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Morphine: Drug information

Morphine: Drug information
(For additional information see "Morphine: Patient drug information" and see "Morphine: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Risks with neuroaxial administration (Infumorph, Duramorph, Mitigo):

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. Single-dose Duramorph neuraxial administration may result in acute or delayed respiratory depression for up to 24 hours. Monitor patients receiving Infumorph or Mitigo, as appropriate, for the first several days after catheter implantation.

Ethanol use (extended-release capsules):

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:

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

Opioid analgesic Risk Evaluation and Mitigation Strategy (REMS):

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the FDA has required a REMS for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS compliant education programs available to health care providers. Health care providers are strongly encouraged to complete a REMS-compliant education program; counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products; emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist; and consider other tools to improve patient, household, and community safety.

Life-threatening respiratory depression:

Serious, life-threatening, or fatal respiratory depression may occur with use of morphine. Monitor for respiratory depression, especially during initiation of morphine or following a dose increase. Swallow morphine ER formulations whole. ER 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. Because of delay in maximum CNS effect with IV administration (30 minutes), rapid IV administration may result in overdosing. Observe patients in a fully equipped and staffed environment for at least 24 hours after each test dose of Infumorph or Mitigo and, as indicated, for the first several days after surgery.

Neonatal opioid withdrawal syndrome:

Prolonged use of morphine 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:

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):

Ensure accuracy when prescribing, dispensing, and administering morphine oral solution. Dosing errors due to confusion between mg and mL, and other morphine solutions of different concentrations, can result in accidental overdose and death

Risks from concomitant use with benzodiazepines or other CNS depressants:

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

Brand Names: US
  • Arymo ER [DSC];
  • Duramorph;
  • Infumorph 200;
  • Infumorph 500;
  • Kadian [DSC];
  • Mitigo;
  • MorphaBond ER [DSC];
  • MS Contin
Brand Names: Canada
  • BAR-Morphine SR;
  • Doloral 1;
  • Doloral 5;
  • Kadian;
  • Kadian SR;
  • M-Ediat;
  • M-Eslon;
  • Morphine Extra Forte [DSC];
  • Morphine Forte [DSC];
  • Morphine LP Epidural;
  • Morphine SR [DSC];
  • Morphine Sulfate SDZ;
  • Morphine-Epd [DSC];
  • MS Contin;
  • MS/IR;
  • SANDOZ Morphine SR;
  • Statex;
  • TEVA-Morphine SR
Pharmacologic Category
  • Analgesic, Opioid
Dosing: Adult

Note: Arymo ER and MorphaBond ER have been discontinued in the United States for >1 year.

Note: When used for managing moderate to severe pain, opioids may be part of a comprehensive, multimodal, patient-specific treatment plan for pain. Maximize nonopioid analgesia, if appropriate, prior to initiation of opioid analgesia (Ref). Dosing provided is based on typical doses and some patients may require higher or lower doses. Individualize dosing and dosing intervals based on patient-specific factors (eg, comorbidities, severity of pain, concomitant medications, cachexia, general condition, degree of opioid experience/tolerance) and titrate to patient-specific treatment goals (eg, improvement in function and quality of life, decrease in pain using a validated pain rating scale). Use the lowest effective dose for the shortest period of time. For acute non-cancer-related pain severe enough to require an opioid, utilize multimodal pain control, maximize nonopioid analgesics, and limit the quantity prescribed to the expected duration of acute pain; a quantity sufficient for ≤3 days is often adequate, whereas >7 days is rarely needed. Do not use long-acting preparations for treatment of acute pain in opioid-naive patients (Ref). Before starting opioid therapy for chronic pain, establish realistic goals for pain and function, and consider how therapy will be discontinued if benefits do not outweigh risks (Ref).

Acute coronary syndrome, refractory ischemic chest pain

Acute coronary syndrome, refractory ischemic chest pain:

Note: Use only in patients with continued ischemic chest pain despite maximally tolerated anti-ischemic medications (Ref). Routine use in patients with acute coronary syndrome has been associated with worse clinical outcomes, and concomitant use with oral P2Y12 inhibitors may diminish antiplatelet effects (Ref).

IV: 2 to 4 mg initially, followed by 2 to 8 mg every 5 to 15 minutes as needed (Ref) or 1 to 5 mg initially, followed by 1 to 5 mg every 5 to 30 minutes as needed (Ref).

Acute pain in opioid-naive patients

Acute pain in opioid-naive patients:

General dosing: Note: Dosing presented in this section is for opioid-naive patients. Patients who are opioid-tolerant will likely require higher dosing; adjust doses accordingly (Ref).

Oral: Opioid-naive patients:

Immediate release: Oral solution, Tablet:

Note: Consider the use of other more commonly prescribed oral opioids (eg, oxycodone) instead of morphine (Ref). The 100 mg/5 mL (or 20 mg/mL) concentrated oral solution is not intended for opioid-naive patients.

Initial: 10 mg every 4 hours as needed; if pain is not relieved, may increase dose as tolerated. May give up to 30 mg every 4 hours as needed for severe, acute pain in hospitalized patients at low risk for respiratory depression (Ref).

IV: Opioid-naive patients:

Intermittent: Initial: 1 to 4 mg every 1 to 4 hours as needed; if pain is not relieved, may increase dose as tolerated. May give up to 10 mg every 4 hours as needed for severe, acute pain in hospitalized patients at low risk for respiratory depression (Ref). For some severe acute pain episodes (eg, trauma), may initially give more frequently (eg, every 5 to 15 minutes) if needed and titrate to pain relief; once pain relief is achieved, reduce frequency (eg, every 3 to 4 hours as needed) (Ref). Note: When IV access is not available, SUBQ administration using similar dosing may be considered; however, repeated intermittent SUBQ injections cause local tissue irritation, pain, and induration and are not recommended (Ref).

Patient-controlled analgesia (Ref) :

Morphine: Example IV Patient-Controlled Analgesia Initial Dose Ranges for Opioid-Naive Patientsa

aFor use to maintain pain control after initial pain control achieved. May adjust dosing and provide rescue bolus doses (eg, 0.5 to 2 mg) if analgesia is inadequate (Mariano 2019).

bThe use of a continuous background infusion for patient-controlled analgesia is generally not recommended for most patients because of the risk of respiratory depression, and use should be limited to carefully selected patients who are opioid tolerant and/or receiving care in a critical care unit, or if required to maintain baseline opioid dosing during intervals when oral or transdermal opioid administration is not possible (Arnold 2019; Mariano 2019).

Usual concentration

1 mg/mL

Demand dose

Usual range: 0.5 to 2 mg

Basal dose

In general, a continuous (basal) infusion is not recommended in an opioid-naive patient (ISMP 2009)b

Lockout interval

5 to 10 minutes

Maximum cumulative dose

7.5 mg within 1 hour (or 30 mg within a 4-hour period)

IM (not recommended for routine use): Opioid-naive patients: Initial: 5 to 10 mg every 3 to 4 hours as needed; if pain is not relieved, may increase dose as tolerated. Note: IM administration is generally not recommended due to pain associated with injection, variable absorption, and delayed time to peak effect (Ref).

