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Morphine (Systemic)

Pronunciation

Pronunciation

(MOR feen)

Index Terms

  • MorphaBond
  • MS (error-prone abbreviation and should not be used)
  • MSO4 (error-prone abbreviation and should not be used)
  • Oramorph SR
  • Roxanol

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule Extended Release 24 Hour, Oral, as sulfate:

AVINza: 30 mg [DSC] [contains fd&c yellow #10 (quinoline yellow), fumaric acid]

AVINza: 45 mg [DSC] [contains fd&c blue #2 (indigotine)]

AVINza: 60 mg [DSC] [contains fumaric acid]

AVINza: 75 mg [DSC]

AVINza: 90 mg [DSC] [contains fd&c red #40, fumaric acid]

AVINza: 120 mg [DSC] [contains brilliant blue fcf (fd&c blue #1), fumaric acid]

Kadian: 10 mg [contains brilliant blue fcf (fd&c blue #1)]

Kadian: 20 mg [contains fd&c yellow #10 (quinoline yellow)]

Kadian: 30 mg [contains brilliant blue fcf (fd&c blue #1)]

Kadian: 40 mg [contains brilliant blue fcf (fd&c blue #1), fd&c yellow #10 (quinoline yellow)]

Kadian: 50 mg, 60 mg [contains brilliant blue fcf (fd&c blue #1), fd&c red #40]

Kadian: 70 mg [DSC] [contains brilliant blue fcf (fd&c blue #1)]

Kadian: 80 mg [contains brilliant blue fcf (fd&c blue #1), fd&c red #40, fd&c yellow #6 (sunset yellow)]

Kadian: 100 mg [contains brilliant blue fcf (fd&c blue #1), fd&c yellow #10 (quinoline yellow)]

Kadian: 130 mg [DSC] [contains brilliant blue fcf (fd&c blue #1), fd&c red #40, fd&c yellow #6 (sunset yellow)]

Kadian: 150 mg [DSC] [contains brilliant blue fcf (fd&c blue #1), fd&c yellow #10 (quinoline yellow)]

Kadian: 200 mg

Generic: 10 mg, 20 mg, 30 mg, 45 mg, 50 mg, 60 mg, 75 mg, 80 mg, 90 mg, 100 mg, 120 mg

Device, Intramuscular, as sulfate:

Generic: 10 mg/0.7 mL (0.7 mL)

Solution, Injection, as sulfate:

Generic: 2 mg/mL (1 mL); 4 mg/mL (1 mL); 5 mg/mL (1 mL); 8 mg/mL (1 mL); 10 mg/mL (1 mL, 10 mL [DSC]); 15 mg/mL (1 mL, 20 mL [DSC])

Solution, Injection, as sulfate [preservative free]:

Astramorph: 0.5 mg/mL (2 mL [DSC]); 1 mg/mL (2 mL [DSC]) [antioxidant free]

Duramorph: 0.5 mg/mL (10 mL); 1 mg/mL (10 mL) [antioxidant free]

Infumorph 200: 200 mg/20 mL (10 mg/mL) (20 mL) [antioxidant free]

Infumorph 500: 500 mg/20 mL (25 mg/mL) (20 mL) [antioxidant free]

Generic: 0.5 mg/mL (10 mL); 1 mg/mL (10 mL)

Solution, Intravenous, as sulfate:

Generic: 1 mg/mL (10 mL [DSC], 30 mL); 25 mg/mL (4 mL, 10 mL); 50 mg/mL (20 mL, 50 mL)

Solution, Intravenous, as sulfate [preservative free]:

Generic: 1 mg/mL (30 mL); 2 mg/mL (1 mL); 4 mg/mL (1 mL); 150 mg/30 mL (30 mL); 8 mg/mL (1 mL); 10 mg/mL (1 mL); 15 mg/mL (1 mL); 25 mg/mL (10 mL)

Solution, Oral, as sulfate:

Generic: 10 mg/5 mL (5 mL, 15 mL, 100 mL, 500 mL); 20 mg/5 mL (5 mL, 100 mL, 500 mL); 100 mg/5 mL (15 mL, 30 mL, 120 mL, 240 mL)

Suppository, Rectal, as sulfate:

Generic: 5 mg (12 ea); 10 mg (12 ea); 20 mg (12 ea); 30 mg (12 ea)

Tablet, Oral, as sulfate:

Generic: 15 mg, 30 mg

Tablet Extended Release, Oral, as sulfate:

MS Contin: 15 mg, 30 mg, 60 mg, 100 mg, 200 mg

Generic: 15 mg, 30 mg, 60 mg, 100 mg, 200 mg

Brand Names: U.S.

  • Astramorph [DSC]
  • AVINza [DSC]
  • Duramorph
  • Infumorph 200
  • Infumorph 500
  • Kadian
  • MS Contin

Pharmacologic Category

  • Analgesic, Opioid

Pharmacology

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

Absorption

Oral: Variable

Distribution

Distributes to skeletal muscle, liver, kidneys, lungs, intestinal tract, spleen and brain; Vd:

Cancer patients (Children age 1.7 to 18.7 years): Median: 5.2 L/kg; a significantly higher Vd was observed in children <11 years (median: 7.1 L/kg) versus >11 years (median: 4.7 L/kg) (Hunt 1999)

Adults: 1 to 6 L/kg; binds to opioid receptors in the CNS and periphery (eg, GI tract)

Metabolism

Hepatic via conjugation with glucuronic acid primarily to morphine-6-glucuronide (M6G) (active analgesic) and morphine-3-glucuronide (M3G) (inactive as analgesic; may contribute to CNS stimulation [Lugo 2002]); minor metabolites include morphine-3-6-diglucuronide; other minor metabolites include normorphine (active) and morphine 3-ethereal sulfate

Excretion

Urine (primarily as morphine-3-glucuronide, neonates: 3% to 15%; adults: ~2% to 12% excreted unchanged); feces (~7% to 10%). It has been suggested that accumulation of morphine-6-glucuronide might cause toxicity with renal insufficiency. All of the metabolites (ie, morphine-3-glucuronide, morphine-6-glucuronide, and normorphine) have been suggested as possible causes of neurotoxicity (eg, myoclonus).

