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Morphine and Naltrexone

Pronunciation

Pronunciation

(MOR feen & nal TREKS one)

Index Terms

  • Morphine Sulfate and Naltrexone Hydrochloride
  • Morphine Sulfate/Naltrexone
  • MS (error-prone abbreviation and should not be used)
  • MSO4 (error-prone abbreviation and should not be used)
  • Naltrexone and Morphine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, extended release, oral:

Embeda 20/0.8: Morphine sulfate 20 mg and naltrexone hydrochloride 0.8 mg

Embeda 30/1.2: Morphine sulfate 30 mg and naltrexone hydrochloride 1.2 mg

Embeda 50/2: Morphine sulfate 50 mg and naltrexone hydrochloride 2 mg

Embeda 60/2.4: Morphine sulfate 60 mg and naltrexone hydrochloride 2.4 mg

Embeda 80/3.2: Morphine sulfate 80 mg and naltrexone hydrochloride 3.2 mg

Embeda 100/4: Morphine sulfate 100 mg and naltrexone hydrochloride 4 mg

Brand Names: U.S.

  • Embeda

Pharmacologic Category

  • Analgesic, Opioid
  • Opioid Antagonist

Pharmacology

Morphine: Binds to opiate receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; produces generalized CNS depression.

Naltrexone: Pure opioid antagonist; reverses the subjective and analgesic effects of mu-opioid receptor agonists by competitively binding at mu-opioid receptors.

Use: Labeled Indications

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

Limitations of use: Reserve morphine/naltrexone ER for use in patients for whom alternative treatment options (eg, nonopioid analgesics, immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Morphine/naltrexone ER is not indicated as an as-needed analgesic.

Contraindications

Hypersensitivity (eg, anaphylaxis) to morphine, naltrexone, or any component of the formulation; significant respiratory depression, acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; GI obstruction, including paralytic ileus (known or suspected); concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days.

Documentation of allergenic cross-reactivity for opioids is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity can not be ruled out with certainty.

Dosing: Adult

Note: These are guidelines and do not represent the doses that may be required in all patients. Individualize treatment based on patient’s prior analgesic treatment experience/tolerance and pain relief. Morphine 100 mg/naltrexone 4 mg; a single dose > morphine 60 mg/naltrexone 2.4 mg or a total daily dose > morphine 120 mg/naltrexone 5 mg are for use in opioid-tolerant patients only.

Pain management: Oral: Opiate-naive (use as the first opioid analgesic or use in patients who are not opioid tolerant): Note: Opioid tolerance is defined as: Patients already taking at least 60 mg of oral morphine daily, 25 mcg transdermal fentanyl per hour, 30 mg of oral oxycodone daily, 8 mg oral hydromorphone daily, 25 mg oral oxymorphone daily, 60 mg oral hydrocodone per day, or an equivalent dose of another opioid for at least 1 week.

Initial: Morphine 20 mg/naltrexone 0.8 mg once daily.

Titration: Dosage adjustments may be made every 1 to 2 days. Breakthrough pain may require a rescue medication with an immediate release analgesic. If once-daily dosing is inadequate may switch to twice daily dosing.

Conversion: The first dose of morphine/naltrexone ER may be taken with the last dose of any immediate release opioid medication.

Conversion from other oral morphine products to morphine/naltrexone ER: Administer 50% of the patient's total daily oral morphine dose as morphine/naltrexone ER every 12 hours or all of the patient's total daily oral morphine dose as morphine/naltrexone ER once daily.

Conversion from other opioids to morphine/naltrexone ER: Discontinue all other around-the-clock opioids when therapy is initiated. Initial dose: Morphine 30 mg/naltrexone 1.2 mg once daily; there are no established conversion ratios from other opioids to morphine/naltrexone ER; consider the following general points when converting patients and provide breakthrough pain relief with rescue medication (eg, immediate release morphine):

Conversion from parenteral to oral morphine: It may take 2 to 6 mg of oral morphine to provide pain relief equivalent to 1 mg of parenteral morphine. An oral dose 3 times the daily parenteral dose may be sufficient.

Conversion from other (non-morphine) oral/parenteral opioids to oral morphine: Specific recommendations are not available; refer to published relative potency data realizing that such ratios are only approximations. It is generally safest to give 50% the estimated daily morphine requirement as the initial dose and manage inadequate relief with immediate release morphine.

Conversion from methadone to morphine/naltrexone ER: Close monitoring is required when converting methadone to another opioid. Ratio between methadone and other opioid agonists varies widely according to previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.

