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Naloxone and Nalmefene

    

Drug Pharmacology ::

I. Pharmacology. Naloxoneand nalmefene are pure opioid antagonists that competitively block mu,kappa, and delta opiate receptors within the CNS. They have no opioidagonist properties and can be given safely in large doses withoutproducing respiratory or CNS depression. Naltrexone isanother potent competitive opioid antagonist that is active orally andis used to prevent recidivism in patients detoxified from opioid abuse.It has also been used to reduce craving for alcohol. It is not used for the acute reversal of opioid intoxication and will not be discussed further in this handbook.

   

Naloxone, a synthetic N-allylderivative of oxymorphone, undergoes extensive first-pass metabolismand is not effective orally but may be given subcutaneously,intramuscularly, intravenously, or even endotracheally. Afterintravenous administration, opioid antagonism occurs within 1–2 minutesand persists for approximately 1–4 hours. The plasma half-life rangesfrom 31–80 minutes.

Nalmefene,an injectable methylene analog of naltrexone, was approved in 1995. Itis 4 times more potent than naloxone at mu receptors and slightly morepotent at kappa receptors. It has a longer elimination half-life(ranging from approximately 8–11 hours after IV dosing) and a durationof action of 1–4 hours (see Table III–10). The prolonged effects ofnalmefene are related to the slow dissociation from the opioidreceptor, which is not reflected in the area under the curve (AUC)plasma curve.

Drug Indications ::

Indications

   

Reversal of acute opioid intoxication manifested by coma, respiratory depression, or hypotension.

Empiric therapy for stupor or coma suspected to be caused by opioid overdose.

Anecdotalreports suggest that high-dose naloxone may partially reverse the CNSand respiratory depression associated with clonidine (see Clonidine andRelated Drugs), ethanol (see Ethanol), benzodiazepine (seeBenzodiazepines), or valproic acid (see Valproic Acid) overdoses,although these effects are inconsistent.

Drug Contra-Indications ::

III. Contraindications. Do not use in patients with a known hypersensitivity to either agent (may have cross-sensitivity).

Drug Adverse Effects ::

IV. Adverse effects. Humanstudies have documented an excellent safety record for both drugs.Volunteers have received up to 24 mg of nalmefene intravenously and 50mg orally.

   

Usein opiate-dependent patients may precipitate acute withdrawal syndrome.This may be more protracted with nalmefene. Neonates of addictedmothers may have more severe withdrawal symptoms, including seizures.Aggressive use of opiate antagonists in so-called rapid opioiddetoxification (ROD) and ultra-rapid opioid detoxification (UROD) hasbeen associated with marked increases in plasma corticotropin,cortisol, sympathetic activity, and catecholamine levels; pulmonary edema; acute renal failure; ventricular bigeminy; psychosis; delirium; and deaths.

Pulmonaryedema or ventricular fibrillation occasionally has occurred shortlyafter naloxone administration in opioid-intoxicated patients. Pulmonaryedema has also been associated with postanesthetic use of naloxone,especially when catecholamines and large fluid volumes have beenadministered. Pulmonary edema has been reported after IV nalmefene.

Reversingthe sedative effects of an opioid may amplify the toxic effects ofother drugs. For example, agitation, hypertension, and ventricularirritability have occurred after naloxone administration to personshigh on a “speedball” (heroin plus cocaine or methamphetamine).

Seizures have been associated with nalmefene use in animal studies but have not been reported in humans.

E. There has been one case report of hypertension after naloxone administration in a patient with clonidine overdose.

F. Use in pregnancy. FDAcategory B (see Table III–1). Naloxone- or nalmefene-induced drugwithdrawal syndrome may precipitate labor in an opioid-dependent mother.

Drug Lab Interactions ::

Drug or laboratory interactions. Naloxoneand nalmefene antagonize the analgesic effect of opioids. Naloxone isnot associated with a positive enzymatic urine screen for opiates. A2-mg IV dose of nalmefene was not associated with a false-positiveurine test (Emit II assay) in one study.

Drug Dose Management ::

Dosage and method of administration for suspected opioid-induced coma

   

Naloxone. Administer0.4–2 mg IV; repeat at 2- to 3-minute intervals until desired responseis achieved. Titrate carefully in opioid-dependent patients (start at0.05 mg). The dose for children is the same as that for adults.