Rectal (may be used as an alternative to IV or oral administration): Opioid-naive patients: Initial: 10 mg every 4 hours scheduled or as needed; may increase or decrease the dose as tolerated following the same precautions as oral dosing up to 30 mg every 4 hours scheduled or as needed.

Acute pain in patients on chronic opioid therapy for pain

Acute pain (eg, breakthrough cancer pain) in patients on chronic opioid therapy for pain:

Oral, IV, SUBQ: Usual dose: In conjunction with the scheduled long-acting opioid, administer 5% to 20% of the basal daily morphine milligram equivalents (MME) requirement given as needed using an IR formulation with subsequent dosage adjustments based upon response (Ref).

Acute postoperative pain

Acute postoperative pain:

Initial pain control in the post-anesthesia care unit: IV: 1 to 3 mg given as frequently as every 5 minutes until adequate pain relief or unwanted side effects (eg, respiratory depression, oxygen desaturation, hypotension) occur. Note: A maximum cumulative dose (eg, 20 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, post-anesthesia care unit orders); refer to institution-specific protocols as appropriate (Ref).

Ongoing pain control: IV: 1 to 4 mg every 1 to 4 hours as needed; may give up to 10 mg every 2 to 4 hours as needed for severe, acute pain in patients at low risk for respiratory depression (Ref). If patient-controlled analgesia is needed, refer to Example IV Patient-Controlled Analgesia Initial Dose Ranges for Opioid-Naive Patients table.

Acute vaso-occlusive pain in sickle cell disease

Acute vaso-occlusive pain in sickle cell disease:

Note: Dosing presented is for patients in emergency department and hospital settings (including day hospitals) whose previous opioid dose for prior episodes is unknown or who rarely require opioids for pain management. If opioid dose given for a prior episode is known, choose initial dose based on intensity of pain in comparison with previous episode and previous effective dose (Ref).

IV: Initial: 0.1 to 0.15 mg/kg (maximum initial dose: 10 mg) given once within 30 minutes of presentation, reassess pain within 20 minutes; if continued severe pain, may repeat with doses of 0.02 to 0.05 mg/kg every 20 to 30 minutes to achieve pain relief (Ref). If IV access is difficult, may administer SUBQ (Ref). If pain relief is not achieved after ≥3 doses, hospitalization for around-the-clock parenteral analgesics is generally indicated. Evaluate need for long-acting opioid; if patient usually requires a long-acting opioid at home, may convert to oral home regimen once IV dose is roughly equivalent to long-acting opioid dose (Ref).

Chronic pain, including chronic cancer pain

Chronic pain, including chronic cancer pain:

Note: Opioids, including morphine, are not the preferred therapy for chronic noncancer pain due to insufficient evidence of benefit and risk of serious harm; nonpharmacologic treatment and nonopioid analgesics are preferred, with the exception of chronic pain from sickle cell disease and end-of-life care. Opioids, including morphine, should only be considered in patients who experience clinically meaningful improvement in pain and function that outweighs patient safety risks (Ref).

Opioid-naive patients: In general, for noncancer pain, morphine requirement should be established using IR formulations (Ref). With cancer pain, may switch to a long-acting formulation earlier in the course of therapy (Ref).

Oral: Immediate release: Oral solution, tablet: Note: The 100 mg/5 mL (or 20 mg/mL) concentrated oral solution is not intended for opioid-naive patients.

Noncancer or cancer pain: Initial: 5 to 30 mg every 4 hours as needed or scheduled around the clock for some patients (eg, cancer pain) (Ref). For chronic noncancer pain, most patients will have pain control with initial doses <50 mg/day (Ref).

Titration: For chronic noncancer pain, may increase the dose slowly in increments of no more than 25% to 50% of the total daily dose (Ref). For chronic cancer pain, may increase the fixed scheduled dose by 30% to 100% of the total dose taken in the prior 24-hour period, while taking into consideration the total amount of rescue medication used; if pain score decreased, continue current effective dosing (Ref). Note: In order to reduce risk of overdose, use caution when increasing opioid dosage to ≥50 MME/day and avoid increasing dosage to ≥90 MME/day or carefully justify a decision to titrate dosage to ≥90 MME/day (Ref).

IV, SUBQ: Note: Typically reserved for acute exacerbations or those who cannot tolerate oral administration. For progressive illnesses (eg, cancer), a continuous IV or SUBQ infusion, with or without a patient-controlled analgesia option, can also be used as pain requirements increase. In general, SUBQ dose is equivalent to IV dose (Ref). Individualize dose based on patient's previous opioid intake and appropriate opioid analgesic equivalents; titrate further, if needed, based on level of pain.

Noncancer or cancer pain: IV: Initial: 2 to 5 mg every 2 to 4 hours as needed (Ref).

Cancer pain or palliative care: SUBQ: Initial: 2 to 5 mg every 3 to 4 hours as needed (Ref). If a continuous SUBQ infusion is employed, refer to institutional protocols; reported dosing varies greatly and is based on practice and patient needs (Ref).

Opioid-tolerant patients (also refer to the section Dose conversions for pain management):

Oral: Extended release:

Note: Although manufacturer's labeling contains directions for initiating ER morphine products in opioid-naive patients with chronic pain, these preparations should not be used as initial therapy. Instead, treatment should be initiated with an IR preparation to more accurately determine the daily opioid requirement and decrease the risk of overdose. Unless pain is associated with cancer, palliative care, or sickle cell disease, the Centers for Disease Control and Prevention recommends that ER opioids be reserved for patients who have received IR opioids daily for ≥1 week yet continue to experience severe, continuous pain (Ref).

Capsules, extended release (Kadian): See Dose conversions for pain management: Calculated dose may be administered once daily or in 2 equally divided doses administered every 12 hours; may consider dose reduction with first several doses when converting from IR formulations. Example initial dose: 30 mg once daily or 15 mg every 12 hours. Dose adjustments may be made as frequently as every 1 to 2 days. Note: For generic ER capsules, some products are unique with varying dosing, schedule, and titration recommendations; refer to product labeling for specific ER capsule product information.

Tablets, extended release (Arymo ER, MorphaBond ER, MS Contin): See Dose conversions for pain management: Calculated dose may be administered in 2 equally divided doses (every 12 hours) or 3 equally divided doses (every 8 hours); may consider dose reduction with first several doses when converting from IR formulations. Example initial dose: 15 mg every 8 or 12 hours. Dose adjustments may be made as frequently as every 1 to 2 days.

Dose conversions for pain management: Note: Equianalgesic conversions serve only as a general guide to estimate opioid dose equivalents. Multiple factors must be considered for safely individualizing conversion of opioid analgesia. In general, for noncancer pain, the decision to convert from an IR to an ER formulation should be individualized and reserved for those with severe continuous pain who have been taking opioids for ≥1 week (Ref).

Converting from oral morphine to parenteral morphine:

Approximate equivalency: 30 mg (oral morphine): 10 mg (IV/SUBQ morphine) (Ref).

Converting from oral IR morphine to oral ER morphine preparations:

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

Kadian: Total daily oral morphine dose administered once daily; in patients experiencing inadequate analgesia with once-daily dosing, total daily dose can be administered in 2 divided doses (every 12 hours).

