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Home , Nalmefene, Nalorphine, Naloxone, Naltrexone, Opioid antagonist, Opioid food peptides

Opioid A4: in Depth

Lewis S. Nelson; Mary Ann Howland

INTRODUCTION

Naloxone, , , and are pure competitive antagonists at the mu (μ), kappa (κ), and delta (δ) receptors. Opioid antagonists prevent the actions of opioid , reverse the effects of both endogenous and exogenous , and cause in opioid-dependent patients. is the primary used to reverse respiratory in patients manifesting opioid . The parenteral dose should be titrated to maintain adequate airway reflexes and ventilation. By titrating the dose, beginning with 0.04 mg and increasing as indicated to 0.4 mg, 2 mg, and finally 10 mg, abrupt opioid withdrawal can be prevented. This titrated low dose method of administration limits withdrawal induced adverse effects, such as and the potential for aspiration pneumonitis, and a surge in catecholamines with the potential for cardiac dysrhythmias and acute respiratory distress syndrome (ARDS). Because of its poor oral , oral naloxone may be used to treat patients with opioid induced constipation. Methylnaltrexone, a parenteral , and , an oral capsule, are effective in reversing opioid-induced constipation without inducing opioid withdrawal. This is because neither is able to enter the central (CNS). Naltrexone is used orally for patients after opioid to maintain opioid abstinence and as an adjunct to achieve abstinence. Nalmefene, no longer available in the United States, has a duration of action between those of naloxone and naltrexone.

HISTORY

The understanding of structure–activity relationships led to the synthesis of many new molecules in the hope of producing potent opioid agonists free of abuse potential. Although this goal has not yet been achieved, opioid antagonists and partial agonists resulted from these investigations. N-Allyl was the first opioid antagonist synthesized (in 1915), and N-allylnormorphine () was synthesized in the 1940s.37,66 Nalorphine was recognized as having both and antagonist effects in 1954. Naloxone was synthesized in 1960, and naltrexone was synthesized in 1963. The synthesis of opioid antagonists that are unable to cross the blood–brain barrier (sometimes called peripherally restricted) allowed patients receiving long-term opioid to avoid opioid induced constipation, one of the most uncomfortable side effects associated with this . Since the mid 1990s, there has been a steady increase in the use of naloxone that has been prescribed or directly dispensed to users for administration by bystanders in case of overdose.10

PHARMACOLOGY

Chemistry Minor alterations can convert an agonist into an antagonist. The substitution of the N-methyl group on by a larger functional group led to nalorphine and converted the agonist to the antagonist .35 Naloxone, naltrexone, and nalmefene are derivatives of - with antagonist properties resulting from addition of organic or other functional groups.35,39 Relatedly, nalmefene is a 6-methylene derivative of naltrexone.

Mechanism of Action The μ receptors are responsible for analgesia, sedation, , , respiratory depression, and decreased gastrointestinal (GI) motility. The κ receptors are responsible for spinal analgesia, miosis, , , nightmares, and . The δ receptors are responsible for analgesia and hunger. The currently available opioid antagonists are most potent at the μ receptor, with higher doses required to affect the κ and δ receptors. They all bind to the in a competitive fashion, preventing the binding of agonists, partial agonists, or mixed agonist–antagonists without producing any independent action.

Pharmacokinetics Naloxone, naltrexone, and nalmefene are similar in their antagonistic mechanism but differ primarily in their . Both nalmefene and naltrexone have longer durations of action than naloxone, and both have adequate oral bioavailability to produce systemic effects. Methylnaltrexone can be given orally or parenterally but is excluded from the CNS and only produces peripheral effects. Selective antagonists for μ, κ, and δ are available experimentally and are undergoing investigation.

The bioavailability of sublingual naloxone is only 10%.5 In contrast, naloxone is well absorbed by all parenteral routes of administration, including the intramuscular (IM), subcutaneous (SC), endotracheal, intranasal, intralingual, and inhalational (nebulized) routes. The with the various routes of administration are as follows: intravenous (IV), 1 to 2 minutes; SC, approximately 5.5 minutes; intralingual, 30 seconds; intranasal, 3.4 minutes; inhalational, 5 minutes; endotracheal, 60 seconds; and IM, 6 minutes.23,41,53,73 The distribution half-life is rapid (~5 minutes) because of its high lipid solubility. The volume of distribution (Vd) is 0.8 to 2.64 L/kg.31

