morphine/naltrexone (Rx)

Brand and Other Names:Embeda
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Dosing & Uses

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Dosage Forms & Strengths

morphine/naltrexone

extended-release capsule: Schedule II

  • 20mg/0.8mg
  • 30mg/1.2mg
  • 50mg/2mg
  • 60mg/2.4mg
  • 80mg/3.2mg
  • 100mg/4mg
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Chronic Severe Pain

Indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate

Opioid naïve: Initiate with lowest dose (ie, morphine/naltrexone 20 mg/0.8 mg PO q24hr); may adjust dose by titrating at 1-2 day intervals (steady-state plasma concentration are reached within 24-36 hr)

Conversion from other PO morphine: Administer one-half of daily dose q12hr OR administer total daily dose qDay

Conversion from PO opioids, parenteral morphine, or other parenteral opioids: Substantial inter-patient variation exist for conversion; for this reason, it is safer to underestimate patient’s 24-hour PO morphine dose during this transition and provide additional prompt-acting rescue analgesics until new daily dose established

Individualize dose

  • Titrate no more frequently than q48hr to allow patient to stabilize before dose escalation
  • For breakthrough pain, supplement with small dose (ie, <20% total daily dose) of short-acting analgesic
  • If qDay dosing does not provide adequate analgesia, administer total daily dose divided q12hr
  • Do not administer more frequently than q12hr

Opioid-tolerant definition

  • Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression
  • Patients who are opioid tolerant are those receiving, for 1 week or longer, at least 60 mg/day PO morphine, 25 mcg/hr transdermal fentanyl, 30 mg/day PO oxycodone, 8 mg/day PO hydromorphone, 25 mg/day PO oxymorphone, or an equianalgesic dose of another opioid

Limitations of use

  • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve for patients whom alternative treatment options (eg, nonopioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain
  • Not indicated as a PRN analgesic
  • Not indicated for acute/postoperative pain, mild pain, or short-term pain relief; only indicated for postoperative use if patient already receiving chronic opioid therapy prior to surgery, or if postoperative pain is expected to be moderate-to-severe and persist for an extended period of time

Renal Impairment

Caution in severe impairment; information on renal impairment dosing not available from the manufacturer

Hepatic Impairment

Caution in severe impairment; information on hepatic impairment dosing not available from the manufacturer

Administration

Swallow capsule whole; chewing, crushing, or dissolving contents of capsules will result in uncontrolled delivery of morphine and can lead to overdose or death

The capsules contain pellets that consist of morphine and sequestered naltrexone; the pellets in the capsules are not to be crushed, dissolved, or chewed due to the risk of rapid release and absorption of a potentially fatal dose of morphine

Consuming capsules that have been altered by crushing, chewing, or dissolving the pellets can release sufficient naltrexone to precipitate withdrawal in opioid-dependent individuals

May sprinkle capsule contents on apple sauce and swallow immediately; do not chew; rinse the mouth to ensure all pellets have been swallowed

Do not administer pellets through a nasogastric or gastric tube

May administer qDay or q12hr; do not administer more frequently than q12hr

Safety and efficacy not established

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Interactions

Interaction Checker

and morphine/naltrexone

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    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            >10%

            Somnolence

            Constipation

            Nausea

            1-10% (selected)

            Edema peripheral

            Anxiety

            Chills

            Depression

            Dizziness

            Fatigue

            Headache

            Insomnia

            Irritability

            Lethargy

            Restlessness

            Sedation

            Tremor

            Hyperhidrosis

            Pruritus

            Hot flush

            Abdominal pain

            Anorexia

            Dry mouth

            Diarrhea

            Dyspepsia

            Decreased appetite

            Flatulence

            Stomach discomfort

            Vomiting

            Arthralgia

            Muscle spasms

            Frequency Not Defined

            Cardiac arrest

            Hypotension

            Shock

            Anaphylaxis

            Apnea

            Respiratory arrest

            Respiratory depression

            Opioid withdrawal

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            Warnings

            Black Box Warnings

            Addiction, abuse, and misuse

            • Risk of opioid addiction, abuse, and misuse, which can lead to overdose and death
            • Assess each patient’s risk prior to prescribing and monitor all patients regularly for the development of these behaviors or conditions