Clearance: Note: In pediatric patients, adult values are reached by 6 months to 2.5 years of age (McRorie 1992)

Preterm: 0.5 to 3 mL/minute/kg

Neonates 1 to 7 days: Median: 5.5 mL/minute/kg (range: 3.2 to 8.4 mL/minute/kg) (McRorie 1992)

Neonates 8 to 30 days: Median: 7.4 mL/minute/kg (range: 3.4 to 13.8 mL/minute/kg) (McRorie 1992)

Infants 1 to 3 months: Median: 10.5 mL/minute/kg (range: 9.8 to 20.1 mL/minute/kg) (McRorie 1992)

Infants 3 to 6 months: Median: 13.9 mL/minute/kg (range: 8.3 to 24.1 mL/minute/kg) (McRorie 1992)

Infants 6 months to Children 2.5 years: Median: 21.7 mL/minute/kg (range: 5.8 to 28.6 mL/minute/kg) (McRorie 1992)

Preschool Children: 20 to 40 mL/minute/kg

Cancer patients ( Children age: 1.7 to 18.7 years): Median: 23.1 mL/minute/kg; a significantly higher clearance was observed in children <11 years (median: 37.4 mL/minute/kg) versus >11 years (median: 21.9 mL/minute/kg) (Hunt 1999)

Children with sickle cell disease (age: 6 to 19 years): ~36 mL/minute/kg (range: 6 to 59 mL/minute/kg) (Dampier 1995)

Adults: 20 to 30 mL/minute/kg

Onset of Action

Patient dependent; dosing must be individualized: Oral (immediate release): ~30 minutes; IV: 5 to 10 minutes

Time to Peak

Plasma:

Tablets, oral solution, epidural: 1 hour

Extended release tablets: 3 to 4 hours; Avinza: 30 minutes (maintained for 24 hours); Kadian: ~10 hours

Suppository: 20 to 60 minutes

SubQ: 50 to 90 minutes

IM: 30 to 60 minutes

IV: 20 minutes

Cerebrospinal fluid: After an oral dose of controlled release morphine concentrations peak at 8 hours for both normal and reduced renal function; morphine-6-glucuronide (active analgesic) and morphine-3-glucuronide distribution into the CNS may be delayed peaking at 12 hours in patients with normal renal function or up to 24 hours in patients with ESRD (peak level of morphine-6-glucuronide is ~15 times higher than patients with normal renal function) (D'Honneur 1994).

Duration of Action

Patient dependent; dosing must be individualized: Pain relief:

Immediate-release formulations (tablet, oral solution, injection): 3 to 5 hours

Extended-release capsule and tablet: 8 to 24 hours (formulation dependent)

Epidural or intrathecal: Single dose: Up to 24 hours (Bujedo 2012)

Suppository: 3 to 7 hours

Half-Life Elimination

Preterm: 10 to 20 hours

Neonates: 7.6 hours (range: 4.5 to 13.3 hours)

Infants 1 to 3 months: Median: 6.2 hours (range: 5 to 10 hours) (McRorie 1992)

Infants 3 to 6 months: Median: 4.5 hours (range: 3.8 to 7.3 hours) (McRorie 1992)

Infants 6 months to Children 2.5 years: Median: 2.9 hours (range: 1.4 to 7.8 hours) (McRorie 1992)

Preschool Children: 1 to 2 hours

Children with sickle cell disease (age: 6 to 19 years): ~1.3 hours (Dampier 1995)

Adults: Immediate-release forms: 2 to 4 hours; Avinza: ~24 hours; Kadian: 11 to 13 hours

Protein Binding

Premature Infants: <20%; Adults: 20% to 35%

Use: Labeled Indications

Immediate-release tablets/oral solution:

Moderate to severe pain: For the relief of moderate to severe acute and chronic pain for which use of an opioid analgesic is appropriate. Morphine 100 mg per 5 mL (20 mg/mL) oral solution is for the relief of moderate to severe acute and chronic pain in opioid-tolerant patients.

Injection:

Severe pain: For the relief of severe pain, such as myocardial infarction and severe injuries

Dyspnea: For the relief of dyspnea of acute left ventricular failure and pulmonary edema

Preanesthetic: For use as a preanesthetic medication

Preservative-free injectable solutions:

Intractable chronic pain:

Infumorph: Used in continuous microinfusion devices for intrathecal or epidural administration in treatment of intractable chronic pain

Duramorph: For intravenous, epidural, or intrathecal administration in the management of pain for extended periods without attendant loss of motor, sensory, or sympathetic function. Note: Not for use in continuous microinfusion devices.

Extended-release tablets/capsules:

Moderate to severe chronic pain: 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: 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 formulations, reserve extended-release formulations 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. MS Contin, MorphaBond, Kadian, and Avinza are not indicated as as-needed analgesics.

Suppository:

Severe pain: For the relief of severe chronic and acute pain.

Contraindications

Note: Some contraindications are product specific. For details, please see detailed product prescribing information.

Hypersensitivity to morphine sulfate or any component of the formulation; significant respiratory depression; acute or severe bronchial asthma in an unmonitored setting or without resuscitative equipment; known or suspected paralytic ileus

Additional contraindication information (based on formulation):

Epidural/intrathecal:

Astramorph/PF, Duramorph: Upper airway obstruction

Astramorph/PF, Duramorph, Infumorph: Usual contraindications related to neuraxial analgesia apply (eg, presence of infection at infusion site, concomitant anticoagulant therapy, uncontrolled bleeding diathesis)

Extended-release tablets (MorphaBond): GI obstruction

Immediate-release tablets/solution: Hypercarbia

Injectable formulation: Heart failure due to chronic lung disease, cardiac arrhythmias; increased intracranial pressure, head injuries, brain tumors; acute alcoholism, deliriums tremens; seizure disorders; use during labor when a premature birth is anticipated

Suppository: Severe CNS depression; cardiac arrhythmias, heart failure due to chronic lung disease; increased intracranial or cerebrospinal pressure, head injuries, brain tumor; acute alcoholism, delirium tremens; seizure disorder; use after biliary tract surgery, suspected surgical abdomen, surgical anastomosis; concurrent use or within 2 weeks of MAO inhibitors

Dosing: Adult

These are guidelines and do not represent the doses that may be required in all patients. Doses and dosage intervals should be titrated to pain relief/prevention.

