General

High Alert Medication: This medication bears a heightened risk of causing significant patient harm when it is used in error.

**REMS Drug**

Pronunciation:
mor-feen

Trade Name(s)

• AVINza
• Doloral 
• Duramorph
• Embeda
• Infumorph
• Kadian 
• M-Eslon 
• Mitigo
• Morphabond ER
• Morphine LP Epidural 
• MS Contin
• Roxanol

Ther. Class.

opioid analgesics

Pharm. Class.

opioid agonists

Controlled Substance Schedule: II

Indications

• Severe pain (the 20 mg/mL oral solution concentration should only be used in opioid-tolerant patients).
• Pain severe enough to require daily, around-the-clock long-term opioid treatment and for which alternative treatment options are inadequate (extended release).
• Pulmonary edema.
• Pain associated with MI.

Action

Binds to opiate receptors in the CNS. Alters the perception of and response to painful stimuli while producing generalized CNS depression.

Therapeutic Effect(s):

Decrease in severity of pain.

Pharmacokinetics

Absorption: Variably absorbed (about 30%) following oral administration. More reliably absorbed from rectal, SUBQ, and IM sites. Following epidural administration, systemic absorption and absorption into the intrathecal space via the meninges occurs.

Distribution: Widely distributed to tissues.

Metabolism and Excretion: Mostly metabolized by the liver. Active metabolites excreted renally.

Half-life: Premature neonates:  10–20 hr;  Neonates:  7.6 hr;  Infants 1–3 mo:  6.2 hr;  Children 6 mo–2.5 yr:  2.9 hr;  Children 3–6 yr:  1–2 hr;  Children 6–19 yr with sickle cell disease:  1.3 hr;  Adults:  2–4 hr.

TIME/ACTION PROFILE (analgesia)

Contraindication/Precautions

Contraindicated in:

• Hypersensitivity;
• Some products contain tartrazine, bisulfites, or alcohol and should be avoided in patients with known hypersensitivity;
• Acute, mild, intermittent, or postoperative pain (extended/sustained release);
• Significant respiratory depression (extended release);
• Acute or severe bronchial asthma (extended release);
• Paralytic ileus (extended release).

Use Cautiously in:

• Personal or family history of substance use disorder or mental illness;
• Head trauma;
• ↑ intracranial pressure;
• Severe renal impairment;
• Severe hepatic impairment;
• Severe pulmonary disease;
• Hypothyroidism;
• Seizure disorder;
• Adrenal insufficiency;
• Undiagnosed abdominal pain;
• Prostatic hyperplasia;
• Patients undergoing procedures that rapidly ↓ pain (cordotomy, radiation); long-acting agents should be discontinued 24 hr before and replaced with short-acting agents;
• OB:  Avoid chronic use; prolonged use of opioids during pregnancy can result in neonatal opioid withdrawal syndrome;
• Lactation:  Use while breastfeeding only if potential maternal benefit justifies potential risk to infant;
• Pedi:  Neonates and infants <3 mo (more susceptible to respiratory depression);
• Pedi:  Neonates (oral solution contains sodium benzoate, which can cause potentially fatal gasping syndrome);
• Geri:  ↑ risk of respiratory depression in older adults; dose ↓ suggested.

Adverse Reactions/Side Effects

CV: hypotension, bradycardia

Derm: flushing, itching, sweating

EENT: blurred vision, diplopia, miosis

Endo: adrenal insufficiency

GI: constipation, nausea, vomiting

GU: urinary retention

Neuro: confusion, sedation, dizziness, dysphoria, euphoria, floating feeling, hallucinations, headache, unusual dreams

Resp: RESPIRATORY DEPRESSION (including central sleep apnea and sleep-related hypoxemia)

Misc: allodynia, opioid-induced hyperalgesia, physical dependence, psychological dependence, tolerance

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

• Use with  extreme caution  in patients receiving  MAO inhibitors  within 14 days prior (may result in unpredictable, severe reactions; ↓ initial dose of morphine to 25% of usual dose).
• Use with  benzodiazepines  or other  CNS depressants, including other  opioids,  nonbenzodiazepine sedative/hypnotics,  anxiolytics,  general anesthetics,  muscle relaxants,  antipsychotics, and  alcohol, may cause profound sedation, respiratory depression, coma, and death; reserve concurrent use for when alternative treatment options are inadequate.
• Drugs that affect serotonergic neurotransmitter systems, including  tricyclic antidepressants,  SSRIs,  SNRIs,  MAO inhibitors,  TCAs,  tramadol,  trazodone,  mirtazapine,  5-HT₃  receptor antagonists,  linezolid,  methylene blue, and  triptans, ↑ risk of serotonin syndrome.
•  Mixed agonist/antagonist analgesics, including  nalbuphine  or  butorphanol, and  partial agonist analgesics, including  buprenorphine, may ↓ morphine's analgesic effects and/or precipitate opioid withdrawal in physically dependent patients.
• May ↑ the anticoagulant effect of  warfarin.
•  Cimetidine  ↓ metabolism and may ↑ effects.
• IV morphine may ↓ levels and antiplatelet effects of  clopidogrel,  prasugrel, and  ticagrelor ; consider IV antiplatelet agent as alternative in patients with acute coronary syndrome if morphine concomitantly used.