A naloxone dose of 13 μg/kg in an adult occupies approximately 50% of the available opioid receptors.54 The duration of action of naloxone is approximately 20 to 90 minutes and depends on the dose of the agonist, the dose and of naloxone, and the rates of elimination of the agonist and naloxone.5,25,68 Naloxone is metabolized by the to several compounds, including a glucuronide. The elimination half-life is 60 to 90 minutes in adults and approximately two to three times longer in neonates. Naltrexone is rapidly absorbed with an oral bioavailability of 5% to 60%, and peak serum concentrations occur at 1 hour.34 Distribution is rapid, with a Vd of approximately 15 L/kg and low protein binding.45 Naltrexone is metabolized in the liver to β-naltrexol (with 2%–8% activity) and 2- hydroxy, 3-methoxy-β-naltrexol and undergoes an enterohepatic cycle.72 The plasma elimination half- life is 10 hours for β-naltrexone and 13 hours for β-naltrexol, with terminal phases of elimination of 96 hours and 18 hours, respectively.70

Nalmefene has an oral bioavailability of 40%, with peak serum concentrations usually reached within 1 to 2 hours.21 After SC administration, peak concentrations do not occur for more than 2 hours, although therapeutic concentrations are reached within 5 to 15 minutes. A 1 mg parenteral dose blocks more than 80% of opioid receptors within 5 minutes. The apparent Vd is 3.9 L/kg for the central compartment and 8.6 L/kg at steady state. Protein binding is approximately 45%.20 Nalmefene has a redistribution half-life of 41 ± 34 minutes and a terminal half-life of 10.8 ± 5 hours after a 1 mg IV dose. It is metabolized in the liver to an inactive glucuronide conjugate that probably undergoes enterohepatic recycling, accounting for approximately 17% of elimination in the feces. Less than 5% is excreted unchanged in the .

Methylnaltrexone is a quaternary methylated derivative of naltrexone that is peripherally restricted because of its poor lipid solubility and inability to cross the blood–brain barrier.79 After SC administration, peak serum concentrations occur in about 30 minutes. The drug has a Vd of 1.1 L/kg and is minimally protein bound (11%–15%). Although there are several metabolites, 85% of the drug is eliminated unchanged in the urine.79

Pharmacodynamics In the proper doses, pure opioid antagonists reverse all of the effects at the μ, κ, and δ receptors of endogenous and exogenous opioid agonists, except for those ofbuprenorphine, which has a very high affinity for and slow rate of dissociation from the μ receptor.54 Actions of opioid agonists that are not mediated by interaction with opioid receptors, such as direct mast cell liberation of histamine or the potassium channel blocking effects of , are not reversed by these antagonists.2 Chest wall rigidity from rapid infusion is usually reversed with naloxone.14 Opioid-induced in animals, such as from propoxyphene, tend to be antagonized by opioid antagonists, although seizures caused by meperidine (normeperidine) and are exceptions.30The benefit in humans is less clear. A report of two newborns who developed seizures associated with fentanyl and morphine infusion demonstrated abrupt clinical and electroencephalographic resolution after administration of naloxone.17

Opioids operate bimodally on opioid receptors.15 At very low concentrations, μ opioid receptor agonism is excitatory at this receptor and actually may increase pain. This antianalgesic effect is modulated through a Gsprotein and usually is less important clinically than the well-known inhibitory actions that result from coupling to a Go protein at usual doses. For this reason, extremely low doses of opioid antagonists (ie, 0.25 μg/kg/h of naloxone) enhance the analgesic of opioids, including morphine, methadone, and .16,29 Naloxone also attenuates or prevents the development of tolerance and dependence.29 Coadministration of these very low doses of antagonists with the opioid also limits opioid-induced adverse effects such as , vomiting, constipation, and pruritus.79

The opioid antagonists may reverse the effects of endogenous opioid peptides, including , , and . Endogenous opioids are found in tissues throughout the body and may work in concert with other systems to modulate many physiologic effects.26,67 For instance, during , the release of circulating endorphins produces an inhibition of central sympathetic tone by stimulating κ receptors within the locus coeruleus, resulting in vasodilation. Vagal tone is also enhanced through stimulation of opioid receptors in the nucleus ambiguus.