Acute pain (moderate to severe):

Oral (immediate-release formulations): Opioid naive: Initial: Note: Usual dosage range: 10 to 30 mg every 4 hours as needed. Patients with prior opioid exposure may require higher initial doses.

Solution: 10 to 20 mg every 4 hours as needed

Tablet: 15 to 30 mg every 4 hours as needed

IM, SubQ: Note: Repeated SubQ administration causes local tissue irritation, pain, and induration. The use of IM injections is no longer recommended especially for repeated administration due to painful administration, variable absorption and lag time to peak effect; other routes are more reliable and less painful (APS, 2008).

Initial: Opioid naive: 5 to 10 mg every 4 hours as needed; usual dosage range: 5 to 15 mg every 4 hours as needed. Patients with prior opioid exposure may require higher initial doses.

IV: Initial: Opioid naive: 2.5 to 5 mg every 3 to 4 hours; patients with prior opioid exposure may require higher initial doses. Note: Administration of 2 to 3 mg every 5 minutes until pain relief or if associated sedation, oxygen saturation <95%, or serious adverse event occurs may be appropriate in treating acute moderate to severe pain in settings such as the immediate postoperative period or the emergency department (Aubrun, 2012; Lvovschi, 2008); dose reduction in the immediate postoperative period (postanesthesia care unit) in the elderly is usually not necessary (Aubrun, 2002). A maximum cumulative dose (eg, 10 mg) prompting reevaluation of continued morphine use and/or dose should be included as part of any medication order intended for short-term use (eg, PACU orders). Refer to institution-specific protocols as appropriate.

Acute myocardial infarction, analgesia (off-label dose): Initial management: 4 to 8 mg (lower doses in elderly patients); subsequently may give 2 to 8 mg every 5 to 15 minutes as needed (O'Gara, 2012)

Critically ill patients, analgesia (off-label dose): 2 to 4 mg every 1 to 2 hours or 4 to 8 mg every 3 to 4 hours as needed (Barr, 2013)

IV, SubQ continuous infusion: Opioid tolerant: 0.8 to 10 mg/hour; usual range: Up to 80 mg/hour. Note: May administer a loading dose (amount administered should depend on severity of pain) prior to initiating the infusion. A continuous (basal) infusion is not recommended in an opioid-naive patient (ISMP 2009)

Continuous infusion for critically ill patients: Usual dosage range: 2 to 30 mg/hour (Barr, 2013)

Patient-controlled analgesia (PCA) (APS, 2008): Note: In opioid-naive patients, consider lower end of dosing range:

Usual concentration: 1 mg/mL

Demand dose: Usual: 1 mg; range: 0.5 to 2.5 mg

Lockout interval: 5 to 10 minutes

Pain management:

Epidural: Note: Must be preservative free. Administer with extreme caution and in reduced dosage to geriatric or debilitated patients. Vigilant monitoring is particularly important in these patients.

Single dose: Lumbar region: Astramorph/PF, Duramorph: 30 to 100 mcg/kg (optimal range: 2.5 to 3.75 mg; may depend upon patient comorbidities) (Bujedo 2012; Sultan 2011)

Continuous infusion (may be combined with bupivacaine): 0.2 to 0.4 mg/hour (Bujedo 2012). According to the manufacturer, Duramorph is not for use in continuous microinfusion devices.

Continuous microinfusion (Infumorph):

Opioid naive: Initial: 3.5 to 7.5 mg over 24 hours

Opioid tolerant: Initial: 4.5 to 10 mg over 24 hours, titrate to effect; usual maximum is ~30 mg per 24 hours

Intrathecal: Note: Must be preservative free. Administer with extreme caution and in reduced dosage to geriatric or debilitated patients. Intrathecal dose is usually 1/10 (one-tenth) that of epidural dosage.

Opioid naive:

Single dose: Lumbar region: Astramorph/PF, Duramorph:

Manufacturer's labeling : 0.2 to 1 mg may provide satisfactory pain relief for up to 24 hours. (Caution: This is only 0.4 to 2 mL of the 0.5 mg/mL potency or 0.2 to 1 mL of the 1 mg/mL potency.) Do not inject intrathecally more than 2 mL of the 0.5 mg/mL potency or 1 mL of the 1 mg/mL potency; repeat doses are not recommended.

Alternative recommendations: 0.1 to 0.3 mg (may provide adequate relief for up to 24 hours; APS, 2008); repeat doses are not recommended. If pain recurs within 24 hours of administration, use of an alternate route of administration is recommended. Note: Although product labeling recommends doses up to 1 mg, an analgesic ceiling exists with doses >0.3 mg and the risk of respiratory depression is higher with doses >0.3 mg (Rathmell, 2005).

Continuous microinfusion (Infumorph): Lumbar region: After initial in-hospital evaluation of response to single-dose injections of Astramorph/PF or Duramorph, the initial dose of Infumorph is 0.2 to 1 mg over 24 hours.

Opioid tolerant: Continuous microinfusion (Infumorph): Lumbar region: Dosage range: 1 to 10 mg over 24 hours, titrate to effect; usual maximum is ~20 mg over 24 hours

Note: Limited experience with continuous intrathecal infusion of morphine has shown that the daily doses have to be increased over time. Employ doses >20 mg/day with caution.

Rectal: 10 to 20 mg every 3 to 4 hours

Chronic pain: Note: Patients taking opioids chronically may become tolerant and require doses higher than the usual dosage range to maintain the desired effect. Tolerance can be managed by appropriate dose titration. There is no optimal or maximal dose for morphine in chronic pain. The appropriate dose is one that relieves pain throughout its dosing interval without causing unmanageable side effects. Consider total daily dose, potency, prior opioid use, degree of opioid experience and tolerance, conversion from previous opioid (including opioid formulation), patient’s general condition, concurrent medications, and type and severity of pain during prescribing process. 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 of oral oxymorphone daily, or an equivalent dose of another opioid for at least 1 week.