Drug-Natural Products:

Concomitant use of  kava-kava,  valerian, or  chamomile  can ↑ CNS depression.

Route/Dosage

Larger doses may be required during chronic therapy

PO Rect:  (Adults  ≥50 kg): Usual starting dose for moderate to severe pain in opioid-naive patients:  30 mg every 3–4 hr initially  or  once 24-hr opioid requirement is determined, convert to extended-release morphine by administering total daily oral morphine dose every 24 hr (as ER capsules), 50% of the total daily oral morphine dose every 12 hr (as  MS Contin ), or 33% of the total daily oral morphine dose every 8 hr (as  MS Contin ). See equianalgesic chart, equianalgesic dosing guidelines. Dose of ER capsules should not exceed 1600 mg/day because of fumaric acid in formulation.

PO Rect:  (Adults and Children  <50 kg): Usual starting dose for moderate to severe pain in opioid-naive patients:  0.3 mg/kg every 3–4 hr initially.

PO (Children  >1 mo): Prompt-release tablets and solution:  0.2–0.5 mg/kg every 4–6 hr as needed.  Controlled-release tablet:  0.3–0.6 mg/kg every 12 hr.

IM IV SUBQ (Adults  ≥50 kg): Usual starting dose for moderate to severe pain in opioid-naive patients:  4–10 mg every 3–4 hr.  MI:  8–15 mg, for very severe pain additional smaller doses may be given every 3–4 hr.

IM IV SUBQ (Adults and Children  <50 kg): Usual starting dose for moderate to severe pain in opioid-naive patients:  0.05–0.2 mg/kg every 3–4 hr, maximum: 15 mg/dose.

IM IV SUBQ (Neonates): 0.05 mg/kg every 4–8 hr, maximum dose: 0.1 mg/kg. Use preservative-free formulation.

IV SUBQ (Adults): Continuous infusion:  0.8–10 mg/hr; may be preceded by a bolus of 15 mg (infusion rates vary greatly; up to 80 mg/hr have been used).

IV SUBQ (Children  >1 mo): Continuous infusion, postoperative pain:  0.01–0.04 mg/kg/hr.  Continuous infusion, sickle cell or cancer pain:  0.02–2.6 mg/kg/hr.

IV (Neonates): Continuous infusion:  0.01–0.03 mg/kg/hr.

Epidural:  (Adults): Intermittent injection:  5 mg/day (initially); if relief is not obtained at 60 min, 1–2 mg increments may be made (total dose not to exceed 10 mg/day).  Continuous infusion:  2–4 mg/24 hr; may ↑ by 1–2 mg/day (up to 30 mg/day).

Epidural:  (Children >1 mo): 0.03–0.05 mg/kg, maximum dose: 0.1 mg/kg or 5 mg/24 hr. Use preservative-free formulation.

IT (Adults): 0.2–1 mg. Use preservative-free formulation.

Availability (generic available)

Immediate-release tablets: 15 mg, 30 mg

Extended-release tablets (MS Contin): 15 mg, 30 mg, 60 mg, 100 mg, 200 mg

Extended-release capsules: 10 mg, 20 mg, 30 mg, 45 mg, 50 mg, 60 mg, 75 mg, 80 mg, 90 mg, 100 mg, 120 mg

Oral solution: 1 mg/mL , 10 mg/5 mL, 20 mg/5 mL, 5 mg/mL , 100 mg/5 mL

Rectal suppositories: 5 mg, 10 mg, 20 mg, 30 mg

Solution for epidural, IV injection (preservative-free): 0.5 mg/mL, 1 mg/mL

Solution for epidural or IT use (continuous microinfusion device; preservative-free): 10 mg/mL, 25 mg/mL

Solution for IM, SUBQ, IV injection: 1 mg/mL, 2 mg/mL, 4 mg/mL, 5 mg/mL, 8 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL

