising
`
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`blocking properties, the dysphoric effect of this opioid dis-
`couraged its widespread clinical use [13]. Additional dedicated
`structure–activity studies led to the discovery of naloxone.
`Naloxone, an allyl derivative of noroxymorphone, was synthe-
`sized first in 1960. The development of naloxone was encour-
`aged by the need for a real opioid antagonist (in contrast to
`the partial agonist, nalorphine) devoid of any agonistic acti-
`vity at the various opioid receptors [14]. Naloxone is a
`non-selective opioid antagonist at the µ-, δ- and κ-opioid
`receptors. Naloxone competitively inhibits the pharmacologic
`effects of opioids and, in line with the classical receptor the-
`ory, produces a parallel right shift in the dose-response curves
`of opioids [15]. When administered to opioid-dependent
`patients, naloxone induces a severe withdrawal syndrome, as
`µ-opioid-receptor-bound heroin is displaced by naloxone.
`Naloxone appears to be readily absorbed after oral adminis-
`tration, but its low bioavailability renders naloxone less
`suitable for this administration route. Following oral adminis-
`tration, naloxone undergoes extensive hepatic metabolism,
`indicating high first-pass effect (> 95%). In the liver, naloxone
`is primarily metabolized
`into
`the
`inactive conjugate
`naloxone-3-glucuronide. In addition to glucuronidation,
`naloxone is also metabolized by N-dealkylation and 6-oxo
`group reduction (note that these metabolism pathways repre-
`sent only minor fraction of total metabolism). Approximately
`30% of the unchanged naloxone dose is excreted in the urine
`within 6 h following intravenous administration; the rest of
`the dose is recovered as conjugated naloxone metabolites in
`the urine [16].
`In healthy volunteers, the elimination half-life of naloxone
`in plasma is ∼ 30 min. Although the elimination half-time is
`not expected to differ among opioid-naive and opioid depend-
`ent patients, differences in naloxone distribution in the body
`may exist. For instance, Handal et al. suggest in their review
`that there may be differences in pharmacokinetics between
`opiate-dependent and non-dependent persons, reporting a
`difference in initial plasma concentration of 30% [17].
`Naloxone is readily transported across the blood–brain bar-
`rier and, therefore, has a fast onset of action in reversing opi-
`oid effects [16]. However, the ability of naloxone to reverse
`opioid effects in vivo is mainly determined by the pharmaco-
`logic characteristics of the interacting opioid agonist (i.e., the
`opioid that requires antagonism). For example, the onset of
`reversal of morphine-induced respiratory depression by
`naloxone can be established within a time frame of 1 – 2 min.
`On the other hand, for an opioid with slow µ-opioid-receptor
`association/dissociation kinetics, such as buprenorphine, the
`interaction with naloxone is rather complex. Not higher doses
`of naloxone per se, but a different mode of naloxone adminis-
`tration (i.e., continuous infusion) is indicated to reverse
`buprenorphine-induced respiratory depression [11,12].
`As naloxone is devoid of agonistic activity at the µ-opioid
`receptor, it is regarded as a safe drug to use. This notion per-
`sists despite earlier clinical experiences showing that naloxone
`use may (under certain specific circumstances) cause serious
`
`van Dorp, Yassen & Dahan
`
`and possibly life-threatening side effects, such as pulmonary
`edema, cardiac arrhythmias, hypertension and cardiac arrest
`[18-20]. It is important to note that all of the patients described
`in these reports were postoperative patients experiencing
`(severe) pain and stress. In a more recent prospective study [21]
`in comatose patients due to opioid overdose, 453 patients
`were treated with naloxone. Six patients suffered from severe
`complications (asystole, pulmonary edema and epileptic sei-
`zures), corresponding to 1.3% of the treated population.
`However, the exact relationship between naloxone treatment
`and the occurrence of the severe complications was not clear.
`The possibility that these complications were related to the
`initial hit (i.e., the opioid overdose) could not be excluded.