Oral (extended-release formulations): A patient's morphine requirement should be established using immediate-release formulations. Conversion to long-acting products may be considered when chronic, continuous treatment is required. Higher dosages should be reserved for use only in opioid-tolerant patients.

Capsules, extended release (Avinza): Daily dose administered once daily (for best results, administer at same time each day). Note: Avinza 90 mg and 120 mg are only indicated for use in opioid-tolerant patents.

Use as the first opioid analgesic or use in patients who are not opioid tolerant: Initial: 30 mg once daily

Titration and maintenance: Adjust in increments ≤30 mg daily every 3 to 4 days. Maximum: 1600 mg daily due to fumaric acid content.

Capsules, extended release (Kadian): Note: Kadian 100 mg, 130 mg, 150 mg, and 200 mg are only indicated for use in opioid-tolerant patients.

Use as the first opioid analgesic: Has not been evaluated. Use an immediate-release morphine formulation and then convert patients to Kadian in the same fashion as initiating therapy in a nonopioid-tolerant patient.

Use in patients who are not opioid tolerant: Initial: 30 mg once daily.

Titration and maintenance: Dose adjustments may be done every 1 to 2 days.

Tablets, extended release (MorphaBond):

Use as the first opioid analgesic: Initial: 15 mg every 12 hours.

Use in patients who are not opioid tolerant: Initial: 15 mg every 12 hours.

Titration and maintenance: Dose adjustments may be done every 1 to 2 days.

Tablets, extended release (MS Contin): Note: MS Contin 100 mg and 200 mg tablets are only indicated for use in opioid-tolerant patients.

Use as the first opioid analgesic: Initial: 15 mg every 8 to 12 hours

Use in patients who are not opioid tolerant: Initial: 15 mg every 12 hours.

Titration and maintenance: Dose adjustments may be done every 1 to 2 days.

Discontinuation of extended-release formulations: In general, gradually titrate dose downward (eg, every 2 to 4 days). Do not discontinue abruptly.

Conversion from other oral morphine formulations to extended-release formulations:

Avinza: Total daily morphine dose administered once daily. The first dose of Avinza may be taken with the last dose of the immediate-release morphine. Maximum: 1,600 mg daily due to fumaric acid content.

Kadian: Total daily oral morphine dose may be either administered once daily or in 2 divided doses daily (every 12 hours).

MorphaBond: Total daily oral morphine dose administered in 2 divided doses (every 12 hours).

MS Contin: Total daily oral morphine dose may be administered either in 2 divided doses daily (every 12 hours) or in 3 divided doses (every 8 hours).

Conversion from parenteral morphine or other opioids to extended-release formulations: Substantial interpatient variability exists in relative potency. Therefore, it is safer to underestimate a patient's daily oral morphine requirement and provide breakthrough pain relief with immediate-release morphine than to overestimate requirements. Consider the parenteral to oral morphine ratio or other oral or parenteral opioids to oral morphine conversions.

Parenteral to oral morphine ratio: Between 2 to 6 mg of oral morphine may be required for analgesia equivalent to 1 mg of parenteral morphine. An oral dose 3 times the daily parenteral dose may be sufficient in chronic pain settings.

Other parenteral or oral nonmorphine opioids to oral morphine: Specific recommendations are not available; refer to published relative potency data realizing that such ratios are only approximations. In general, it is safest to administer half of the estimated daily morphine requirement as the initial dose, and to manage inadequate analgesia by supplementation with immediate-release morphine.

Conversion from methadone to extended-release formulations: 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.

Dosing: Geriatric

Refer to adult dosing. Use with caution; may require reduced dosage in the elderly and debilitated patients.

Dosing: Pediatric

These are guidelines and do not represent the doses that may be required in all patients. Doses and dosage intervals should be titrated to pain relief/prevention.

Acute pain (moderate to severe): Note: The use of IM injections is no longer recommended, especially for repeated administration due to painful administration, variable absorption, and lag time to peak effect; other routes are more reliable and less painful (American Pain Society 2008).

Infants ≤6 months, nonventilated: Note: Infants <3 months of age are more susceptible to respiratory depression; lower doses are recommended (American Pain Society 2008):

Oral: Oral solution (2 mg/mL or 4 mg/mL): 0.08 to 0.1 mg/kg/dose every 3 to 4 hours (American Pain Society 2008; Berde 2002)

IV or SubQ: 0.025 to 0.03 mg/kg/dose every 2 to 4 hours as needed (American Pain Society 2008; Berde 2002).

Infants >6 months, Children, and Adolescents:

Oral: Immediate-release tablets, oral solution (2 mg/mL or 4 mg/mL):

Patient weight <50 kg: 0.2 to 0.5 mg/kg/dose every 3 to 4 hours as needed; some experts have recommended an initial dose of 0.3 mg/kg for severe pain; usual initial maximum dose: 15 to 20 mg (American Pain Society 2008; APA 2012; Berde 2002)

Patient weight ≥50 kg: 15 to 20 mg every 3 to 4 hours as needed (American Pain Society 2008; Berde 2002)

IM, IV, or SubQ; intermittent dosing:

Patient weight <50 kg: Initial: 0.05 mg/kg/dose; usual range: 0.1 to 0.2 mg/kg/dose every 2 to 4 hours as needed; usual maximum dose: Infants: 2 mg/dose; Children 1 to 6 years: 4 mg/dose; Children 7 to 12 years: 8 mg/dose; Adolescents: 10 mg/dose

Patient weight ≥50 kg: Initial: 2 to 5 mg every 2 to 4 hours as needed; higher doses have been recommended (5 to 8 mg every 2 to 4 hours as needed) and may be needed in tolerant patients (Berde 2002; Kliegman 2011)

Continuous IV infusion, SubQ continuous infusion:

Patient weight <50 kg: Initial: 0.01 mg/kg/hour (10 mcg/kg/hour); titrate carefully to effect; dosage range: 0.01 to 0.04 mg/kg/hour (10 to 40 mcg/kg/hour) (APA 2012; Friedrichsdorf 2007; Golianu 2000)

Patient weight ≥50 kg: 1.5 mg/hour (Berde 2002)

Conversion from intermittent IV morphine: Administer the patient's total daily IV morphine dose over 24 hours as a continuous infusion; titrate dose to appropriate effect