Converting from oral morphine to rectal morphine:

Although the bioavailability of rectal morphine is believed to approximate oral morphine (ie, 1:1), absorption is variable and may be higher or lower than expected. Therefore, when switching from oral to rectal dosing, a reduction in rectal dose may be necessary (Ref).

Converting to/from morphine (parenteral or oral) to/from a different opioid (parenteral or oral):

Refer to published equianalgesic opioid conversion data for guidance (or refer to institutional protocols). Provided conversion ratios are only approximations and substantial interpatient variability exists; therefore, it is safer to underestimate a patient's daily oral requirement and provide breakthrough pain relief with IR formulations rather than risk overestimating daily requirements. When switching to a new opioid (except to/from methadone), reduce the initial daily calculated equianalgesic dose of the new opioid by 25% to 50% to adjust for lack of complete mu receptor cross-tolerance (conversions to/from methadone are highly variable and require extreme caution) (Ref).

Discontinuation or tapering of therapy:

When discontinuing or tapering long-term opioid therapy, the dose should be gradually tapered. An optimal tapering schedule has not been established (Ref). Proposed schedules range from slow (eg, 10% reduction per week or 10% reduction per month depending on duration of long-term therapy) to rapid (eg, 25% to 50% reduction every few days) (Ref). Individualize based on discussions with patient to minimize withdrawal while considering patient-specific goals and concerns as well as the opioid’s pharmacokinetics. Slower tapers may be appropriate after long-term use (eg, years), particularly in the final stage of tapering, whereas more rapid tapers may be appropriate in patients experiencing severe adverse effects (Ref). Monitor carefully for signs/symptoms of withdrawal. If the patient displays withdrawal symptoms, consider slowing the taper schedule; alterations may include increasing the interval between dose reductions, decreasing amount of daily dose reduction, pausing the taper and restarting when the patient is ready, and/or coadministration of an alpha-2 agonist (eg, clonidine) to blunt withdrawal symptoms (Ref). Continue to offer nonopioid analgesics as needed for pain management during the taper; consider nonopioid adjunctive treatments for withdrawal symptoms (eg, GI complaints, muscle spasm) as needed (Ref).

Critically ill patients in the ICU, pain and sedation

Critically ill patients in the ICU, pain and sedation (off-label use):

Note: Multimodal approaches (eg, a combination of analgesics and techniques) should typically be employed for pain control in this setting. Pain should be monitored using validated scales (eg, behavioral pain scale, critical-care observation tool) in medical, postoperative, or trauma (excluding brain injury) ICU patients who are unable to self-report (Ref).

IV:

Loading dose: 2 to 10 mg, followed by maintenance dosing (Ref). Note: More than 1 loading dose may be needed; onset of action following IV administration is 5 to 10 minutes. Reduce or omit initial loading dose in select patients (eg, older, hypovolemic, at-risk for hemodynamic compromise) (Ref).

Maintenance dosing: 2 to 4 mg every 1 to 2 hours or 4 to 8 mg every 3 to 4 hours (Ref).

Dyspnea in palliative care patients

Dyspnea in palliative care patients (off-label use):

Opioid-naive patients:

Moderate dyspnea:

Oral, sublingual: Immediate release (may use 100 mg/5 mL [20 mg/mL] solution): Initial: 2 mg every 2 hours as needed or 5 mg every 4 hours with 2.5 mg every 2 hours as needed or on an “offer, may refuse” basis (most patients will not need every dose) (Ref).

SUBQ: Initial: 2 mg every 2 hours as needed or on an “offer, may refuse” basis (most patients will not need every dose) (Ref).

Severe dyspnea: SUBQ, IV: Initial: 2.5 mg; if dyspnea persists and initial dose is well tolerated, may repeat every 30 to 60 minutes (SubQ) or every 15 to 30 minutes (IV). If 2 doses are well tolerated but fail to reduce dyspnea adequately, the dose may be doubled (Ref).

Opioid-tolerant patients: Note: Higher initial doses will likely be needed.

Moderate or severe dyspnea: Immediate release: Oral: Consider giving 10% to 15% of the basal daily opioid requirement (calculated in morphine equivalents) every 2 hours as needed or on an “offer, may refuse” basis. Consider increasing the regular daily dose by ~25% taking into consideration breakthrough doses used in the previous 24 hours (Ref).

Severe dyspnea: SUBQ, IV: Consider giving 5% of the oral basal daily opioid requirement (calculated in morphine equivalents) every 1 hour as needed or on an “offer, may refuse” basis. For breakthrough dyspnea, if already taking a parenteral opioid, may give ~10% of the current parenteral opioid daily dose (Ref).

Neuraxial analgesia

Neuraxial analgesia:

Epidural:

Note: Reserve use for severe pain (eg, after surgery, cancer pain). Must be administered by health care providers skilled in the care of patients receiving intraspinal opioids. Use a preservative-free formulation intended for neuraxial use.

Single dose (using 0.5 or 1 mg/mL preservative-free solution): Opioid-naive patients: Usual range: 2 to 3.75 mg (may depend upon patient comorbidities) (Ref).

Continuous infusion (using 0.5 or 1 mg/mL preservative-free solution): Opioid-naive patients: 0.2 to 0.4 mg/hour (Ref). May be given alone or usually in combination with local anesthetics (eg, bupivacaine, ropivacaine); when combined with a local anesthetic, analgesic effect is increased due to synergy (Ref).

Continuous microinfusion (using a device intended for continuous microinfusion): Note: Must use a 10 or 25 mg/mL preservative-free solution (eg, Infumorph); dilution may be required.

Initial: 3 to 7.5 mg over 24 hours.

Intrathecal:

Note: Reserve use for severe pain (eg, after surgery, cancer pain). Must be administered by health care providers skilled in the care of patients receiving intraspinal opioids. Use a preservative-free formulation intended for neuraxial use. Intrathecal dose is usually one-tenth that of epidural dosage.

Single dose (using 0.5 or 1 mg/mL preservative-free solution): Usual range: 0.1 to 0.3 mg coadministered with a local anesthetic; repeat doses are not recommended. If pain recurs, use of an alternative route of administration is recommended (Ref). Note: Doses vary depending on the clinical scenario and other medications administered as part of multimodal analgesia. Risk of adverse effects (eg, nausea, pruritus, respiratory depression) is higher with doses >0.3 mg; however, some patients with chronic intractable pain (eg, cancer pain) may require doses up to 0.5 mg (Ref).

Continuous microinfusion (using a device intended for continuous microinfusion): Note: Must use a 10 or 25 mg/mL preservative-free solution (eg, Infumorph); dilution may be required.

Initial: 0.2 to 1 mg over 24 hours.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Note: Morphine clearance is similar in patients with altered and normal kidney function. However, glucuronide metabolites (M3G [inactive as an analgesic; may contribute to CNS stimulation and lower seizure threshold] and M6G [active analgesic]) significantly accumulate in patients with reduced kidney function (Ref). As kidney function deteriorates, M6G accounts for an increasing proportion of the analgesic effect and attainment of steady state is delayed; consequently, patients may experience CNS depression, sedation, and severe and prolonged respiratory depression, which may be delayed in presentation (Ref).