Solution for IV injection (PCA device): 1 mg/mL, 2 mg/mL, 3 mg/mL, 5 mg/mL

Assessment

• Assess type, location, and intensity of pain prior to and 1 hr following PO, SUBQ, and IM and 20 min (peak) following IV administration. When titrating opioid doses, ↑ of 25–50% should be administered until there is either a 50% ↓ in the patient's pain rating on a numerical or visual analogue scale or the patient reports satisfactory pain relief. When titrating doses of short-acting morphine, a repeat dose can be safely administered at the time of the peak if previous dose is ineffective and side effects are minimal.
• Patients on a continuous infusion should have additional bolus doses provided every 15–30 min as needed for breakthrough pain. The bolus dose is usually set to the amount of drug infused each hr by continuous infusion.
• Patients taking extended-release morphine may require additional short-acting opioid doses for breakthrough pain. Doses of short-acting opioids should be equivalent to 10–20% of 24 hr total and given every 2 hr as needed.
• An equianalgesic chart (see equianalgesic dosing guidelines) should be used when changing routes or when changing from one opioid to another.
• High Alert: Assess level of consciousness, BP, HR, and respiratory rate before and periodically during administration. If respiratory rate <10/min, assess level of sedation. Physical stimulation may be sufficient to prevent significant hypoventilation. Subsequent doses may need to be ↓ by 25–50%. Initial drowsiness will ↓ with continued use. Monitor for respiratory depression, especially during initiation or following dose ↑; serious, life-threatening, or fatal respiratory depression may occur. May cause sleep-related breathing disorders (central sleep apnea, sleep-related hypoxemia). Geri:  Assess older adults frequently, as they may be more sensitive to the effects of opioid analgesics and may experience side effects and respiratory complications more frequently. Pedi:  Assess pediatric patients frequently; children are more sensitive to the effects of opioid analgesics and may experience respiratory complications, excitability, and restlessness more frequently.
• Prolonged use may lead to physical and psychological dependence and tolerance. This should not prevent patient from receiving adequate analgesia. Patients who receive morphine for pain rarely develop psychological dependence. Progressively higher doses may be required to relieve pain with long-term therapy; may ↑ risk of overdose. Prolonged use of opioids should be reserved for patients whose pain remains severe enough to require them and when alternative treatment options continue to be inadequate. Many acute pain conditions treated in the outpatient setting require no more than a few days of an opioid pain medicine.
• Assess bowel function routinely. Institute prevention of constipation with ↑ intake of fluids and bulk and with laxatives to minimize constipating effects. Administer stimulant laxatives routinely if opioid use exceeds 2–3 days, unless contraindicated. Consider drugs for opioid-induced constipation.
• Assess risk for opioid addiction, abuse, or misuse prior to administration. Abuse or misuse of extended-release preparations by crushing, chewing, snorting, or injecting dissolved product will result in uncontrolled delivery of morphine and can result in overdose and death.
• Assess for opioid-induced hyperalgesia, which can appear as ↑ levels of pain on increasing the dose of the opioid, ↓ levels of pain on decreasing the dose of the opioid, or pain from ordinarily nonpainful stimuli (allodynia). This condition is different from tolerance. If a patient is suspected to be experiencing opioid-induced hyperalgesia, consider ↓ the dose of the current opioid or switching to a different opioid analgesic.

Lab Test Considerations:

May ↑ plasma amylase and lipase levels.

If an opioid antagonist is required to reverse respiratory depression or coma, naloxone is the antidote. Dilute the 0.4-mg ampule of naloxone in 10 mL of 0.9% NaCl and administer 0.5 mL (0.02 mg) by IV push every 2 min. For children and adults weighing <40 kg, dilute 0.1 mg of naloxone in 10 mL of 0.9% NaCl for a concentration of 10 mcg/mL and administer 0.5 mcg/kg every 2 min. Titrate dose to avoid withdrawal, seizures, and severe pain.

Implementation

• High Alert: Do not confuse MS Contin with Oxycontin. Do not confuse morphine with hydromorphone. Do not confuse morphine (nonconcentrated oral liquid) with morphine (concentrated oral liquid).
• Use only preservative-free formulations for neonates and for epidural and intrathecal routes in all patients.

• Explain therapeutic value of medication prior to administration to enhance the analgesic effect.