`The primary reason for the development of cardiorespiratory
`complications after naloxone therapy is the sudden release of
`central catecholamines [21]. Especially when naloxone is
`administered shortly after the occurrence of opioid-induced
`vasodilation (this may occur just minutes after the opioid is
`administered via the intravenous route and is visible as a sud-
`den drop in blood pressure) or the patient is sympathetically
`unstable (due to pain or stress), high-dose naloxone and/or
`rapidly infused naloxone (i.e., not titrated) can cause catecho-
`lamine-mediated vasoconstriction. This then may cause car-
`diac arrhythmias and a fluid shift from the systemic
`circulation to the pulmonary vascular bed, resulting in pul-
`monary edema [18]. Proper monitoring of patients receiving
`naloxone is, therefore, mandatory, especially of the patient
`that just recently received an opioid dose via the intravenous
`route or the sympathetically unstable patient. Studies in ani-
`mals and healthy volunteers confirm the safety of naloxone
`use in patients [22,23], even at higher doses up to 10 mg [24] or
`following constant exposure to intermediate-to-high concen-
`trations of naloxone during 1 – 2 h [25]. Taking into account
`the fact that there are only few reports in the literature on
`naloxone-related complications (as well as taking into account
`their own experience), the authors consider naloxone a
`relatively safe drug with little chance of complications.
`As an alternative to naloxone, a second µ-opioid-receptor
`antagonist, naltrexone, was synthesized with more favorable
`pharmacokinetic properties than naloxone. Although naltrex-
`one has a relatively low bioavailability (up to 60%), it is two-
`to three-times more potent than naloxone [13]. It undergoes
`extensive hepatic metabolism, but because its metabolite,
`6-β-naltrexol, is also highly active, oral administration can be
`effective. Elimination half-life is ∼ 4 h, with a far longer
`half-life (up to 13 h) reported for the active metabolite. Effec-
`tively, a dose of naltrexone 50 mg will block the pharmaco-
`logic effects of heroin 25 mg for up to 24 h [26]. It is employed
`in rapid and ultra-rapid detoxification and in abstinence
`maintenance therapy [27]. When compared with methadone
`maintenance therapy, naltrexone is the less favorable option,
`as the lack of agonistic effects reduces compliance [26]. If
`retention of patients, however, is high enough (for example
`with highly motivated patients or with patients that cannot be
`included in a methadone maintenance program), naltrexone
`
`Expert Opin. Drug Saf. (2007) 6(2)
`
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`Naloxone treatment in opioid addiction: the risks and benefits
`
`maintenance therapy is an effective way of treating opioid
`addiction [28].
`
`5. Naloxone in the treatment of opioid
`addiction
`
`5.1 Naloxone use in treatment of opioid overdose
`The most common use of naloxone is for the treatment of
`opioid overdose. Heroin overdose is one of the leading causes
`[103] and
`of death among opioid-dependent patients
`non-fatal overdoses are also highly prevalent among these
`patients. Overdose often occurs after a drug-free period and
`is related to a reduction of tolerance and hence a relatively
`increased opioid potency. Naloxone is effective in the treat-
`ment of opioid-overdose and opioid-induced coma in hospi-
`tal practice. Note, however, that it is vital to take into
`account the specific opioid that is responsible for causing the
`overdose. Most opioids used by addicts have relatively long
`half-lifes, whereas naloxone has a half-life of only 30 min. As
`a consequence, respiratory depression, caused by long-acting
`opioids (methadone, heroin, morphine), returns after the
`effect of naloxone has worn off [14,29]. It is, therefore, neces-
`sary to adequately dose and monitor the patient [30]. The ini-
`tial naloxone bolus dose required to reverse opioid overdose
`should be determined clinically, starting from 0.4 mg given
`as a slow bolus injection, continuing until the patient
`improves. If after naloxone 4 – 10 mg, the patient shows no
`sign of recovery, the cause of the respiratory depression is
`most likely not opioid related. After initial recovery, patients
`should be started on a continuous intravenous naloxone
`infusion and closely monitored for signs of deteriorating
`clinical status for at least 24 h.
`It is important to note that the patient may enter an acute
`withdrawal syndrome after administration of naloxone, with
`consequent nausea and vomiting. The airway must, therefore,
`be guarded at all times. Another symptom of acute with-
`drawal may be patient violence [31] and adequate preparation
`for this situation in the form of restraints is needed. All this
`taken into account, naloxone remains the first drug of choice
`in suspected opioid overdose in the hospital setting.