Research investigating the cardioprotective effects of opioid agonists through their action at the sarcolemmal and mitochondrial K+-ATP (adenosine triphosphate) channels is ongoing.27 Nonselective opioid antagonists may negate these protective effects.

ROLE IN OPIOID TOXICITY

Naloxone has been used for decades by medical personnel for the management of patients with opioid toxicity. Initial studies found the use of naloxone to be relatively safe and highly effective in awakening opioid-toxic patients.40,76 Although recommended to be administered empirically to nearly every patient with a depressed level of consciousness and respiratory depression,38 as complications of precipitated opioid withdrawal became more apparent, aggressive use of naloxone has been scaled back.6 Currently, the empiric dose that is considered safe for all opioid-dependent patients is 0.04 mg, although in nondependent patients, higher doses may be administered without concern for precipitating withdrawal. The goal of reversal of opioid is to improve the patient’s ventilation while avoiding withdrawal, which is associated with significant complications (see later discussion).

Take-home naloxone programs are developing around the world. In these programs, opioid abusers and their families are supplied naloxone to be administered to others after , generally by the SC (by needle and syringe) or intranasal (by atomizer) route.1,42,76 An autoinjector containing 0.4 mg naloxone was approved for IM use in 2014. These bystander programs are credited with saving numerous lives, although the absolute number and rate are unknown.10,13 However, concerns exist regarding proper dosing, relative safety, use in mixed overdose (eg, or for distinct reasons), attempts to overcome precipitated withdrawal with larger doses of agonist, comfort pushing the opioid dose because of the availability of rescue therapy, risk of arrest with drug paraphernalia (covered in most jurisdictions with Good Samaritan clauses), and refusal of emergency medical services involvement (with subsequent recrudescent opioid toxicity after naloxone effect wanes). (See Adverse Effects and Safety Issues.)

ROLE IN MAINTENANCE OF OPIOID ABSTINENCE Opioid dependence is managed by substitution of the abused opioid, typically heroin or a prescription opioid, with methadone or buprenorphine or by detoxification and subsequent abstinence. Maintenance of abstinence is often assisted by naltrexone, although any pure opioid antagonist could be used.62 Typically, naltrexone is chosen because of its oral absorption and long duration of action compared with those of naloxone.48,62

Before naltrexone can be administered for abstinence maintenance, the patient must be weaned from opioid dependence and be a willing participant. Naloxone should be administered IV to confirm that the patient is no longer opioid dependent and safe fornaltrexone. With naloxone, opioid withdrawal, if it occurs, will be short lived instead of prolonged after use of naltrexone. Naltrexone does not produce tolerance, although prolonged treatment with naltrexone produces up regulation of opioid receptors.77

ROLE IN ETHANOL ABSTINENCE

Naltrexone, particularly the IM depot form (Vivitrol), is used as adjunctive therapy in ethanol dependence based on the theory that the endogenous opioid system modulates ethanol intake.65 Naltrexone reduces ethanol craving, the number of drinking days, and relapse rates.46,57 Naltrexone induces moderate to severe nausea in 15% of patients, possibly as a result of alterations in endogenous opioid tone induced by prolonged ethanol ingestion.

OTHER USES

Poorly orally bioavailable opioid antagonists (eg, naloxone) and peripherally restricted opioid antagonists (eg, methylnaltrexone) are used to prevent or treat the constipation that occurs as a side effect of opioid use, whether for or drug abuse maintenance therapy.8 Methylnaltrexone administered SC results in evacuation within 4 hours in nearly half of those who receive the drug for this indication.64

Opioid antagonists are sometimes used in the management of overdoses with nonopioids such as ethanol,22 ,61 ,69 and valproic acid.63 In none of these instances is the reported improvement as dramatic or consistent as in the reversal of an opioid. The mechanisms for each of these, although undefined, may relate to reversal of endogenous opioid peptides at opioid receptors.

Naloxone has been used to reverse the effects of endogenous opioid peptides in patients with , although the results are variable.19 Treatment is often ineffective and may result in adverse effects, particularly in patients who are opioid tolerant. Naloxone may have a temporizing effect via elevation of mean arterial pressure.