Analgesia for minor procedures/sedation: Infants, Children, and Adolescents: IV: 0.05 to 0.1 mg/kg/dose; administer 5 minutes before the procedure; maximum dose: 4 mg; may repeat dose in 5 minutes if necessary (Cramton 2012; Zeltzer 1990)

Patient-controlled analgesia (PCA), opioid-naive: Note: All patients should receive an initial loading dose of an analgesic (to attain adequate control of pain) before starting PCA for maintenance. Adjust doses, lockouts, and limits based on required loading dose, age, state of health, and presence of opioid tolerance. Use lower end of dosing range for opioid-naïve. Assess patient and pain control at regular intervals and adjust settings if needed (American Pain Society 2008): IV:

Children ≥5 years and Adolescents, weighing <50 kg: Note: PCA has been used in children as young as 5 years of age; however, clinicians need to assess children 5 to 8 years of age to determine if they are able to use the PCA device correctly (American Pain Society 2008).

Usual concentration: 1 mg/mL

Demand dose: Usual initial: 0.02 mg/kg/dose; usual range: 0.01 to 0.03 mg/kg/dose

Lockout: Usual initial: 5 doses/hour

Lockout interval: Range: 6 to 8 minutes

Usual basal rate: 0 to 0.03 mg/kg/hour

Children ≥5 years and Adolescents, weighing ≥50 kg:

Usual concentration: 1 mg/mL

Demand dose: Usual initial: 1 mg; usual range: 0.5 to 2.5 mg

Lockout interval: Usual initial: 6 minutes; usual range: 5 to 10 minutes

Dosing: Renal Impairment

According to the manufacturer's labeling, no specific dosage adjustments are provided (all formulations). In general, the manufacturers recommend starting cautiously with lower doses; titrating slowly while carefully monitoring for side effects . However, the choice of an alternate opioid may be prudent in patients with baseline renal impairment or rapidly changing renal function especially since other analgesics may be safer and reduced initial morphine dosing may result in suboptimal analgesia. Although clearance of morphine is similar to patients with normal renal function, glucuronide metabolites (M3G [inactive as an analgesic; may contribute to CNS stimulation] and M6G [active analgesic]) accumulate in renal impairment resulting in increased sensitivity; patients may experience severe and prolonged respiratory depression which may even be delayed (Lugo 2002; Niscola 2010).

Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturer's labeling. Pharmacokinetics unchanged in mild liver disease; substantial extrahepatic metabolism may occur. In cirrhosis, increases in half-life and AUC suggest dosage adjustment required.

Extemporaneously Prepared

A 0.4 mg/mL oral solution may be made using the 2 mg/mL oral morphine solution. Measure 10 mL (20 mg) of the 2 mg/mL oral morphine solution and transfer to a plastic amber bottle. Measure 40 mL of sterile water for irrigation and add to bottle containing the morphine. Shake to mix. Store at room temperature. Stable for 60 days.

Sauberan J, Rossi S, Kim JH. Stability of dilute oral morphine solution for neonatal abstinence syndrome. J Addict Med. 2013;7(2):113-115.23370932

Administration

Oral: Do not crush, chew, or dissolve extended release drug product; swallow whole. Kadian and Avinza capsules can be opened and sprinkled on applesauce and eaten immediately without chewing; do not crush, dissolve, or chew the beads as it can result in a rapid release of a potentially fatal dose of morphine. Ensure all pellets have been swallowed by rinsing mouth. Contents of Kadian capsules may be opened and sprinkled over 10 mL water and flushed through prewetted 16F gastrostomy tube; do not administer Kadian through gastric/nasogastric tubes.

IV: Administer single-use prefilled syringes/cartridges via slow IV push over 4 to 5 minutes (rapid administration may result in chest wall rigidity). Concentrated vials are available for preparation of continuous IV infusion or PCA; refer to indication-specific infusion rates in dosing for detailed recommendations.

Epidural, intrathecal: Use preservative-free solutions for intrathecal or epidural use. Infumorph may only be used as a continuous microinfusion via catheter. Astramorph/PF may be administered as a continuous infusion via the epidural route only. Duramorph is not for use in continuous microinfusion devices.

Dietary Considerations

Morphine may cause GI upset; take with food if GI upset occurs. Be consistent when taking morphine with or without meals.

Compatibility

Stable in dextran 6% in dextrose, dextran 6% in NS, D5LR, D51/4NS, D51/2NS, D5NS, D5W, D10W, LR, 1/2NS, NS.

Y-site administration: Incompatible with alteplase, alatrofloxacin, amphotericin B cholesteryl sulfate complex, azithromycin, doxorubicin liposome, gallium nitrate, lansoprazole, micafungin, minocycline, phenytoin, sargramostim.

Compatibility in syringe: Incompatible with haloperidol, meperidine, pantoprazole, thiopental.

Storage

Capsule, extended release: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light and moisture.

Injection: Store at controlled room temperature of 20°C to 25°C (68°F to 77°F); do not freeze. Protect from light. Degradation depends on pH and presence of oxygen; relatively stable in pH ≤4; darkening of solutions indicate degradation.

Astramorph/PF, Duramorph, Infumorph: Store in carton until use at controlled room temperature of 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F); do not freeze; do not heat-sterilize. Contains no preservative or antioxidant. Protect from light.

Oral solution: Store at controlled room temperature of 15°C to 30°C (59°F to 86°F); do not freeze. Protect from moisture.

Suppositories: Store below controlled room temperature 25°C (77°F).

Tablet, extended release: Store at controlled room temperature of 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Tablet, immediate release: Store at controlled room temperature of 15°C to 30°C (59°F to 86°F). Protect from moisture.

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): 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

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

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 (Systemic): 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: May enhance the CNS depressant effect of CNS Depressants. CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. 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

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

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

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 [INT]: CNS Depressants may enhance the CNS depressant effect of Piribedil [INT]. 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

Some quinolones may produce a false-positive urine screening result for opioids using commercially-available immunoassay kits. This has been demonstrated most consistently for levofloxacin and ofloxacin, but other quinolones have shown cross-reactivity in certain assay kits. Confirmation of positive opioid screens by more specific methods should be considered.