`Because an overdose often occurs outside the hospital set-
`ting (i.e., at home or on the street), naloxone may not be read-
`ily available and it is, therefore, difficult to treat the patient
`timely. Both healthcare professionals and opioid addicts
`themselves regarded
`the
`idea of so-called
`‘take-home
`naloxone’ a good strategy in the prevention of fatal opioid
`overdose [32-34]. Several pilot studies investigated this inter-
`vention strategy and although the sample sizes in the studies
`were small, results were promising, with 90 – 100% of
`naloxone administrations preventing death from heroin
`overdose [35-37].
`In the UK (June 2005), naloxone was added to the list of
`drugs that ‘may be administered by anyone for the purpose of
`saving life in an emergency’ (that is, everyone is allowed to
`administer naloxone to an individual with a suspected opioid
`
`overdose) [38]. It is important to educate both the patient and
`his or her caretakers (not necessarily healthcare professionals)
`in the use of naloxone in case of a suspected overdose. The
`caretakers should learn how to recognize an overdose, how to
`perform mouth-to-mouth resuscitation and how to adminis-
`ter naloxone (either subcutaneously, intramuscularly or intra-
`venously) [39]. In addition, they should be made aware of the
`necessity of always alerting emergency medical services, to
`provide the monitoring and further treatment needed in case
`of an overdose. Often, fear of the police and subsequent crim-
`inalization will halt the bystanders (usually fellow addicts) in
`calling an ambulance – one more reason for distributing
`take-home naloxone among addicts, thus providing necessary
`first aid to their peers [35]. Providing the family, caretakers and
`friends of opioid-addicted patients are well instructed in the
`use of naloxone, take-home naloxone could be a helpful
`strategy in combating fatal heroin overdose.
`
`5.2 Naloxone in detoxification and maintenance
`The conventional way of detoxification is treating the patients
`with tapering doses of opioid agonists (methadone or
`buprenorphine) and/or with clonidine or
`lofexidine
`(α2-adrenergic-receptor agonists that can relieve the symp-
`toms of withdrawal). The protracted nature of these tech-
`niques however, leads to a high number of initial dropouts
`(dropout rates in the literature are in the range of 30 – 90%
`[28,40]). This was one of the major reasons for the development
`of new withdrawal strategies, which take less time and may be
`more comfortable to the patient. Rapid or ultrarapid detoxifi-
`cation under anesthesia or heavy sedation is one such therapy.
`It consists of the intravenous administration of an opioid
`antagonist (usually naloxone). The effect of the ensuing acute
`withdrawal syndrome (lasting 4 – 6 h) is either treated (or
`masked) with general anesthesia or heavy sedation (using ben-
`zodiazepines), both combined with clonidine and β-adrener-
`gic-receptor blockers (to prevent tachycardia). After this initial
`phase, patients are introduced on an oral dosing of naltrexone
`as maintenance therapy, with additional psychologic counsel-
`ling as support. The effectiveness of this approach has recently
`been called into question, as there is little evidence of its supe-
`riority above ‘ordinary’ opioid maintenance treatment and it
`appears to have a higher risk of adverse events. In recent years,
`a few randomised clinical trials were conducted investigating
`rapid detoxification [41,42]. All concluded that rapid opioid
`detoxification had no proven benefits above buprenor-
`phine/clonidine detoxification. As the risk associated with this
`therapy (e.g., the risk of anesthesia or sedation) is much larger
`than in the other treatment groups, and the costs are signifi-
`cantly higher, it is generally agreed that this form of treatment
`should not be pursued further [43].
`Naloxone can also be used to speed up clonidine or lofexi-
`dine-assisted opioid detoxification (i.e., rapid detoxification
`with naloxone/clonidine). These α2-adrenergic agonists
`alleviate withdrawal symptoms in detoxifying patients, and
`have proven to be as effective as tapering methadone doses in
`
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`Table 1. Uses and side effects of naloxone in
`opioid-dependent individuals.