Opioid antagonists at low doses are used for treatment of morphine-induced pruritus resulting from systemic or epidural opioids and for treatment of pruritus associated with .52,55

ADVERSE EFFECTS AND SAFETY ISSUES Pure opioid antagonists produce no clinical effects in opioid-naïve or nondependent patients even when administered in massive doses.7

When patients dependent on opioid agonists are exposed to opioid antagonists or agonist– antagonists such as , they exhibit opioid withdrawal, including yawning, lacrimation, diaphoresis, rhinorrhea, piloerection, mydriasis, vomiting, , myalgias, mild elevations in heart rate and blood pressure, and . Antagonist-precipitated withdrawal may result in an “overshoot” phenomenon, from an increase in circulating catecholamines, resulting in hyperventilation, , and hypertension.44Under these circumstances, there is a potential for related complications such as myocardial ischemia, heart failure, and CNS .43 Delirium, although rarely reported in patients withdrawing by opioid abstinence, may occur when an opioid antagonist is used to reverse effects in patients dependent on high doses of opioids or during rapid opioid detoxification.32 These severe manifestations of precipitated opioid withdrawal may occur with ultrarapid opioid detoxification and are associated with fatalities occurring in the postadministration period.36 This rapid form of deliberate detoxification differs significantly from the opioid withdrawal associated with volitional opioid abstinence (Chap. 15).

Case reports describe ARDS, hypertension, and cardiac dysrhythmias in association with naloxone administration almost uniformly in opioid-dependent patients.56,60 The clinical complexities of the setting make it difficult to analyze and attribute these adverse effects solely to naloxone.9 ARDS occurs after heroin overdose in the absence of naloxone,24making the exact contribution of naloxone to the problem unclear. Rather, in certain patients, naloxone may unmask ARDS previously induced by the opioid but unrecognized because of the patient’s concomitant opioid-induced respiratory depression.

If the patient’s airway is unprotected during withdrawal and vomiting occurs, aspiration pneumonitis may complicate the recovery.12 Given the frequency of polysubstance abuse and overdose associated with altered consciousness, the risk of precipitating withdrawal associated vomiting should always be a concern.

Resedation is a function of the relatively short duration of action of the opioid antagonist compared with the opioid agonist. Most opioid agonists have durations of action longer than that of naloxone and shorter than that of naltrexone. A long duration of action is advantageous when the antagonist is used to promote abstinence (naltrexone) but is undesired when inappropriately administered to an opioid-dependent patient.

Unmasking underlying cocaine or other toxicity may explain some of the cardiac dysrhythmias that develop after naloxone-induced opioid reversal in a patient simultaneously using both opioids and (Chaps. 76 and 78).50

Antagonists stimulate the release of hormones from the pituitary, resulting in increased concentrations of luteinizing hormone, follicle-stimulating hormone, and adrenocorticotropic hormone and stimulate the release of in women.58 Management of Iatrogenic Withdrawal Excessive administration of an opioid antagonist to an opioid-dependent patient will predictably result in opioid withdrawal. When induced by naloxone, all that is generally required is protecting the patient from harm and reassuring the patient that the effects will be short lived. Symptomatic care may be necessary on occasion. After inadvertent administration of naltrexone, the expected duration of the withdrawal syndrome generally mandates the use of pharmacologic intervention.28,47 Overcoming the opioid receptor antagonism is difficult, but if used in titrated doses, morphine or fentanyl may be successful. Adverse effects from histamine release from morphine and chest wall rigidity from fentanyl should be anticipated. If more moderate withdrawal is present, the administration of metoclopramide, clonidine, or a benzodiazepine is usually adequate.43

What constitutes an appropriate observation period after antagonist administration depends on many factors. After IV bolus naloxone, observation for two hours should be adequate to determine whether sedation and respiratory depression will return. Although no fatalities were identified in medical examiner records after the rapid prehospital release of patients who had presumably overdosed with heroin and were administered naloxone, the true safety of this practice remains questionable.11 Although the matched pharmacokinetics of heroin and naloxone suggests potential utility for such a practice, the high frequency of methadone or sustained-release prescription opioids use in many communities raises concerns. That is, the pharmacokinetic mismatch between naloxone and both methadone and sustained-release results in recurrent opioid toxicity and prevents widespread implementation of this program.71 Similarly, patients on continuous naloxone infusion must be observed for 2 hours or more after its discontinuation to ensure that respiratory depression does not recur.