Altered kidney function:

Oral, IM, IV, SUBQ, Rectal:

Note: There are no specific dose adjustments provided in the manufacturer's labeling. ER formulations should preferably be avoided in patients with altered kidney function (Ref). The following suggestions are based on expert opinion and selected references (Ref):

CrCl ≥60 mL/minute: No dosage adjustment necessary.

CrCl 30 to <60 mL/minute: Consider use of an alternative opioid analgesic. If necessary, administer 50% to 75% of usual initial dose; may also consider extending dose interval. Titrate cautiously to response.

CrCl 15 to <30 mL/minute: Avoid use. If necessary, administer 25% to 50% of usual initial dose; may also consider extending dose interval. Titrate cautiously to response.

CrCl <15 mL/minute: Avoid use.

Epidural/intrathecal:

Moderate to severe impairment: There are no specific dose adjustments recommended; however, use with caution and monitor closely. Use of an alternative opioid analgesic may be preferred in patients with more severe impairment.

Hemodialysis, intermittent (thrice weekly): Morphine and M6G are dialyzable, although the extent of removal is not fully quantified (Ref); slow distribution from CNS to plasma may result in prolonged CNS depression even after reduction in plasma levels following dialysis (Ref).

Oral, IM, IV, SUBQ, Rectal:

Note: There are no specific dose adjustments provided in the manufacturer's labeling. ER formulations should preferably be avoided in patients with altered kidney function (Ref). The following suggestions are based on expert opinion and selected references (Ref):

Avoid use; consider alternative opioid analgesic. If necessary, administer 25% to 50% of usual dose; may also consider extending dose interval. Titrate cautiously to response.

Epidural/intrathecal: There are no specific dose adjustments recommended; however, use with caution and monitor closely. Use of an alternative analgesic may be preferred.

Peritoneal dialysis: Avoid use; consider alternative opioid analgesic (Ref). Morphine, M3G, and M6G are not significantly removed by peritoneal dialysis (Ref).

CRRT: Other opioids are preferred (eg, hydromorphone, fentanyl) due to more reliable pharmacokinetic profiles (Ref). Morphine is not significantly removed by hemofiltration or hemodiafiltration (Ref), and the extent of M3G and M6G removal is unknown.

PIRRT (eg, sustained, low-efficiency diafiltration): Other opioids are preferred (eg, hydromorphone, fentanyl) due to more reliable pharmacokinetic profiles. The extent of morphine, M3G, and M6G removal is unknown (Ref).

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the 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.

Dosing: Pediatric

(For additional information see "Morphine: Pediatric drug information")

Note: Arymo ER and MorphaBond ER have been discontinued in the United States for >1 year.

Doses should be titrated to appropriate effect; use lowest effective dose for the shortest duration to meet treatment goals; use caution when changing routes of administration, potency differs between some products. Assess need and discuss availability of naloxone for emergent treatment of opioid overdose with patient and/or caregiver upon initiating and renewing treatment. Dosage forms (parenteral and oral) are available in multiple concentrations; precautions should be taken to avoid confusion between the different concentrations; medication orders (prescriptions) should have the concentration specified as well as the dose clearly represented as milligram (mg) of morphine, not volume (mL).

Acute pain, severe

Acute pain, severe (opioid-naive patients): Note: Repeated SUBQ administration may cause 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 (Ref).

Infants ≤6 months:

Note: Infants <3 months are more susceptible to respiratory depression and cardiovascular adverse effects; use extra caution and consider frequent or continuous cardiorespiratory monitoring and administer in a setting that permits rapid management of respiratory insufficiency (Ref).

Intermittent dosing: Infants ≤6 months:

Oral: Oral solution (2 mg/mL or 4 mg/mL): Initial: 0.08 to 0.1 mg/kg/dose every 3 to 4 hours (Ref).

IV or SUBQ: Initial: 0.025 to 0.05 mg/kg/dose every 2 to 4 hours (Ref).

Continuous IV infusion: Infants ≤6 months: Initial: 0.008 to 0.02 mg/kg/hour (8 to 20 mcg/kg/hour); titrate carefully to effect (Ref). Higher initial doses of 0.05 mg/kg/hour (50 mcg/kg/hour) have been recommended in critically ill patients in the ICU (Ref).

Infants >6 months, Children, and Adolescents:

Intermittent dosing:

Oral: Infants >6 months, Children, and Adolescents:

Weight <50 kg: Oral: Immediate-release tablets, oral solution: Initial: 0.15 to 0.3 mg/kg/dose every 3 to 4 hours as needed; some experts have recommended higher initial doses of up to 0.5 mg/kg; usual initial maximum dose: 20 mg/dose (Ref).

Weight ≥50 kg: Oral: Immediate-release tablets, oral solution: 10 to 20 mg every 3 to 4 hours as needed (Ref).

IV, SUBQ: Infants >6 months, Children, and Adolescents:

Weight <50 kg: IV, SUBQ: Initial: 0.05 to 0.1 mg/kg/dose every 2 to 4 hours; titrate based on patient response (Ref).

Weight ≥50 kg: IV, SUBQ: Initial: 2 to 5 mg every 2 to 4 hours as needed. Use lower end of the dosing range in opioid naive patients; higher doses have been recommended (5 to 8 mg every 2 to 4 hours as needed) (Ref).

Continuous IV infusion, SUBQ continuous infusion: Note: Patients should have continuous respiratory monitoring (eg, pulse oximetry) and be in a setting that permits rapid management of respiratory insufficiency (Ref).

Infants >6 months, Children, and Adolescents:

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) (Ref). Higher initial doses of 0.05 mg/kg/hour (50 mcg/kg/hour) have been recommended in critically ill patients in the ICU (Ref).

Weight ≥50 kg: Initial: 1.5 mg/hour; titrate carefully based on clinical response; usual maintenance dose: 0.8 to 3 mg/hour (Ref). Higher initial doses of 2 mg/hour have been recommended in critically ill patients in the ICU (Ref).

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.

Tapering after prolonged therapy (ie, physical dependence): Note: Do not discontinue morphine abruptly; optimal taper schedule not established; individualize taper based on patient response; use of a withdrawal assessment tool is recommended; manufacturer labeling recommends:

Continuous IV infusion: Infants, Children, and Adolescents: Decrease dose by 25% to 50% every 2 to 4 days; monitor closely for signs and symptoms of withdrawal with each reduction in dose.

Oral solution: Children ≥2 years and Adolescents: Decrease dose by no greater than 10% to 25% of total daily dose every 2 to 4 weeks; monitor closely for signs and symptoms of withdrawal with each reduction in dose. Patients who have been taking opioids for short periods of time may tolerate a more rapid taper.

Chronic pain

Chronic pain:

Note: 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. Assess need and discuss availability of naloxone for emergent treatment of opioid overdose with patient and/or caregiver upon initiating and renewing treatment.

Oral: Note: A patient's morphine requirement should be established using immediate-release formulations (Ref). 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.