`
`Naloxone use
`
`Opioid overdose
`Detoxification
`
`Maintenance
`(combined with buprenorphine)
`
`Side effects
`
`Acute withdrawal syndrome
`Recurrence of respiratory
`depression
`Cardiac arrhythmias
`
`Pulmonary edema
`
`the treatment of opiate dependence [44]. The addition of an opi-
`oid antagonist, such as naloxone, to this form of detoxification
`therapy, leads to a more intense, but less prolonged, withdrawal
`syndrome. The exact implications for long-term treatment in
`the form of antagonist maintenance are not yet clear.
`In the past, naloxone has been used as an oral abstinence
`maintenance agent, but its low oral bioavailability and (very)
`short duration of action make it unsuitable for this purpose
`[45]. However, it can be used as test medication before admin-
`istering naltrexone to possibly dependent patients. For exam-
`ple, if intravenous naloxone causes no or little withdrawal
`symptoms in these patients, it is safe to administer the more
`potent and long-lasting naltrexone in an oral formulation [46].
`Furthermore, it may be used as diagnostic tool in discriminat-
`ing between opioid-dependent and non-dependent patients
`(e.g., the occasional abusers or a patient behaving like an
`addict, but ailing from another disorder such as diabetes).
`
`5.3 Naloxone in combination with buprenorphine
`In 2002, sublingual buprenorphine (SubutexTM, Reckitt
`Benckiser) and the combination of buprenorphine and
`naloxone (for sublingual use only, SubuxoneTM, Reckitt
`Benckiser) was approved by the FDA for use in opioid addic-
`tion treatment. Because buprenorphine alone, as a (partial)
`µ-opioid-receptor agonist, is subject to abuse, the combina-
`tion treatment was intended to minimize the abuse and mis-
`use of the compound [47]. As this form of therapy gains in
`popularity, the use of buprenorphine combined with
`naloxone needs further consideration. When Subuxone is
`administered sublingually some opioid withdrawal symptoms
`are only seen in those individuals who are heavily dependent
`on heroin and/or recently took heroin. Most likely, the bio-
`availability of naloxone after sublingual administration is too
`low to cause severe and protracted withdrawal symptoms.
`However, when a sublingual dose of Suboxone is administered
`intravenously, all addicts will experience an immediate opioid
`withdrawal syndrome [48]. On the basis of the pharmacologic
`properties of buprenorphine, partial agonism and high affin-
`ity at the µ-opioid receptor, one would expect competitive
`displacement of heroin by buprenorphine rather than by
`naloxone. Surprisingly, however, there is ample evidence that
`withdrawal
`symptoms
`in
`this particular population
`(opioid-dependent patients) are caused by naloxone [48,49].
`
`van Dorp, Yassen & Dahan
`
`This may be related to the fact that several structures in the
`brain, and more specifically the opioid-receptor system, are
`subject to changes following chronic exposure to opioids [2,6],
`thereby significantly altering the interaction of buprenorphine
`with the µ-opioid receptor. One possibility is that chronic
`exposure to opioids changes the behavior of intravenous
`buprenorphine from a partial agonist to a full agonist at the
`µ-opioid receptor with lesser affinity for the receptor than
`observed in opioid-naive volunteers. Further studies are
`needed to elucidate this matter. Several studies [49-52] con-
`cluded that buprenorphine/naloxone was a good alternative
`for either methadone or buprenorphine maintenance therapy.
`Not much is known about whether or not the addition of
`naloxone truly prevents the misuse of the combination. Evi-
`dence is only circumstantial, as it is difficult to monitor the
`amount of misuse [53,54].
`
`6. Summary and conclusions
`
`Naloxone competitively inhibits the pharmacologic effects of
`exogenously administered opioids and, in line with the classi-
`cal receptor theory, produces a parallel right shift in the
`dose-response curves of opioids. Naloxone is readily trans-
`ported across the blood–brain barrier and, therefore, has a fast
`onset of action in reversing opioid effects. Its duration of
`action is limited due to its short elimination half-life of
`30 min. The ability of naloxone to reverse opioid effects
`in vivo is mainly determined by the pharmacologic character-
`istics of the interacting opioid agonist (i.e., the opioid that
`requires antagonism).