PREGNANCY AND LACTATION

Naloxone is a Category C drug. A risk to benefit analysis must be considered in pregnant women, particularly those who are opioid tolerant, and their newborns. Inducing opioid withdrawal in the mother probably will induce withdrawal in the fetus and should be avoided. Likewise, administering naloxone to newborns of opioid-tolerant mothers may induce and should be used cautiously (Chaps. 31, 32, and 38).51

DOSING AND ADMINISTRATION

The initial dose of antagonist depends on the dose of agonist and the relative binding affinity of the agonist and antagonist at the opioid receptors. The presently available antagonists have a greater affinity for the μ receptor than for the κ or δ receptors. Some opioids, such as buprenorphine, require greater than expected doses of antagonist to reverse the effects at the μ receptor.68,75,85,95 The duration of action of the antagonist depends on many drug and patient variables, such as the dose and the clearance of both the antagonist and agonist. A dose of 0.4 mg of IV naloxone will reverse the respiratory depressant effects of most opioids and is an appropriate starting dose in non opioid-dependent patients. However, this dose in an opioid- dependent patient usually produces withdrawal, which should be avoided if possible. The goal is to produce a spontaneously and adequately ventilating patient without precipitating significant or abrupt opioid withdrawal. Therefore, 0.04 mg IV is a practical starting dose in most patients, increasing to 0.4 mg, 2 mg, and finally 10 mg if the patient has no response at lower doses.6 If the patient has no response to 8 to 10 mg, then an opioid is not likely to be responsible for the respiratory depression. The dose in children without opioid dependence is essentially the same as for adults. However, for those with the possibility of withdrawal or recrudescence of severe underlying pain, more gentle reversal with 0.001 mg/kg, with concomitant supportive care, is warranted. Although both the adult and pediatric doses recommended here are lower than those conventionally suggested in other references, the availability of safe and effective interim ventilatory therapy permits these lower doses and lowers the acceptable risk of precipitating withdrawal.

When 1 mg of naloxone is administered IV, it prevents the action of 25 mg of IV heroin for 1 hour, but 50 mg of oral naltrexone antagonizes this dose of heroin for 24 hours; 100 mg of oral naltrexone has a blocking effect for 48 hours, and 150 mg of oral naltrexone is effective for 72 hours.

The use of low doses of IV naloxone to reverse opioid overdose may prolong the time to improvement of ventilation, and during this period, assisted ventilation may be required. The same limitation exists with SC naloxone administration, and the absorbed dose is more difficult to titrate than when administered IV.73 Naloxone can also be administered intranasally, although this route results in the delivery of unpredictable doses. In the prehospital setting, the time to onset of clinical effect of intranasal naloxone is comparable to that of IV or IM naloxone, largely because of the delay in obtaining IV access and slow absorption, respectively.3,41 Intranasal naloxone is not recommended as first-line treatment by health care providers.42 Nebulized naloxone (2 mg is mixed with 3 mL of 0.9% sodium chloride solution) has similar limitations in dose accuracy and is further limited in patients with severe ventilatory depression, the group most in need of naloxone. Although reports suggest successful use of nebulized naloxone, these patients are not optimal candidates for inhalation therapy because of the likelihood of over- or underdosing of naloxone.74 Although needleless delivery is a clear prehospital advantage,49 there appears to be little role for hospital use of intranasal or nebulized naloxone by health professionals.

Evaluation for the redevelopment of respiratory depression requires nearly continuous monitoring. Resedation should be treated with either repeated dosing of the antagonist or, in some cases, such as after a long-acting opioid agonist, with another bolus followed by a continuous infusion of naloxone. Two-thirds of the bolus dose of naloxone that resulted in reversal, when given hourly, usually maintains the desired effect.33 This dose can be prepared for an adult by multiplying the effective bolus dose by 6.6, adding that quantity to 1000 mL, and administering the solution IV at an infusion rate of 100 mL/h. It must be emphasized that if resedation occurs rebolus with the dose of naloxone that provided reversal and titrate the infusion upward. Titration upward or downward is easily accomplished as necessary to both maintain adequate ventilation and avoid withdrawal. A continuous infusion of naloxone is not a substitute for continued vigilance. A period of 12 to 24 hours often is chosen for observation based on the presumed opioid, the route of administration, and the dosage form (sustained release). Body packers are a unique subset of patients who, because the reservoir of drug in the GI tract, require individualized antagonist management strategies (Special Considerations: SC5).