Tablets, extended release (eg, MS Contin): Limited data available: Children and Adolescents able to swallow tablets whole:

Fixed dosing (Ref):

Weight 20 to <35 kg: 10 to 15 mg every 8 to 12 hours; Note: 10 mg strength not available in the United States.

Weight 35 to <50 kg: 15 to 30 mg every 8 to 12 hours.

Weight ≥50 kg: 30 to 45 mg every 8 to 12 hours.

Weight-directed dosing: 0.3 to 0.6 mg/kg/dose every 12 hours (Ref).

Discontinuation of extended-release formulations: In general, gradually titrate dose downward (eg, decrease dose 10% to 25% every 2 to 4 weeks). Do not discontinue abruptly.

Conversion from parenteral morphine or other opioids to extended-release formulation: Substantial interpatient variability exists in relative potency. Therefore, it is safer to underestimate a patient's daily oral morphine requirement rather than overestimate requirements. Consider the parenteral to oral morphine ratio or other parenteral opioids to oral morphine conversions; divide total daily oral morphine dose into the appropriate interval for desired extended-release product.

Conversion from other oral morphine formulations to extended-release formulation: Children and Adolescents who can swallow whole tablets: 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) (Ref).

Continuous IV infusion: Children and Adolescents: Initial: 0.01 to 0.04 mg/kg/hour (10 to 40 mcg/kg/hour) (Ref); opioid-tolerate patients may require higher doses (Ref).

Epidural

Epidural : Limited data available: Note: Must use preservative-free formulation:

Intermittent: Infants, Children, and Adolescents: Epidural: 0.015 to 0.05 mg/kg/dose (15 to 50 mcg/kg/dose) (Ref); epidural administration can provide pain relief for 12 to 24 hours (Ref). Maximum dose: 0.1 mg/kg (100 mcg/kg) or 5 mg per 24 hours (Ref).

Continuous epidural infusion: Infants >6 months, Children, and Adolescents: Epidural: 0.001 to 0.005 mg/kg/hour (1 to 5 mcg/kg/hour) (Ref).

Palliative care, dyspnea management

Palliative care, dyspnea management:

Inhalation (nebulization; preservative-free injection): Note: Dose should be individualized and is dependent upon patient's previous or current systemic opioid exposure; doses not intended to provide analgesic activity; current systemic analgesia should be continued:

Infants, Children, and Adolescents: Very limited data available, efficacy results variable:

Initial dose: Inhalation: Equivalent to patient's 4-hour systemic morphine requirement (eg, IV or oral dose); titrate to effect (Ref); every 4 to 6 hour administration has been suggested (Ref). In the only pediatric case report (end-stage cystic fibrosis, age: 10 years, weight: 20 kg), an initial dose of 2.5 mg was used and the final dose was 10 mg every 4 to 6 hours (Ref).

Oral:

Infants, Children, and Adolescents: Limited data available:

Immediate-release preparations: Oral: Initial: 0.075 to 0.15 mg/kg/dose every 4 hours as needed (Ref); titrate for comfort.

Continuous IV or SUBQ infusion: Note: Use is recommended when oral therapy is ineffective:

Infants, Children, and Adolescents: Limited data available:

Continuous IV or SUBQ infusion: Initial: 0.005 mg/kg/hour (5 mcg/kg/hour); titrate for comfort (Ref); dosing based on palliative management of terminal infants with spinal muscular atrophy (type 1).

Patient-controlled analgesia, opioid naive

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. Assess patient and pain control at regular intervals and adjust settings if needed (Ref):

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 (Ref).

Usual IV concentration: 1 mg/mL.

Demand dose: Usual initial: IV: 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: IV: 0 to 0.03 mg/kg/hour.

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 (Ref).

Usual IV concentration: 1 mg/mL.

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

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

Procedural pain and sedation

Procedural pain and sedation: Infants, Children, and Adolescents: IV: 0.05 to 0.1 mg/kg/dose; consider lowest dose in older children and adolescents; administer 5 minutes before the procedure; maximum dose: 4 mg; may repeat dose in 5 minutes if necessary (Ref).

Tetralogy of fallot, hypercyanotic spell

Tetralogy of fallot, hypercyanotic spell (infundibular spasm): Limited data available:

Infants and Children:

IV: 0.1 mg/kg as a single dose (Ref).

IM: 0.1 to 0.2 mg/kg as a single dose (Ref).

SUBQ: 0.2 mg/kg as a single dose (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

Infants, Children and Adolescents: There are no specific dosage adjustments provided in the manufacturer's labeling. 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, morphine 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 (Ref).

Dosing: Hepatic Impairment: Pediatric

Infants, Children and Adolescents: There are no dosage adjustments provided in manufacturer's labeling. Pharmacokinetics are unchanged in mild liver disease; substantial extrahepatic metabolism may occur. In patients with cirrhosis, the manufacturers recommend starting cautiously with lower doses, titrating slowly while carefully monitoring for adverse effects.

Dosing: Older Adult

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

Dosage Forms: US

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

Capsule Extended Release 24 Hour, Oral, as sulfate:

Kadian: 10 mg [DSC] [contains corn starch, fd&c blue #1 (brilliant blue)]

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

Kadian: 20 mg [DSC] [contains corn starch, quinoline yellow (d&c yellow #10)]

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

Kadian: 30 mg [DSC] [contains corn starch, fd&c blue #1 (brilliant blue)]

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

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

Kadian: 50 mg [DSC], 60 mg [DSC] [contains corn starch, fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye)]

Kadian: 60 mg [DSC] [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye)]

Kadian: 80 mg [DSC] [contains corn starch, fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), fd&c yellow #6 (sunset yellow)]

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

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

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

Kadian: 200 mg [DSC]

Kadian: 200 mg [DSC] [contains corn starch]

Generic: 10 mg, 20 mg, 30 mg, 40 mg [DSC], 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 [DSC])

Solution, Injection, as sulfate:

Generic: 2 mg/mL (1 mL)

Solution, Injection, as sulfate [preservative 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]

Mitigo: 200 mg/20 mL (10 mg/mL) (20 mL); 500 mg/20 mL (25 mg/mL) (20 mL)

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

Solution, Intravenous, as sulfate:

Generic: 1 mg/mL (2 mL, 5 mL, 25 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 [DSC]); 8 mg/mL (1 mL); 10 mg/mL (1 mL); 25 mg/mL (10 mL [DSC]); 50 mg/mL (20 mL, 50 mL)

Solution, Oral, as sulfate:

Generic: 10 mg/5 mL (5 mL, 15 mL [DSC], 100 mL, 500 mL); 20 mg/5 mL (5 mL [DSC], 100 mL, 500 mL); 10 mg/0.5 mL (1 ea); 20 mg/mL (30 mL, 118 mL, 120 mL, 240 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 ER 12 Hour Abuse-Deterrent, Oral, as sulfate:

MorphaBond ER: 15 mg [DSC] [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), fd&c yellow #6 (sunset yellow)]

MorphaBond ER: 30 mg [DSC] [contains fd&c blue #2 (indigotine), fd&c red #40 (allura red ac dye)]

MorphaBond ER: 60 mg [DSC] [contains fd&c red #40 (allura red ac dye), fd&c yellow #6 (sunset yellow)]