   

1. Thetotal dose required to reverse the effects of the opioid is highlyvariable and is dependent on the concentration and receptor affinity ofthe opioid. Some drugs (eg, propoxyphene, diphenoxylate/atropine[Lomotil], buprenorphine, pentazocine, and the fentanyl derivatives) donot respond to usual doses of naloxone. However, if no response isachieved by a total dose of 10–15 mg, the diagnosis of opioid overdoseshould be questioned.

2. Caution:Resedation can occur when the naloxone wears off in 1–2 hours. Repeateddoses of naloxone may be required to maintain reversal of the effectsof opioids with prolonged elimination half-lives (eg, methadone) orsustained-release formulations or when packets or vials have beeningested.

3. Infusion.Give 0.4–0.8 mg/h in normal saline or 5% dextrose, titrated to clinicaleffect (in infants, start with 0.04–0.16 mg/kg/h). Another method is toestimate two-thirds of the initial dose needed to awaken the patientand give that amount each hour.

Nalmefene. Ina non-opioid-dependent adult, give an initial dose of 0.5 mg/70 kg,followed by 1.0 mg/70 kg 2–5 minutes later. No added benefit of dosagehigher than 1.5 mg/70 kg has been established. If opioid dependency issuspected, give a challenge dose of 0.1 mg/70 kg, followed by a2-minute wait for signs or symptoms of opioid withdrawal (nausea,chills, myalgia, dysphoria, abdominal cramps, joint pain). If there isno indication of withdrawal, give standard doses. The effect of thedrug may be prolonged in patients with end-stage renal failure orhepatic disease.

   

1. Dosage,safety, and efficacy in children have not been established. However, ithas been shown to be safe and effective in reversing proceduralsedation in children when given in postoperative incremental doses of0.25 mcg/kg every 2–5 minutes to a maximum total dose of 1 mcg/kg.Nalmefene pharmacokinetics in children is similar to that in adults.

2. As with naloxone, the total dose required to reverse the effects of the opioid is highly variable.

3. Caution:The duration of action of nalmefene will vary with the half-life andconcentration of the opioid being reversed, the presence of othersedating drugs, and the dose of nalmefene. Smaller doses of nalmefenemay have a shorter duration because of rapid redistribution of the drugout of the brain. Fully reversing doses (1–1.5 mg in a 70-kg person)have been shown to last several hours. However, this may not be longenough for patients who have overdosed on a long-acting opioid such asmethadone or have ingested a drug-containing condom or packet withunpredictable breakage and absorption.

Note:Although both drugs can be given by the intramuscular or subcutaneousroute, absorption is erratic and incomplete. Naloxone is not effectiveorally. Huge doses of nalmefene have been used orally in experimentalstudies, but this route is not recommended at this time.

Drug Chemical Formulations ::

Formulations

   

Naloxone hydrochloride (Narcan): 0.02, 0.4, or 1 mg/mL; 1-, 2-, or 10-mL syringes, ampules, or vials. The suggested minimum stocking level to treat a 70-kg adult for the first 24 hours is 30 mg (three vials, 1 mg/mL, 10 mL each, or equivalent).

Nalmefenehydrochloride (Revex): 100 mcg in 1-mL ampules (blue label); 1 mg/mL in2-mL vials (green label); syringes containing 2 mL of 1 mg/mLnalmefene. The suggested minimum stocking level to treat a 70-kg adult for the first 24 hours is 16 mg (eight vials, 1 mg/mL, 2 mL each, or equivalent).

Table III–10. Characteristics of Naloxone and Nalmefene


 Naloxone Nalmefene Elimination half-life 60–90 min10–13 hDuration of action 1 h1–4 ha
 Metabolism Liver (glucuronidation)Liver (glucuronidation)Advantages Lower cost; shorter action; more human experienceLonger duration lowers risk of recurrent respiratory depression for most (but not all) opioidsDisadvantages More frequent dosing or constant infusionCost; may cause prolonged opioid withdrawal

aHigh doses (eg, > 6 mg) may increase the duration of action but are not recommended at this time.

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