            Life-threatening respiratory depression

            • Serious, life-threatening, or fatal respiratory depression may occur
            • Monitor for respiratory depression, especially during initiation or following a dose increase
            • Instruct patients to swallow tablet/capsule whole; crushing, chewing, or dissolving can cause rapid release and absorption of a potentially fatal morphine dose

            Accidental exposure

            • Accidental ingestion of even 1 dose, especially by children, can result in a fatal overdose

            Neonatal opioid withdrawal syndrome

            • Prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts
            • Syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight
            • Onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn
            • If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available

            Interaction with alcohol

            • Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products that contain alcohol
            • Coingestion of alcohol may cause rapid release of opioid content from long-acting tablet/capsule and result in increased plasma levels and a potentially fatal overdose

            Central nervous system (CNS) depressants

            • Coadministration with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death
            • Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation
            • Instruct patients not to consume alcoholic beverages or use alcohol-containing drug products while taking morphine due to risk of additive sedation and respiratory depression

            Contraindications

            Known hypersensitivity to morphine, morphine slats, naltrexone, or in any situation where opioids are contraindicated

            Respiratory depression

            Acute or severe asthma or hypercarbia

            Gastrointestinal obstruction, including paralytic ileus

            Cautions

            Abuse-deterrent properties: Releases only the morphine in the capsule when swallowed whole; when crushed, the naltrexone blocks some of the euphoric effects of the morphine and can precipitate withdrawal in persons dependent on opioids

            Pharmacologic effects vary widely; in addition to its therapeutic analgesic effect, may cause adverse effects including dysphoria, euphoria, somnolence, respiratory depression, diminished gastrointestinal motility, altered circulatory dynamics, histamine release, physical dependence, & alterations of the endocrine and autonomic nervous systems

            Cases of serotonin syndrome, a potentially life-threatening condition, reported with concomitant use of serotonergic drugs; this may occur within the recommended dosage range; the onset of symptoms generally occur within several hours to a few days of concomitant use, but may occur later than that; discontinue therapy immediately if serotonin syndrome is suspected

            Therapy may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients; there is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics); monitor patients for signs of hypotension after initiating or titrating dosage; in patients with circulatory shock, therapy may cause vasodilation that can further reduce cardiac output and blood pressure; avoid therapy in patients with circulatory shock

            In patients who may be susceptible to intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), therapy may reduce respiratory drive, and resultant CO2 retention can further increase intracranial pressure; monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy; opioids may obscure clinical course in a patient with a head injury; avoid the use in patients with impaired consciousness or coma

            Contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus; may cause spasm of sphincter of Oddi; opioids may cause increases in serum amylase; monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms

            Therapy may increase frequency of seizures in patients with seizure disorders and in other clinical settings associated with seizures; monitor patients for worsened seizure control during therapy

            Avoid use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic; mixed agonist/antagonist and partial agonist analgesics may reduce analgesic effect and/or precipitate withdrawal symptoms; when discontinuing therapy in physically-dependent patient, gradually taper dosage; do not abruptly discontinue therapy in these patients

            Warn patients not to drive or operate dangerous machinery unless they are tolerant to effects of drug and know how they will react to medication

            While serious, life-threatening, or fatal respiratory depression can occur at any time during therapy, risk is greatest during initiation of therapy or following dosage increase; monitor patients closely for respiratory depression, especially within first 24 to 72 hr of initiating therapy with and following dosage increases; accidental ingestion of even one dose, especially by children, can result in respiratory depression and death due to overdose of opioid

            Monoamine oxidase inhibitors (MAOIs) may potentiate effects of opioid, opioid’s active metabolite, including respiratory depression, coma, and confusion; therapy should not be administered within 14 days of initiating or stopping MAOIs

            Not indicated for acute/postoperative pain, mild pain, or short-term pain relief; only indicated for postoperative use if patient already receiving chronic opioid therapy prior to surgery, or if postoperative pain is expected to be moderate-to-severe and persist for an extended period of time