MorphaBond ER: 100 mg [DSC] [contains fd&c blue #2 (indigotine), fd&c red #40 (allura red ac dye), fd&c yellow #6 (sunset yellow)]

Tablet Extended Release, Oral, as sulfate:

MS Contin: 15 mg [contains fd&c blue #2 (indigotine)]

MS Contin: 30 mg [contains fd&c blue #1 (brilliant blue)]

MS Contin: 60 mg [contains quinoline yellow (d&c yellow #10)]

MS Contin: 100 mg

MS Contin: 200 mg [contains fd&c blue #1 (brilliant blue), quinoline yellow (d&c yellow #10)]

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

Tablet Extended Release Abuse-Deterrent, Oral, as sulfate:

Arymo ER: 15 mg (100 ea [DSC]); 30 mg (100 ea [DSC]) [contains fd&c blue #2 (indigotine)]

Arymo ER: 60 mg (100 ea [DSC])

Generic Equivalent Available: US

May be product dependent

Dosage Forms: Canada

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

Capsule, Oral:

M-Ediat: 5 mg [contains corn starch, fd&c blue #2 (indigotine)]

M-Ediat: 10 mg [contains corn starch]

M-Ediat: 20 mg [contains corn starch, fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye)]

M-Ediat: 30 mg [contains corn starch, fd&c blue #2 (indigotine), quinoline yellow (d&c yellow #10)]

Capsule Extended Release 12 Hour, Oral:

M-Eslon: 10 mg, 15 mg, 30 mg, 60 mg, 100 mg, 200 mg

Capsule Extended Release 24 Hour, Oral, as sulfate:

Kadian: 20 mg, 50 mg, 100 mg

Kadian SR: 10 mg

Solution, Injection:

Generic: 1 mg/mL ([DSC]); 25 mg/mL ([DSC]); 50 mg/mL (1 mL, 5 mL, 10 mL, 50 mL)

Solution, Injection, as sulfate:

Generic: 0.5 mg/mL (10 mL); 1 mg/mL (5 mL); 2 mg/mL (1 mL); 5 mg/mL ([DSC]); 10 mg/mL (1 mL, 5 mL); 15 mg/mL (1 mL, 30 mL)

Solution, Intravenous, as sulfate:

Generic: 100 mg /100 mL in NaCl 0.9% (100 mL)

Suppository, Rectal, as sulfate:

Statex: 5 mg ([DSC]); 10 mg ([DSC]); 20 mg ([DSC]); 30 mg ([DSC])

Syrup, Oral:

Doloral 1: 1 mg/mL (225 mL, 500 mL) [contains alcohol, usp, fd&c blue #1 (brilliant blue), fd&c yellow #5 (tartrazine), methylparaben, propylparaben]

Doloral 5: 5 mg/mL (10 mL, 250 mL, 500 mL)

Statex: 1 mg/mL ([DSC])

Tablet, Oral:

MS/IR: 5 mg, 10 mg, 20 mg

Statex: 5 mg, 10 mg, 25 mg, 50 mg

Tablet, Oral, as sulfate:

MS/IR: 30 mg

Tablet Extended Release, Oral, as sulfate:

MS Contin: 15 mg [contains fd&c blue #1 (brill blue) aluminum lake, fd&c blue #2 (indigotine), quinoline (d&c yellow #10) aluminum lake]

MS Contin: 30 mg [contains fd&c blue #2 (indigo carm) aluminum lake, fd&c yellow #6(sunset yellow)alumin lake]

MS Contin: 60 mg [contains fd&c yellow #6(sunset yellow)alumin lake, quinoline (d&c yellow #10) aluminum lake]

MS Contin: 100 mg [contains fd&c blue #2 (indigo carm) aluminum lake]

MS Contin: 200 mg [contains fd&c yellow #6(sunset yellow)alumin lake]

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

Product Availability

Arymo ER and MorphaBond ER have been discontinued in the United States for >1 year.

Controlled Substance

C-II

Administration: Adult

Oral: Do not crush, chew, or dissolve ER formulations; swallow whole. Cutting, breaking, crushing, chewing, or dissolving ER formulations may result in uncontrolled delivery of morphine, leading to overdose and death.

Arymo ER: Swallow tablets whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth; do not pre-soak, lick, or wet tablets prior to placing in the mouth.

Kadian: Capsules may 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 capsules may be opened and sprinkled over 10 mL water and flushed through prewetted 16F gastrostomy tube; do not administer through gastric/nasogastric tubes.

Bariatric surgery: Tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. ER tablet should be swallowed whole. Do not break, crush, cut, chew, dissolve, presoak, wet, or split as this will result in uncontrolled delivery of morphine that can lead to overdose or death. Take one abuse deterrent dose at a time and with sufficient water to avoid tablet becoming sticky and difficult to swallow. IR tablet, oral solution, and rectal suppository are available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery; however, clinicians should be advised that oral morphine has been shown to have significantly increased Cmax and decreased Tmax in the immediate (1 to 2 weeks) and long-term (6 months) periods after bariatric surgery (Ref).

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 only preservative-free solutions indicated for intrathecal or epidural use; refer to indication-specific infusion rates in dosing for detailed recommendations.

Rectal: Remove suppository from plastic packet and moisten suppository with water to avoid irritation. Gently insert (rounded end first) approximately a finger's length into rectum, angling it toward the umbilicus, and placing it against the rectal wall; after suppository is inserted, hold buttocks together until urge to expel ceases (Ref).

SUBQ continuous infusions: Change site every 3 to 7 days or when erythema occurs (Ref). To maintain comfort, the SUBQ infusion rate should generally not exceed 5 mL/hour (Ref).

Administration: Pediatric

Oral: Administer with food.

Immediate release: Oral solution: Available in multiple strengths, including a concentrated oral solution (20 mg/mL). Precautions should be taken to avoid confusion between the different concentrations; medication orders (prescriptions) should have the concentration specified as well as the dose clearly represented as milligram (mg) of morphine, not volume (mL).

Oral solution: The enclosed calibrated dosing syringe should always be used to ensure the dose is measured and administered accurately.

Extended-/controlled-release products: Do not chew, crush, break, or dissolve extended- and controlled-release products as it can result in uncontrolled delivery and can lead to overdose or death; swallow whole.

Parenteral: Note: Solutions for injection should be visually inspected for particulate matter and discoloration prior to administration. Do not use if contains a precipitate or is darker in color than pale yellow or discolored in any other way. Precautions should be taken to avoid confusion between the different concentrations; medication orders (prescriptions) should have the concentration specified as well as the dose clearly represented as milligram (mg) of morphine, not volume (mL).

IV push: Administer undiluted or diluted solution over 4 to 5 minutes (Ref); rapid IV administration may increase adverse effects.

Intermittent IV infusion: Further dilute and administer over 15 to 30 minutes.

Continuous IV infusion: Administer as a continuous infusion via an infusion pump.

Epidural and intrathecal: Use only preservative-free injections.