Adverse Reactions

Note: Individual patient differences are unpredictable and percentage may differ in acute pain (surgical) treatment. Reactions may be dose, formulation, and/or route dependent.

Frequency not always defined.

>10%

Cardiovascular: Oxygen saturation decreased

Central nervous system: Drowsiness (9% to >10%), headache (<2% to >10%)

Gastrointestinal: Constipation (9% to >10%), nausea (7% to >10%), vomiting (2% to >10%)

Genitourinary: Urinary retention (<2% to 16%; primarily in males; may be prolonged, up to 20 hours, following epidural or intrathecal use)

Hypersensitivity: Histamine release

Local: Pain at injection site

Neuromuscular & skeletal: Weakness

1% to 10%:

Cardiovascular: Peripheral edema (3% to 10%), chest pain (2% to <3%), atrial fibrillation (<2% to <3%), bradycardia (<2%), edema (<2%), facial flushing (<2%), flushing (<2%), hypertension (<2%), hypotension (<2%), palpitations (<2%), syncope (<2%), tachycardia (<2%), vasodilatation (<2%), circulatory depression, orthostatic hypotension, presyncope, shock

Central nervous system: Depression (5% to 10%), insomnia (<2% to 10%), paresthesia (<2% to 10%), dizziness (6%), anxiety (<2% to 6%), abnormality in thinking (<2% to <5%), confusion (<2% to <5%), convulsions (<5%), pain (3%), agitation (<2%), amnesia (<2%), apathy (<2%), ataxia (<2%), chills (<2%), decreased cough reflex (<2%), dream abnormalities (<2%), euphoria (<2%), hallucination (<2%), hypoesthesia (<2%), lack of concentration (<2%), lethargy (<2%), malaise (<2%), myoclonus (<2%), seizure (<2%), slurred speech (<2%), vertigo (<2%), voice disorder (<2%), withdrawal syndrome (<2%), abnormal gait, apprehension, coma, delirium, drug dependence, dysphoria, false sense of well-being, feeling abnormal, mood changes, nervousness, restlessness, rigors, sedation

Dermatologic: Diaphoresis (5% to 10%), skin rash (3% to 10%), decubitus ulcer (<2%), pallor (<2%), pruritus (<2%, may be dose related), urticaria, xeroderma

Endocrine & metabolic: Gynecomastia (<2% to <3%), amenorrhea (<2%), decreased libido (<2%), hyponatremia (<2%), antidiuretic effect, hypogonadism, hypokalemia, increased release of antidiuretic hormone, increased thirst, weight loss

Gastrointestinal: Abdominal pain (5% to 10%), diarrhea (5% to 10%), anorexia (3% to 10%), xerostomia (3% to 10%), biliary colic (<2%), delayed gastric emptying (<2%), dyspepsia (<2%), dysphagia (<2%), gastric atony (<2%), gastroesophageal reflux disease (<2%), hiccups (<2%), abdominal distension, dysgeusia, flatulence, gastroenteritis, GI irritation, paralytic ileus, rectal disease

Genitourinary: Urinary tract infection (5% to 10%), impotence (<2%), prolonged labor (<2%), urinary hesitancy (<2%), urine abnormality (<2%), abnormal ejaculation, bladder spasm, decreased urine output, dysuria, hypogonadism, oliguria

Hematologic & oncologic: Anemia (2% to <5%), thrombocytopenia (<2% to <5%), leukopenia (2%), hematocrit decreased

Hepatic: Increased liver function enzymes

Hypersensitivity: Hypersensitivity reaction

Infection: Infection

Local: Local irritation

Neuromuscular & skeletal: Back pain (<2% to 10%), asthenia (2%), tremor (2%), arthralgia (<2%), bone pain (<2%), foot-drop (<2%), decreased bone mineral density, muscle rigidity, muscle twitching

Ophthalmic: Amblyopia (<2%), blurred vision (<2%), conjunctivitis (<2%), diplopia (<2%), miosis (<2%), nystagmus (<2%), eye pain, visual disturbance

Respiratory: Dyspnea (3% to 10%), flu-like symptoms (<2% to 10%), hypoventilation (<5%), asthma (<2%), atelectasis (<2%), hypoxia (<2%), pulmonary edema (noncardiogenic, <2%), respiratory depression (<2%), respiratory insufficiency (<2%), rhinitis (<2%), hypercapnia

Miscellaneous: Accidental injury (2% to 10%), fever (2% to 10%)

<1% (Limited to important or life-threatening): Anaphylaxis, apnea, biliary tract spasm, bronchospasm, decreased cough reflex, dehydration, disorientation, disruption of body temperature regulation, genitourinary tract spasm, hemorrhagic urticaria, hyperalgesia, hypertonia, increased intracranial pressure, intestinal obstruction, laryngospasm, menstrual irregularities, myoclonus, paradoxical central nervous system stimulation, sepsis, toxic psychoses

ALERT: U.S. Boxed Warning

Risk of overdose (Infumorph):

Infumorph is not recommended for single-dose intravenous (IV), intramuscular (IM), or subcutaneous administration because of the very large amount of morphine in the ampul and the associated risk of overdosage.

Product interchange (Infumorph):

Improper or erroneous substitution of Infumorph 200 or 500 (10 or 25 mg/mL, respectively) for regular Duramorph (0.5 or 1 mg/mL) is likely to result in serious overdosage, leading to seizures, respiratory depression and, possibly, fatal outcome.

Intrathecal use (Duramorph):

Intrathecal dosage is usually 1/10 that of epidural dosage.

Appropriate administration (Infumorph, Duramorph):

Because of the risk of severe adverse effects when the epidural or intrathecal route of administration is employed, patients must be observed in a fully equipped and staffed environment for at least 24 hours after the initial dose.

Infumorph: Naloxone injection and resuscitative equipment should be immediately available for use in case of case of life-threatening or intolerable side effects and whenever Infumorph therapy is being initiated, the reservoir is being refilled or any manipulation of the reservoir system is taking place.

Duramorph: Naloxone injection and resuscitative equipment should be immediately available for administration in case of life-threatening or intolerable side effects and whenever Duramorph therapy is being initiated.