Discontinuation of therapy: Decrease dose by 25% to 50% every 2 to 4 days; monitor carefully for signs/symptoms of withdrawal. If patient displays withdrawal symptoms, increase dose to previous dose and then reduce dose more slowly by increasing interval between dose reductions, decreasing amount of daily dose reduction, or both.

Dosage adjustment for concomitant therapy: Concomitant CNS depressants: Initiate morphine/naltrexone ER with 33% to 50% of the recommended initial dose.

Dosing: Geriatric

Refer to adult dosing. Use with caution; may require reduced dosage.

Dosing: Renal Impairment

There are no specific dosage adjustments provided in the manufacturer's labeling; initiate with a lower than usual dosage and titrate slowly.

Dosing: Hepatic Impairment

There are no specific dosage adjustments provided in the manufacturer's labeling; initiate with a lower than usual dosage and titrate slowly.

Administration

Swallow whole; do not crush, chew, or dissolve pellets in the capsule prior to swallowing. Contents of the capsule may be sprinkled on applesauce (do not divide in separate doses) and swallowed immediately without chewing. Rinse mouth to ensure all contents have been swallowed. Do not administer morphine/naltrexone ER pellets through a nasogastric or gastric tube.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light.

Drug Interactions

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Alvimopan: Analgesics (Opioid) may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Consider therapy modification

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Amphetamines: May enhance the analgesic effect of Analgesics (Opioid). Monitor therapy

Analgesics (Opioid): Naltrexone may diminish the therapeutic effect of Analgesics (Opioid). Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Consider therapy modification

Anticholinergic Agents: May enhance the adverse/toxic effect of Analgesics (Opioid). Specifically, the risk for constipation and urinary retention may be increased with this combination. Monitor therapy

Antiplatelet Agents (P2Y12 Inhibitors): Morphine (Systemic) may diminish the antiplatelet effect of Antiplatelet Agents (P2Y12 Inhibitors). Morphine (Systemic) may decrease the serum concentration of Antiplatelet Agents (P2Y12 Inhibitors). Management: Consider alternative anti-ischemic/analgesic therapies (eg, beta-blockers, nitroglycerin) in patients with acute coronary syndromes treated with a P2Y12 inhibitor when possible. The risks associated with other opioids are unknown. Exceptions: Cangrelor. Consider therapy modification

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

CNS Depressants: May enhance the CNS depressant effect of Analgesics (Opioid). Management: Avoid concomitant use of opioid analgesics and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Desmopressin: Analgesics (Opioid) may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Diuretics: Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics. Analgesics (Opioid) may diminish the therapeutic effect of Diuretics. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Eluxadoline: Analgesics (Opioid) may enhance the constipating effect of Eluxadoline. Avoid combination

Esmolol: Morphine (Systemic) may increase the serum concentration of Esmolol. Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Gabapentin: May enhance the CNS depressant effect of Morphine (Systemic). Morphine (Systemic) may increase the serum concentration of Gabapentin. Monitor therapy

Gastrointestinal Agents (Prokinetic): Analgesics (Opioid) may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Lumacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

MAO Inhibitors: May enhance the adverse/toxic effect of Morphine (Systemic). Avoid combination

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Methylnaltrexone: May enhance the adverse/toxic effect of Opioid Antagonists. Specifically, the risk for opioid withdrawal may be increased. Avoid combination

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mixed Agonist / Antagonist Opioids: May diminish the analgesic effect of Analgesics (Opioid). Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Avoid combination

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nalmefene: May diminish the therapeutic effect of Analgesics (Opioid). Management: Avoid the concomitant use of nalmefene and opioid analgesics. Discontinue nalmefene 1 week prior to any anticipated use of opioid analgesics. If combined, larger doses of opioid analgesics will likely be required. Consider therapy modification

Naloxegol: Opioid Antagonists may enhance the adverse/toxic effect of Naloxegol. Specifically, the risk for opioid withdrawal may be increased. Avoid combination

Naltrexone: May diminish the therapeutic effect of Analgesics (Opioid). Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Consider therapy modification

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Pegvisomant: Analgesics (Opioid) may diminish the therapeutic effect of Pegvisomant. Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Ramosetron: Analgesics (Opioid) may enhance the constipating effect of Ramosetron. Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

RifAMPin: May decrease the serum concentration of Morphine (Systemic). Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Serotonin Modulators: Analgesics (Opioid) may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Succinylcholine: May enhance the bradycardic effect of Analgesics (Opioid). Monitor therapy

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Test Interactions

Refer to individual agents.

Adverse Reactions

Frequency not always defined.