Inhalation: Limited data available; utilize preservative free parenteral morphine and further dilute prior to administration (Ref)

Usual Infusion Concentrations: Adult

IV infusion: 1 mg/mL

Usual Infusion Concentrations: Pediatric

IV infusion: 0.04 mg/mL, 0.1 mg/mL, 0.5 mg/mL, or 1 mg/mL.

Use: Labeled Indications

Pain management , acute and chronic pain:

Injection: Management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Preservative-free solutions only:

Duramorph: Epidural or intrathecal management of pain without attendant loss of motor, sensory, or sympathetic function. Note: Not for use in continuous microinfusion devices.

Infumorph, Mitigo: Used in continuous microinfusion devices for intrathecal or epidural administration in management of intractable chronic pain severe enough to require an opioid analgesic and for which less invasive means of controlling pain are inadequate. Note: Not for single-dose IV, IM, or subcutaneous administration or single-dose neuraxial injection.

Oral:

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

Immediate release:

Oral solution: Management of acute pain (pediatric patients ≥2 years of age and adults) and chronic pain (adults only) severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Oral solution 100 mg per 5 mL (20 mg/mL) is for opioid-tolerant adults only.

Tablets: Management of acute pain (pediatric patients ≥50 kg and adults) and chronic pain (adults only) severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Rectal: Management of acute and chronic pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Limitations of use: Reserve morphine for use in patients for whom alternative treatment options (eg, nonopioid analgesics, opioid combination products) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. ER formulations are not indicated as as-needed analgesics.

Use: Off-Label: Adult

Critically ill patients in the ICU (analgesia and sedation); Dyspnea in palliative care patients

Medication Safety Issues
Sound-alike/look-alike issues:

Morphine may be confused with diamorphine, HYDROmorphone, methadone

Morphine sulfate may be confused with magnesium sulfate

Kadian may be confused with Kapidex [DSC]

MS Contin may be confused with OxyCONTIN

MSO4 and MS are error-prone abbreviations (mistaken as magnesium sulfate)

Roxanol may be confused with OxyFast, Roxicet, Roxicodone

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication (with special emphasis on the 20 mg/mL oral solution) among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Other safety concerns:

Use care when prescribing and/or administering morphine solutions. These products are available in different concentrations. Always prescribe dosage in mg; not by volume (mL).

Use caution when selecting a morphine formulation for use in neurologic infusion pumps (eg, Medtronic delivery systems). The product should be appropriately labeled as “preservative-free” and suitable for intraspinal use via continuous infusion. In addition, the product should be formulated in a pH range that is compatible with the device operation specifications.

Significant differences exist between oral and IV dosing. Use caution when converting from one route of administration to another.

Adverse Reactions (Significant): Considerations
Opioid-induced constipation

Opioid-induced constipation (OIC) is the most common subtype of opioid-induced bowel dysfunction (OIBD), which is a broader term that encompasses additional GI opioid-induced adverse reactions, including nausea, vomiting, and gastroesophageal reflux. Tolerance does not develop to OIC (Ref).

Mechanism: Time-related; activity in both the central and enteric nervous systems, predominantly via the mu-opioid receptor, delays gastric emptying, inhibits peristalsis, impairs enzyme release, and produces antisecretory effects (Ref).

Onset: Varied; changes in peristalsis may occur 5 to 25 minutes after administration of opioids (Ref). However, OIC is defined based on a 7-day period of change (Ref).

Risk factors:

• Chronic opioid administration (Ref)

Opioid-induced respiratory depression

Serious, life-threatening, or fatal opioid-induced respiratory depression (OIRD) may occur with use of morphine in adult and pediatric patients (Ref).

Mechanism: Dose-related; mediated predominately via the mu-opioid receptor. Activates specific CNS sites (ie, pre-Bötzinger complex and Kölliker-Fuse nucleus) that control respiratory rhythms (Ref).

Onset: Rapid; OIRD reported from 5 minutes to 1.2 hours (Ref).

Risk factors:

• Overdose (but may also occur at therapeutic doses)

• Initiation or dose escalation

• Opioid naive (Ref)

• Opioid misuse/abuse (Ref)

• Respiratory disease (eg, obstructive sleep apnea) (Ref)

• Cardiac disease (Ref)

• Morbid obesity (Ref)

• Older adults

• Kidney and/or liver impairment

• Cachectic or debilitated

• Concurrent benzodiazepines or other CNS depressants

• Rapid IV administration or neuraxial administration

Opioid-induced withdrawal

Abrupt discontinuation or dose reduction in patients who are physically dependent (ie, have opioid dependence) to opioids has been associated with a serious opioid-induced withdrawal syndrome (OIW), uncontrolled pain, attempts to find other opioids (including illicit), and suicide. Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics may also precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu-opioid agonists. Reversal of analgesia, irritability, nausea, vomiting, abdominal cramping, tachycardia, restlessness, and sweating are common symptoms. Symptoms typically dissipate over 4 to 7 days and fully resolve within 14 days (depending on half-life); may cause significant distress but are rarely life-threatening (Ref).

Mechanism: Withdrawal; abrupt discontinuation in patients who are physically dependent on opioids results in noradrenergic hyperactivity. This hyperactivity occurs due to abrupt reversal of adaptive mechanisms related to cAMP, locus coeruleus firing rate, and norepinephrine levels that occur with prolonged exposure to opioids (Ref).

Onset: Rapid; symptoms typically occur within 12 hours after discontinuation and peak at 36 to 72 hours; varies based on half-life of opioid (Ref).

Risk factors:

• Prolonged exposure to opioids (Ref)

• Opioid use disorder (Ref)

• Abrupt discontinuation or dose reduction (Ref)

• Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist (eg, buprenorphine) analgesics

Pruritus

Pruritus may occur with morphine use, and ranges from mild to severe; associated with both neuraxial and systemic opioids. Antihistamines tend to be ineffective (Ref).

Mechanism: Non–dose-related; directly stimulates mast cell degranulation. For neuraxially administered opioids, mu-opioid receptors and kappa-opioid receptors may be involved in neuronally mediated pruritus. Systemic opioids may also induce centrally mediated pruritus (Ref).

Onset: Rapid; may occur quickly after the first dose with systemic opioids but may be delayed by several hours with a longer duration for neuraxially administered opioids (Ref).