Safety and handling (Infumorph, Duramorph):

Infumorph and Duramorph are supplied in sealed ampuls. Accidental dermal exposure should be treated by the removal of any contaminated clothing and rinsing the affected area with water.

Each ampul of Infumorph and Duramorph contains a large amount of a potent narcotic which has been associated with abuse and dependence among health care providers. Due to the limited indications for this product, the risk of overdosage and the risk of its diversion and abuse, it is recommended that special measures be taken to control this product within the hospital or clinic. Infumorph and Duramorph should be subject to rigid accounting, rigorous control of wastage and restricted access.

Parenteral drug products should be inspected for particulate matter before opening the amber ampul and again for color after removing contents from the ampul. Do not use if the solution in the unopened ampul contains a precipitate which does not disappear upon shaking. After removal, do not use unless the solution is colorless or pale yellow.

Ethanol use (Avinza, Kadian):

Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products that contain alcohol while taking morphine extended-release (ER) capsules. The coingestion of alcohol with morphine ER may result in increased plasma levels and a potentially fatal overdose of morphine.

Addiction, abuse, and misuse (Avinza, Kadian, MorphaBond, MS Contin):

Morphine 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 ER and monitor all patients regularly for the development of these behaviors or conditions.

Respiratory depression (Avinza, Kadian, MorphaBond, MS Contin):

Serious, life-threatening, or fatal respiratory depression may occur with use of morphine ER. Monitor for respiratory depression, especially during initiation of morphine ER or following a dose increase. Instruct patients to swallow morphine ER formulations whole; Avinza capsule contents may be sprinkled on applesauce and swallowed immediately without chewing. Crushing, chewing, or dissolving the tablets or contents within the capsule can cause rapid release and absorption of a potentially fatal dose of morphine.

Neonatal opioid withdrawal syndrome (Avinza, Kadian, MorphaBond, MS Contin):

Prolonged use of morphine 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.

Accidental ingestion (Avinza, Kadian, MorphaBond, MS Contin):

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

Risk of medication errors (oral solution):

Morphine oral solution is available in 10 mg per 5 mL, 20 mg per 5 mL, and 100 mg per 5 mL (20 mg/mL) concentrations.

The 100 mg per 5 mL (20 mg/mL) concentration is indicated for use in opioid-tolerant patients only.

Take care when prescribing and administering morphine oral solution to avoid dosing errors due to confusion between different concentrations and between milligrams and milliliters, which could result in accidental overdose and death. Take care to ensure the proper dose is communicated and dispensed.

Keep morphine oral solution out of the reach of children. In case of accidental ingestion, seek emergency medical help immediately.

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 hypotension; use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), circulatory shock, or drugs that may exaggerate hypotensive effects (including phenothiazines or general anesthetics). May cause orthostatic hypotension and syncope in ambulatory patients.

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

• Respiratory depression: All morphine sulfate formulations are capable of causing respiratory depression; risk increased in elderly patients, debilitated patients, and patients with conditions associated with hypoxia or hypercapnia. Monitor for respiratory depression especially during initiation and titration.

- Extended-release formulations: [US Boxed Warning]: May cause serious, life-threatening, or fatal respiratory depression. Monitor closely for respiratory depression, especially during initiation or dose escalation. Instruct patients to swallow extended-release morphine formulations whole (or may sprinkle the contents of the Avinza capsule on applesauce and swallow without chewing); crushing, chewing, or dissolving the extended-release formulations can cause rapid release and absorption of a potentially fatal dose of morphine. 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. May worsen gastrointestinal ileus due to reduced GI motility. Contraindicated in patients with paralytic ileus; avoid use in patients with GI obstruction.

• Abuse/misuse/diversion: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance and psychological and physical dependence may occur with prolonged use.

- Chronic pain: Use opioids with caution in patients at increased risk for misuse; factors associated with increased risk include previous substance use disorder, 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]).

- Extended-release formulations: [US Boxed Warning]: Users are exposed 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. Risk of opioid abuse is increased in patients with a history or family history of alcohol or drug abuse or mental illness.

• Adrenal insufficiency: Use with caution in patients with adrenal insufficiency, including Addison's disease. Chronic 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 including acute pancreatitis. Use may cause constriction of sphincter of Oddi diminishing biliary and pancreatic secretions.

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

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

• Increased intracranial pressure (ICP): Use with extreme caution in patients with head injury, intracranial lesions, or elevated ICP; exaggerated elevation of ICP may occur if respiratory drive is depressed and CO2 retention occurs. Some dosage forms are contraindicated with increased ICP or head trauma.

• 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.

• 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 with morphine; even therapeutic doses may decrease respiratory drive to the point of apnea. Consider the use of alternative nonopioid analgesics in these patients. Some dosage forms may be contraindicated in patients with severe respiratory disorders.

• 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]).

• Seizure disorders: Use with caution in patients with seizure disorders; may cause or exacerbate preexisting seizures. Some dosage forms may be contraindicated in patients with seizure disorder.

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

Concurrent drug therapy issues:

• 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.

• Sedatives: Effects may be potentiated when used with other CNS depressants (eg, sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). In the setting of chronic pain, avoid prescribing opioids and benzodiazepines concurrently whenever possible; epidemiologic studies suggest there is an increased risk for potentially fatal overdose with concurrent use (Dowell [CDC 2016]).

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.

• Elderly: Use with caution in elderly patients; may be more sensitive to adverse effects, including life-threatening respiratory depression. Decrease initial dose. Use epidural/intrathecal formulations (Astramorph/PF, Duramorph, Infumorph) with extreme caution in elderly patients. 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]).

• Neonates: Neonatal withdrawal syndrome: Extended-release formulations: [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, 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.

• Pediatric: Infants <3 months of age, especially if premature, are more susceptible to respiratory depression and/or apnea; use with caution and generally in reduced doses in this age group.