Cardiovascular: Flushing (≤2%), peripheral edema

Central nervous system: Drowsiness (1% to 14%), dizziness (1% to 8%), headache (2% to 7%), fatigue (1% to 4%), insomnia (1% to 3%), anxiety (2%), chills, depression, irritability, lethargy, restlessness, sedation

Dermatologic: Pruritus (≤6%), hyperhidrosis (3%)

Endocrine & metabolic: Hot flash

Gastrointestinal: Constipation (7% to 31%), nausea (11% to 22%), vomiting (4% to 8%), xerostomia (2% to 6%), abdominal pain, anorexia, decreased appetite, dyspepsia, flatulence

Neuromuscular & skeletal: Arthralgia, muscle spasm, tremor

<1% (Limited to important or life-threatening): Abdominal distention, abdominal tenderness, abnormal dreams, abnormality in thinking, ataxia, blurred vision, central nervous system depression, cholecystitis, confusion, diaphoresis, diarrhea, disorientation, drug dependence, dyspnea, dysuria, emotional lability, erectile dysfunction, euphoria, hallucination, hypogonadism (Brennan, 2013; Debono, 2011), hypotension, increased serum ALT, increased serum AST, jitteriness, malaise, memory impairment, mental deficiency, mental status changes, myalgia, nervousness, night sweats, orthostatic hypotension, pancreatitis, paresthesia, piloerection, rhinorrhea, skin rash, stupor, urinary retention, weakness, withdrawal syndrome

ALERT: U.S. Boxed Warning

Addiction, abuse, and misuse:

Morphine/naltrexone ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing morphine/naltrexone ER 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 with use of morphine/naltrexone ER. Monitor for respiratory depression, especially during initiation of morphine/naltrexone ER or following a dose increase. Swallow morphine/naltrexone ER capsules whole or to sprinkle the contents of the capsule on applesauce and swallowed immediately without chewing. Crushing, chewing, or dissolving the pellets in morphine/naltrexone ER can cause rapid release and absorption of a potentially fatal dose of morphine.

Accidental ingestion:

Accidental ingestion of even one dose of morphine/naltrexone ER, especially by children, can result in a fatal overdose of morphine.

Neonatal opioid withdrawal syndrome:

Prolonged use of morphine/naltrexone ER 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. 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 non-prescription products that contain alcohol while taking morphine/naltrexone ER. The co-ingestion of alcohol with morphine/naltrexone ER may result in increased plasma levels and a potentially fatal overdose of morphine.

Risks from concomitant use with benzodiazepines or other CNS depressants:

Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of morphine/naltrexone ER and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Constipation: May cause constipation which may be problematic in patients with unstable angina and patients post-myocardial infarction. Consider preventive measures (eg, stool softener, increased fiber) to reduce the potential for constipation.

• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), circulatory shock, or drugs which may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Avoid use in patients with circulatory shock.

• Phenanthrene hypersensitivity: Use with caution in patients with hypersensitivity reactions to other phenanthrene derivative opioid agonists (codeine, hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone).

• Respiratory depression: [US Boxed Warning]: Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely for respiratory depression, especially during initiation or dose escalation. Swallow capsules whole or sprinkle contents of the capsule on applesauce and swallow immediately without chewing. Crushing, chewing, or dissolving the pellets in morphine/naltrexone ER can cause rapid release and a potentially fatal dose. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

Disease-related concerns:

• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.

• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction, infertility, mood disorders, and osteoporosis (Brennan, 2013).

• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction or acute pancreatitis; opioids may cause constriction of sphincter of Oddi.

• CNS depression/coma: Avoid use in patients with CNS impaired consciousness or coma as these patients are susceptible to intracranial effects of CO2 retention.

• Delirium tremens: Use with caution in patients with delirium tremens.

• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur.

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, anxiety disorders, post-traumatic stress disorder) due to increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (Dowell [CDC 2016]).

• Obesity: Use with caution in patients who are morbidly obese.

• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.

• Psychosis: Use with caution in patients with toxic psychosis.

• Renal impairment: Use with caution in patients with renal impairment.

• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercarbia, or preexisting respiratory depression, particularly when initiating therapy and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

• Seizure disorders: Use with caution in patients with seizure disorders, may cause or exacerbate seizures.

• Sleep-disordered breathing: Use opioids with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing, including HF and obesity. Avoid opioids in patients with moderate to severe sleep-disordered breathing (Dowell [CDC 2016]).

• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.