  • Regularly administered doses may be more effective than as needed administration. Analgesic is more effective if given before pain becomes severe.
  • Coadministration with nonopioid analgesics may have additive analgesic effects and may permit lower doses.
  • When transferring from other opioids or other forms of morphine to extended-release tablets, administer a total daily dose of oral morphine equivalent to previous daily dose (see equianalgesic dosing guidelines) and divided every 8 hr (MS Contin), every 12 hr (MS Contin), or every 24 hr.
  • Morphine should be discontinued gradually to prevent withdrawal symptoms after long-term use. For patients on long-acting agents who are physically opioid-dependent, initiate the taper by a small enough increment (no greater than 10–25% of total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2–4 wk. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. Monitor frequently to manage pain and withdrawal symptoms (restlessness; lacrimation; rhinorrhea; yawning; perspiration; chills; myalgia; mydriasis; irritability; anxiety; backache; joint pain; weakness; abdominal cramps; insomnia; nausea; anorexia; vomiting; diarrhea; or ↑ BP, respiratory rate, or HR). If withdrawal symptoms occur, pause the taper for a period of time or ↑ the dose of opioid analgesic to the previous dose, and then proceed with a slower taper. Also, monitor patients for changes in mood, emergence of suicidal thoughts, or use of other substances. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic.
• PO Doses may be administered with food or milk to minimize GI irritation.
  • Administer oral solution with properly calibrated measuring device; may be diluted in a glass of fruit juice just prior to administration to improve taste. Verify correct dose (mg) and correct volume (mL) prior to administration. Use an oral syringe when using 20 mg/mL concentration of oral solution.
  •  DNC: Swallow extended-release tablets whole; do not break, crush, dissolve, or chew (could result in rapid release and absorption of a potentially toxic dose). 
  • Extended-release capsules may be opened and the pellets sprinkled onto applesauce immediately prior to administration. Patients should rinse mouth and swallow to assure ingestion of entire dose.  DNC: Pellets should not be chewed, crushed, or dissolved.  Capsules may also be opened and sprinkled on approximately 10 mL of water and flushed while swirling through a prewetted 16 French gastrostomy tube fitted with a funnel at the port end. Additional water should be used to transfer and flush any remaining pellets. Do not administer extended-release capsules via a nasogastric tube.
• Rect:  MS Contin  has been administered rectally.
• IM SUBQ IM is the preferred route for repeated doses. SUBQ administration may cause tissue irritation.
  • Pedi:  Avoid IM administration in children. Fear of pain from IM injection may lead to inadequate pain control.
•  REMS: FDA strongly encourages health care professionals to complete a REMS-compliant education program that includes all the elements of the FDA Education  Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain,  available at www.fda.gov/OpioidAnalgesicREMSBlueprint. Information on programs can be found at 1-800-503-0784 or www.opioidanalgesicrems.com.
• Discuss availability of naloxone for emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing therapy, especially if patient has household members (including children) or other close contacts at risk for accidental exposure or overdose. Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. However, the presence of risk factors for overdose should not prevent the proper management of pain in any patient.

• Epidural:  Administer undiluted. Do not use an in-line filter. Do not admix or administer other medications in epidural space for 48 hr after administration. Administer within 4 hr after removing from vial. Store in refrigerator; do not freeze.

Patient/Family Teaching

• Explain purpose and side effects of morphine to patient. Instruct them to take medication as directed. Advise patient to read  Patient Information before starting and with each Rx refill in case of changes.
•  REMS: Instruct patient how and when to ask for pain medication. Do not stop taking without discussing with health care professional; may cause withdrawal symptoms if discontinued abruptly after prolonged use. Do not ↑ doses without discussing with health care professional; may lead to overdose. Discuss safe use, risks, and proper storage and disposal of opioid analgesics with patients and caregivers with each Rx. The Patient Counseling Guide is available at www.fda.gov/OpioidAnalgesicREMSPCG.
• Medication may cause drowsiness or dizziness. Advise patient to call for assistance when ambulating and to avoid driving or other activities that require alertness until response to the medication is known.
• Advise patient that morphine is a drug with known abuse potential. Protect it from theft, and never give to anyone other than the individual for whom it was prescribed. Store out of sight and reach of children, and in a location not accessible by others.
• Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose. Inform patients and caregivers about various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (Rx, direct from pharmacist, or state programs). OTC naloxone nasal spray is available at pharmacies nationwide for overdose or accidental ingestion.
• Advise patient to notify health care professional if pain control is not adequate or if severe or persistent side effects occur.
• Advise patient to change positions slowly to minimize orthostatic hypotension.
• Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications.
• Emphasize the importance of aggressive prevention of constipation with the use of morphine.
• Caution patient to avoid concurrent use of alcohol or other CNS depressants with this medication.
• Encourage patients who are immobilized or on prolonged bedrest to turn, cough, and breathe deeply every 2 hr to prevent atelectasis.
• Advise patient that good oral hygiene, frequent mouth rinses, and sugarless gum or candy may decrease dry mouth.
• Rep:  Advise patient to notify health care professional if pregnancy is planned or suspected or if breastfeeding. Inform patient of potential for neonatal opioid withdrawal syndrome with prolonged use during pregnancy. Monitor neonate for signs and symptoms of withdrawal (irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, failure to gain weight); these usually occur the first days after birth. Monitor infants exposed to morphine through breast milk for excess sedation and respiratory depression. Chronic use may ↓ fertility in females and males.
• Home Care Issues: High Alert: Explain to patient and family how and when to administer morphine and how to care for infusion equipment properly. Pedi:  Teach parents or caregivers how to accurately measure liquid medication and to use only the measuring device dispensed with the medication.

Evaluation/Desired Outcomes

• Decrease in severity of pain without a significant alteration in level of consciousness or respiratory status.
• Decrease in symptoms of pulmonary edema.