Dosage form specific issues:

• Appropriate administration: Astramorph/PF, Duramorph, Infumorph: [US Boxed Warning]: Due to the risk of severe and/or sustained cardiopulmonary depressant effects of Astramorph/PF, Duramorph, and Infumorph, they must be administered in a fully equipped (ie, for resuscitation) and staffed environment. Naloxone injection should be immediately available. Patient should remain in this environment for at least 24 hours following the initial dose. For patients receiving Infumorph via microinfusion device, patient may be observed, as appropriate, for the first several days after catheter implantation. Thoracic epidural administration has been shown to dramatically increase the risk of early and late respiratory depression. [US Boxed Warning]: Accidental dermal exposure to Astramorph/PF, Duramorph, and Infumorph should be rinsed with water. Contaminated clothing should be removed. Prior to administration, inspect parenteral products for particulate matter and discoloration if possible. Do not use if color is darker than pale yellow or if discolored.

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors, 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer’s labeling.

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

• Extended-release formulations: Therapy should only be prescribed by health care professionals familiar with the use of potent opioids for chronic pain. Extended-release products are not interchangeable. When determining a generic equivalent or switching from one extended-release product to another, a thorough understanding of the pharmacokinetic properties is important in determining the proper generic equivalent or proper dose of the other extended-release product (review of the manufacturer's label may be necessary).

- Avinza capsules: Dosage form contains fumaric acid; dangerous quantities of fumaric acid may be ingested when >1600 mg/day is used. Serious renal toxicity may occur above the maximum dose.

• Highly concentrated oral solutions: [US Boxed Warning]: Check doses carefully when using highly concentrated oral solutions. The 100 mg/5 mL (20 mg/mL) concentration is indicated for use in opioid-tolerant patients only.

• Injections: Products are designed for administration by specific routes (ie, IV, intrathecal, epidural). Use caution when prescribing, dispensing, or administering to use formulations only by intended route(s).

• Product interchange: Infumorph solutions: [US Boxed Warning]: Improper or erroneous substitution of Infumorph for regular Duramorph is likely to result in serious overdosage, leading to seizures, respiratory depression, and possibly a fatal outcome. Infumorph should only be used in microinfusion devices; not for IV, IM, or SubQ administration or for single-dose administration. Monitor closely, especially in the first 24 hours. Inflammatory masses (eg, granulomas), some resulting in severe neurologic impairment have occurred when receiving Infumorph via indwelling intrathecal catheter; monitor carefully for new neurologic signs/symptoms.

• Sulfites: Some intravenous preparations contain sulfites that may cause allergic reactions in sulfite sensitive patients.

Other warnings/precautions:

• Accidental exposure: Extended-release formulations: [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 non-opioid 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]).

• Epidural use: Astramorph/PF, Duramorph, Infumorph: When used as an epidural injection, monitor for delayed sedation and respiratory depression. Physician should evaluate patient for contraindications for epidural injection (eg, anticoagulant therapy, bleeding, diathesis, etc).

• Intrathecal: Astramorph/PF, Duramorph, Infumorph: [US Boxed Warning]: Intrathecal dosage is usually 1/10 (one-tenth) that of epidural dosage.

• 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.

• 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. Abrupt discontinuation following prolonged use may also lead to withdrawal symptoms; taper dose gradually when discontinuing.

Monitoring Parameters

Assess efficacy of pain control, vital signs, and mental status; signs of drug abuse, addiction, or diversion; signs or symptoms of hypogonadism or hypoadrenalism with long-term use (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 o f 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 with consideration for re-checking 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]).

Astramorph/PF, Duramorph, Infumorph: Patients should be observed in a fully equipped and staffed environment for at least 24 hours following initiation, and as appropriate for the first several days after catheter implantation. Naloxone injection should be immediately available. Patient should remain in this environment for at least 24 hours following the initial dose. For patients receiving Infumorph via microinfusion device, patient may be observed, as appropriate, for the first several days after catheter implantation.

Alternative monitoring recommendations (Bujedo 2012): Epidural: Note: All patients receiving neuraxial opioids should be monitored for adequate ventilation (eg, respiratory rate, depth of respiration [without disturbing patient]), oxygenation (eg, pulse oximetry when appropriate), and level of consciousness.

Single dose: Monitor patient for a minimum of 24 hours after administration with a frequency of at least once per hour for the first 12 hours after administration, followed by at least once every 2 hours for the next 12 hours (ie, from 12 to 24 hours after administration). After 24 hours, frequency dictated by overall clinical condition and concurrent medications.

Continuous infusion or patient controlled epidural analgesia (PCEA): Monitor patient during the entire duration of the infusion with a frequency of at least once per hour for the first 12 hours, followed by at least once every 2 hours for the next 12 hours (ie, from 12 to 24 hours after administration). After 24 hours, monitor at least once every 4 hours. After discontinuation of infusion or PCEA, frequency dictated by overall clinical condition and concurrent medications.

Note: Also refer to institution specific protocols as appropriate.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. Morphine crosses the human placenta. The frequency of congenital malformations has not been reported to be greater than expected in children from mothers treated with morphine during pregnancy. However, following in utero exposure, infants may exhibit withdrawal, decreased brain volume (reversible), small size, decreased ventilatory response to CO2, and increased risk of sudden infant death syndrome.

Morphine sulfate injection may be used for the management of pain during labor (ACOG, 2002); however, some manufacturers specifically contraindicate use of the injection during labor when a premature birth is anticipated. When used for pain relief during labor, opioids may temporarily affect the heart rate of the fetus. Morphine injection may also be used to treat pain following delivery (ACOG, 2002).

[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. If chronic opioid exposure occurs in pregnancy, adverse events in the newborn (including withdrawal) may occur; monitoring of the neonate is recommended. The minimum effective dose should be used if opioids are needed (Chou, 2009). Neonatal abstinence syndrome following opioid exposure may present with autonomic (eg, fever, temperature instability), gastrointestinal (eg, diarrhea, vomiting, poor feeding/weight gain), or neurologic (eg, high-pitched crying, increased muscle tone, irritability, seizure, tremor) symptoms (Dow, 2012; Hudak, 2012).

Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction or infertility (Brennan, 2013).

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 dry mouth, nausea, vomiting, headache, anxiety, abdominal pain, sweating a lot, or tablet shell in stool. Have patient report immediately to prescriber difficulty breathing, slow breathing, shallow breathing, noisy breathing, severe dizziness, passing out, angina, tachycardia, seizures, severe constipation, loss of strength and energy, mood changes, or severe fatigue (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 health care 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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