Use of longer acting opioid antagonists, such as naltrexone, places the patient at substantial risk for protracted withdrawal syndromes. The use of a long-acting opioid antagonist in acute care situations should be reserved for carefully considered special indications together with extended periods of observation or careful follow-up. For example, the unintentional ingestion of long acting opioid agonists in naive patients. An oral dose of 150 mg of naltrexone generally lasts 48 to 72 hours and should be adequate as an for the majority of opioid-intoxicated patients. Discharge of opioid-toxic patients after successful administration of a long-acting opioid antagonist, although theoretically attractive, is not well studied. There are concerns about attempts by patients to overcome opioid antagonism by administering high doses of opioid agonist, with subsequent respiratory depression as the effect of the antagonist wanes.

Naltrexone is administered orally in a variety of dosage schedules for treatment of opioid dependence. A common dosing regimen is 50 mg/day Monday through Friday and 100 mg on Saturdays. Alternatively, 100 mg every other day or 150 mg every third day can be administered. The IM extended-release suspension is injected monthly at a recommended dose of 380 mg.

Methylnaltrexone SC dosing for opioid-induced constipation is weight based.78 The dose is 0.15 mg/kg for patients who weigh less than 38 kg and more than 114 kg. For patients who weigh between 38 and less than 62 kg, 8 mg is administered, and for those between 62 and 114 kg, 12 mg is provided. Patients with stage 4 or 5 chronic disease should receive half the recommended dose.

Alvimopan (Entereg) is approved by the Food and Drug Administration for the management of postoperative ileus or constipation in the hospital setting. The dose is 12 mg orally 0.5 to 5 hours before surgery. The day after surgery, the maintenance dosage is 12 mg twice a day. The total maximum number of doses is 15 during hospitalization.

Buprenorphine Naloxone reverses the respiratory depressant effects of buprenorphine in a bell-shaped dose– response curve.18,59,68,75 Bolus doses of naloxone of 2 to 3 mg followed by a continuous infusion of 4 mg/h in adults were able to fully reverse the respiratory depression associated with IV buprenorphine administered in a total dose of 0.2 and 0.4 mg over 1 hour.68 Reversal was not apparent until about 45 to 60 minutes after the infusion. A reappearance of respiratory depression occurred when the naloxone infusion was stopped because the distribution of naloxone out of the brain and its subsequent elimination from the body are much faster than those of buprenorphine. Consistent with a bell-shaped response curve, doses of naloxone greater than 4 mg/h actually led to the recurrence of respiratory depression. It is postulated that buprenorphine has differential effects on the μ opioid receptor subtypes (Chap. 38), with agonist activity at low doses and antagonist action at high doses. Therefore, excess naloxone antagonizes the antagonistic effects of buprenorphine, worsening respiratory depression.

FORMULATION AND ACQUISITION

Naloxone (Narcan) for IV, IM, or SC administration is available in concentrations of 0.4 and 1.0 mg/mL with and without parabens in 1 and 2 mL ampoules, vials, and syringes and in 10 mL multidose vials with parabens. Naloxone can be diluted in 0.9% sodium chloride solution or 5% dextrose to facilitate continuous IV infusion. Naloxone is stable in 0.9% sodium chloride solution at a variety of concentrations for up to 24 hours.

Naltrexone (Revia, Trexan) is available as a 50-mg capsule-shaped . It is also available as a 380 mg vial for reconstitution with a carboxymethylcellulose and polysorbate diluent to form an injectable suspension intended for monthly IM administration (Vivitrol).

Methylnaltrexone (Relistor) is available as a 12-mg/0.6 mL solution for SC .67

Alvimopan is available as a 12-mg capsule.

SUMMARY

 Naloxone, naltrexone, and methylnaltrexone are pure competitive opioid antagonists at the μ, κ, and δ receptors. Methylnaltrexone does not enter the CNS.

 Naloxone is the primary opioid antagonist used to reverse respiratory depression in patients manifesting opioid toxicity.

 This titrated low dose method of administration, starting at 0.04 mg in an adult, limits withdrawal-induced adverse effects, such as vomiting and the potential for aspiration pneumonitis, and a surge in catecholamines with the potential for cardiac dysrhythmias and ARDS.

 Naltrexone is used orally for patients after opioid detoxification to maintain opioid abstinence and as an adjunct to achieve ethanol abstinence.

Acknowledgment Richard S. Weisman, PharmD, contributed to this Antidote in Depth in previous editions.

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