`The most common use of naloxone is for the treatment of
`opioid overdose both in a hospital and out-patient setting.
`The safety of naloxone in the treatment of opioid overdose is
`well established in patients and healthy volunteers over a wide
`dose range (0.4 – 10 mg). There is a special role for intra-
`venous naloxone in rapid detoxification, in which naloxone is
`combined with the α2-agonist, clonidine, and β-adrener-
`gic-receptor-blocking agents to treat withdrawal symptoms.
`The effectiveness of this approach has recently been called
`into question as there is little evidence of its superiority above
`‘ordinary’ opioid maintenance treatment and it appears to
`have a higher risk of adverse events. Finally, naloxone is used
`in combination with buprenorphine maintenance therapy.
`Addition of naloxone minimizes the abuse and misuse of
`buprenorphine and the buprenorphine/naloxone combina-
`tion is considered a good alternative for either methadone or
`buprenorphine maintenance therapy (Table 1).
`Although naloxone is relatively safe to use, there are some
`apparent risks and disadvantages associated with its use.
`Naloxone induces an acute withdrawal syndrome in opi-
`oid-dependent persons. Due to its short half-life its effect may
`wear off prematurely when used for treatment of opi-
`oid-induced respiratory depression. High-dose or rapidly
`infused naloxone administered to a patient who is overdosed
`with an opioid given for the treatment of acute pain may
`
`Expert Opin. Drug Saf. (2007) 6(2)
`
`129
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`For personal use only.
`
`Opiant Exhibit 2027
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00690
`Page 5
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`

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`Naloxone treatment in opioid addiction: the risks and benefits
`
`cause catecholamine release and consequently pulmonary
`edema and cardiac arrhythmias.
`
`7. Expert opinion
`
`The non-selective opioid-receptor antagonist, naloxone, is
`widely used in clinical practice. Anesthesiologists use naloxone
`for reversal of postoperative respiratory depression induced by
`potent opioid analgesics, such as fentanyl, sufentanil and mor-
`phine. Similarly, naloxone may be used to treat opioid overdose
`in opioid-dependent patients. There are some subtle differences
`in use between the two patients groups, most importantly there
`are differences in dosing. In postoperative patients, the initial
`intravenous dose is 40 – 80 µg, which can be increased to
`desired effect using 40- to 80-µg titration boluses. When respi-
`ration has returned to the desired level, an equivalent naloxone
`dose is administered via the intramuscular route. Reversal is
`often rapid and the intramuscular depot ensures that reversal
`lasts for 30 – 45 min, a time frame which is often sufficient to
`overcome the respiratory problems. In opioid-dependent
`patients, the initial dose is 0.4 mg. Depending on the clinical
`status of the patient slow titration with doses up to 10 mg of
`naloxone may be applied. Note, however, that for both patient
`groups the mode and dose of naloxone administration is
`dependent on the pharmacologic properties of the opioid that
`induced the overdose. For long-acting potent opioids, such as
`methadone and buprenorphine, a continuous infusion of
`naloxone rather than multiple bolus injections is indicated. An
`interesting new development that deserves support is the use of
`naloxone outside the hospital setting by non-medically trained
`people, so-called ‘take-home naloxone’. Some caution is needed
`
`though. Acute withdrawal may occur with vomiting, hyperten-
`sion, tachycardia and delirium. These require acute treatment
`to prevent further damage (such as aspiration). Training of fam-
`ily and friends of opioid addicts who receive take-home
`naloxone should, therefore, not be restricted to instructions
`how to administer naloxone in case of a heroin overdose, but
`also be aimed at the acute treatment of the patient. Often the
`required measures are very simple: put the patient on one side,
`remove the vomit and get professional help.
`There is some scanty data on the deleterious effects of
`naloxone on the cardiovascular system. The data are relatively
`old (1970s) with little new data. The data indicate that rapid
`infusion and high-dose naloxone may be dangerous to one
`specific type of patient: the patient who was treated for acute
`and severe pain with an opioid. When overdosed and the
`patient is treated with high-dose naloxone (or na