Concurrent drug therapy issues:

• Benzodiazepines or other CNS depressants: [US Boxed Warning]: Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of morphine and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosage and durations to the minimum required and follow patients for signs and symptoms of respiratory depression and sedation.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Ethanol use: [US Boxed Warning]: Patients should not consume alcoholic beverages or medication containing ethanol while taking morphine/naltrexone ER; ethanol may increase morphine plasma levels resulting in a potentially fatal overdose.

Special populations:

• Cachectic or debilitated patients: Use with caution in cachectic or debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

• Elderly: Use with caution in elderly patients; may be more sensitive to adverse effects, including life-threatening respiratory depression. Decrease initial dose. In the setting of chronic pain, monitor closely due to an increased potential for risks, including certain risks such as falls/fracture, cognitive impairment, and constipation. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increasing the risk for respiratory depression or overdose (Dowell [CDC 2016]). Consider the use of alternative nonopioid analgesics in these patients.

• Neonates: Neonatal withdrawal syndrome: [US Boxed Warning]: Prolonged maternal use of opioids during pregnancy can cause neonatal withdrawal syndrome in the newborn which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If prolonged opioid therapy is required in a pregnant woman, ensure treatment is available and warn patient of risk to the neonate. Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. Onset, duration and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.

Dosage form specific issues:

• Appropriate patient selection: Embeda 100 mg/4 mg: For use in opioid-tolerant patients only; may cause fatal respiratory depression in patients not already tolerant to high doses of opioids.

Other warnings/precautions:

• Abuse/misuse/diversion:[US Boxed Warning]: Use exposes patients and other users to the risks of addiction, abuse, and misuse, potentially leading to overdose and death. Assess each patient's risk prior to prescribing; monitor all patients regularly for development of these behaviors or conditions. Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Other factors associated with increased risk include younger age, concomitant depression (major), and psychotropic medication use. Consider offering naloxone prescriptions in patients with factors associated with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents/day orally), and concomitant benzodiazepine use (Dowell [CDC 2016]).

• Accidental exposure: [US Boxed Warning]: Accidental ingestion of even one dose, especially in children, can result in a fatal overdose of morphine.

• Appropriate use: Chronic pain (outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder) in outpatient setting in adults: Opioids should not be used as first-line therapy for chronic pain management (pain >3-month duration or beyond time of normal tissue healing) due to limited short-term benefits, undetermined long-term benefits, and association with serious risks (eg, overdose, MI, auto accidents, risk of developing opioid use disorder). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg. NSAIDS, acetaminophen, certain anticonvulsants and antidepressants). If opioid therapy is initiated, it should be combined with nonpharmacologic and nonopioid therapy, as appropriate. Prior to initiation, known risks of opioid therapy should be discussed and realistic treatment goals for pain/function should be established, including consideration for discontinuation if benefits do not outweigh risks. Therapy should be continued only if clinically meaningful improvement in pain/function outweighs risks. Therapy should be initiated at the lowest effective dosage using immediate-release opioids (instead of extended-release/long-acting opioids). Risk associated with use increases with higher opioid dosages. Risks and benefits should be re-evaluated when increasing dosage to ≥50 morphine milligram equivalents (MME)/day orally; dosages ≥90 MME/day orally should be avoided unless carefully justified (Dowell [CDC 2016]). Therapy should only be prescribed by healthcare professionals familiar with the use of potent opioids for chronic pain.

• Optimal regimen: An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients; doses should be titrated to pain relief/prevention.

• Surgery: Opioids decrease bowel motility; monitor for decreased bowel motility in postoperative patients receiving opioids. Use with caution in the perioperative setting; individualize treatment when transitioning from parenteral to oral analgesics.

• Withdrawal: Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics may precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists. Taper dose gradually when discontinuing.

Monitoring Parameters

Pain relief, respiratory and mental status, blood pressure; signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013)

Alternate recommendations: Chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder): Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of treatment initiation and with dose increases. Re-evaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder. Urine drug testing is recommended prior to initiation and re-checking should be considered at least yearly (includes controlled prescription medications and illicit drugs of abuse). State prescription drug monitoring program (PDMP) data should be reviewed by clinicians prior to initiation and periodically during therapy (frequency ranging from every prescription to every 3 months) (Dowell [CDC 2016]).

Pregnancy Considerations

Animal reproduction studies have not been conducted with this combination. [US Boxed Warning]: Prolonged use of opioids during pregnancy can cause neonatal withdrawal syndrome which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. 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. The naltrexone component may precipitate withdrawal in the fetus. Refer to individual monographs.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache or xerostomia. Have patient report immediately to prescriber severe dizziness, syncope, significant nausea, intolerable constipation, angina, tachycardia, considerable fatigue, or severe dyspepsia (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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