            Schedule II opioid analgesics expose users to the risks of addiction, abuse, and misuse; there is a greater risk for overdose and death with extended-release opioids due to the larger amount of active opioid present (see Black Box Warnings)

            Addiction, abuse, and misuse risks are increased in patients with a personal or family history of substance abuse or mental illness (eg, major depression); the potential for these risks should not, however, prevent the prescribing of proper pain management in any given patient; intensive monitoring is necessary (see Black Box Warnings)

            Accidental exposure reported, including fatalities (see Black Box Warnings)

            Neonatal opioid withdrawal syndrome reported with long-term use during pregnancy (see Black Box Warnings)

            Opioid pharmacokinetics may be altered in patients with renal failure; clearance may be decreased and metabolites may accumulate much higher plasma levels in patients with renal failure as compared to patients with normal renal function; start with a lower than normal dosage or with longer dosing intervals and titrate slowly while monitoring for signs of respiratory depression, sedation, and hypotension

            Profound sedation, respiratory depression, coma, and death may result from concomitant administration with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol); because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate; must not consume alcohol while taking morphine/naloxone

            If the decision to begin morphine/naloxone is made, start with 20 mg/0.8 mg q24hr, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant

            Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients

            Use caution when selecting dosage for an elderly patient, usually starting at low end of dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy; because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and may be useful to monitor renal function

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            Pregnancy & Lactation

            Pregnancy

            Prolonged use of opioid analgesics during pregnancy can cause neonatal opioid withdrawal syndrome; there are no available data in pregnant women to inform a drug associated risk for major birth defects and miscarriage; published studies with morphine use during pregnancy have not reported a clear association with morphine and major birth defects

            Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth; the onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of drug by newborn; observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly

            Labor and delivery

            • Opioids cross placenta and may produce respiratory depression and psycho-physiologic effects in neonates; an opioid antagonist, such as naloxone, must be available for reversal of opioid induced respiratory depression in neonate; drug is not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate; opioid analgesics can prolong labor through actions that temporarily reduce strength, duration, and frequency of uterine contractions; however, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor; monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression

            Infertility

            • Due to effects of androgen deficiency, chronic use of opioids may cause reduced fertility in females and males of reproductive potential; it is not known whether effects on fertility are reversible

            Lactation

            Morphine is present in breast milk; published lactation studies report variable concentrations of morphine in breast milk with administration of immediate-release morphine to nursing mothers in the early postpartum period with a milk-to-plasma morphine AUC ratio of 2.5:1 measured in one lactation study; however, there is insufficient information to determine effects of morphine on breastfed infant and effects of morphine on milk production; no information is available on effects of drug on breastfed infant or effects of drug on milk production

            The developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from therapy or from underlying maternal condition

            Monitor infants exposed to therapy through breast milk for excess sedation and respiratory depression; withdrawal symptoms can occur in breastfed infants when maternal administration of morphine is stopped, or when breastfeeding is stopped

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Morphine is a pure opioid agonist, relatively selective for the mu-opioid receptor; inhibits ascending pain pathways, which causes alteration in response to pain; produces analgesia, respiratory depression, and sedation

            Naltrexone is a centrally acting mu-opioid antagonist; only becomes active and antagonizes opioid agonsists when the tablet is either chewed, crushed, or dissolved

            Pharmacokinetics

            Pharmacokinetic parameters are for morphine unless otherwise stated

            Bioavailability: 20-40%  

            Peak Plasma Time: 7.5 hr  

            Protein Binding:  30-35%  

            Half-Life: 29 hr  

            Volume of distribution: 3-4 L/kg  

            Metabolism: Glucuronidation and sulfation in the liver to produce including morphine-3-glucuronide, M3G (about 50%) and morphine-6-glucuronide, M6G (about 5 to 15%) or morphine-3-etheral sulfate; naltrexone extensively metabolized to 6-beta-naltrexol

            Clearance: 20-30 mL/min/kg

            Excretion: Morphine: 10% excreted unchanged in urine, 55-65 metabolites excreted in urine

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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            Code Definition
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