Risk factors:

• Neuraxial administration (Ref)

• Extended use of IV PCA (Ref)

• Previous allergy to various drugs or foods (eg, seafood, alcohol, antibiotics) (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

1% to 10%:

Cardiovascular: Atrial fibrillation, bradycardia, chest pain (2%), edema, facial flushing, flushing, hypertension, hypotension, palpitations, peripheral edema (3%), syncope, tachycardia, vasodilation

Dermatologic: Diaphoresis (2%), pallor, pressure ulcer, pruritus, skin rash (3%)

Endocrine & metabolic: Amenorrhea, decreased libido, gynecomastia, hyponatremia, SIADH

Gastrointestinal: Abdominal pain (3%), anorexia (3%), biliary colic, constipation (9%), delayed gastric emptying, diarrhea (3%), dyspepsia, dysphagia, gastric atony, gastroesophageal reflux disease, hiccups, nausea (7%), vomiting (2%), xerostomia (3%)

Genitourinary: Impotence, prolonged labor, urinary hesitancy, urinary retention, urine abnormality

Hematologic & oncologic: Anemia (2%), leukopenia (2%), thrombocytopenia

Nervous system: Abnormal dreams, abnormality in thinking, agitation, amnesia, anxiety (5%), apathy, ataxia, chills, confusion (4%), decreased cough reflex, depression, dizziness (6%), drowsiness (9%), euphoria, hallucination, headache (2%), hypoesthesia, insomnia, lack of concentration, lethargy, malaise, myoclonus, paresthesia, seizure, slurred speech, vertigo, voice disorder, withdrawal syndrome

Neuromuscular & skeletal: Arthralgia, asthenia (2%), back pain, foot-drop, ostealgia, tremor (2%)

Ophthalmic: Amblyopia, blurred vision, conjunctivitis, diplopia, miosis, nystagmus disorder

Respiratory: Asthma, atelectasis, dyspnea (3%), flu-like symptoms, hypoventilation, hypoxia, pulmonary edema (includes noncardiogenic), respiratory depression (including severe respiratory depression), respiratory insufficiency, rhinitis

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

Frequency not defined:

Cardiovascular: Circulatory depression, orthostatic hypotension, peripheral vascular insufficiency (IV), phlebitis (IV), presyncope, shock

Dermatologic: Hemorrhagic urticaria, skin irritation, xeroderma

Endocrine & metabolic: Antidiuretic effect, increased thirst, weight loss

Gastrointestinal: Decreased appetite, dysgeusia, gastroenteritis, gastrointestinal hypermotility (IV; in patients with chronic ulcerative colitis), rectal disease, toxic megacolon (IV; patients with chronic ulcerative colitis)

Genitourinary: Dysuria, ejaculatory disorder, erectile dysfunction, hypogonadism, oliguria, ureteral spasm (IV)

Hematologic & oncologic: Granuloma (inflammatory mass: IV, epidural, intrathecal)

Hypersensitivity: Nonimmune anaphylaxis

Local: Erythema at injection site (IV), induration at injection site (SC), local swelling (IV, intrathecal, epidural; genital swelling in males following infusion device implant surgery), pain at injection site (SC)

Nervous system: Abnormal gait, altered mental status, coma, delirium, disorientation, disruption of body temperature regulation (IV, epidural, intrathecal), drug abuse, dysphoria, fear, feeling abnormal, increased intracranial pressure, mood changes, neonatal withdrawal, nervousness, paradoxical central nervous system stimulation (IV, epidural, intrathecal), sedated state, toxic psychosis (IM, IV, epidural, intrathecal)

Neuromuscular & skeletal: Decreased bone mineral density, laryngospasm, muscle rigidity, muscle spasm (IV, epidural, intrathecal; myoclonic spasm of lower extremities), muscle twitching, vesicle sphincter spasm (IV)

Ophthalmic: Eye pain, visual disturbance

Respiratory: Apnea

Miscellaneous: Impaired physical performance

Postmarketing:

Dermatologic: Urticaria (McLelland 1986)

Endocrine & metabolic: Increased serum prolactin (Molitch 2008; Vuong 2010)

Gastrointestinal: Intestinal obstruction

Hepatic: Increased liver enzymes

Hypersensitivity: Anaphylaxis (Stefanutto 2005)

Nervous system: Difficulty thinking, fatigue, hyperalgesia, hypertonia, opioid dependence (Bluthenthal 2020)

Respiratory: Bronchospasm

Contraindications

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

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

Additional contraindications:

Epidural/intrathecal: Infection at infusion site; concomitant anticoagulant therapy; uncontrolled bleeding diathesis; presence of any other concomitant therapy or medical condition that would render administration hazardous; upper airway obstruction.

Canadian labeling: Additional contraindications (not in US labeling):

Contraindications may vary per product labeling; refer also to product labels: Suspected surgical abdomen (eg, acute appendicitis, pancreatitis); disease/condition that affects bowel transit (known or suspected); chronic obstructive airway; status asthmaticus; management of acute pain, including use in outpatient or day surgeries; mild, intermittent, or short-duration pain that can be managed with other pain medications; acute respiratory depression; hypercarbia; cor pulmonale; acute alcoholism; delirium tremens; convulsive disorders; severe CNS depression; increased cerebrospinal; intracranial pressure; brain tumor; head injury; cardiac arrhythmias; pregnancy; use during labor and delivery; breastfeeding; alcohol consumption or medications containing alcohol (Kadian, M-Eslon product monographs); toxic psychosis and severe kyphoscoliosis (Kadian product monograph); severe cirrhosis (M-Ediat product monograph); hypotension (M-Eslon product monograph), emotional instability and/or suicidal ideation (Statex product monograph); surgical anastomosis (morphine sulfate inj Sandoz product monograph)

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 that require mental alertness (eg, operating machinery or driving). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Some dosage forms may be contraindicated in patients with severe CNS depression.

• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), circulatory shock, or drugs that may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Avoid use in patients with circulatory shock. Some dosage forms may be contraindicated in patients with cardiac arrhythmias or heart failure due to chronic lung disease.

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

Disease-related concerns:

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

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

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

• Cardiovascular conditions: Morphine may cause constipation, which may be problematic in patients with unstable angina and patients post–myocardial infarction.

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

• Delirium tremens: Use with caution in patients with delirium tremens. Some dosage forms may be contraindicated in patients with delirium tremens.

• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur. Some dosage forms may be contraindicated in patients with increased intracranial or cerebrospinal pressure, head injuries, or brain tumor.

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

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

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

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

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

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

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

• Sleep-related disorders: Opioid use increases the risk for sleep-related disorders (eg, central sleep apnea [CSA], hypoxemia) in a dose-dependent fashion. Use with caution for chronic pain and titrate dosage cautiously in patients with risk factors for sleep-disordered breathing (eg, heart failure, obesity). Consider dose reduction in patients presenting with CSA. Avoid opioids in patients with moderate to severe sleep-disordered breathing (CDC [Dowell 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:

• Benzodiazepines or other CNS depressants: Some dosage forms may be contraindicated in patients with acute alcoholism.

Special populations:

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

Dosage form specific issues:

• Infumorph, Duramorph, Mitigo: Neuroaxial administration: Naloxone injection should be immediately available. Thoracic epidural administration has been shown to dramatically increase the risk of early and late respiratory depression. High doses (> 20 mg/day) of neuraxial morphine may produce myoclonic events. Patients with reduced circulating blood volume or impaired myocardial function, or on concomitant sympatholytic drugs should be monitored for orthostatic hypotension, a frequent complication in single-dose neuraxial morphine.

• 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.

• 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).

- Arymo ER: Moistened tablets may become sticky, leading to difficulty in swallowing the tablets; choking, gagging, regurgitation, and tablets getting stuck in the throat may occur. Tablet stickiness and swelling may also predispose patients to intestinal obstruction and exacerbation of diverticulitis. Do not to pre-soak, lick, or otherwise wet tablets prior to placing in the mouth; take one tablet at a time with enough water to ensure complete swallowing. Consider use of an alternative analgesic in patients who have difficulty swallowing and patients at risk for underlying GI disorders resulting in a small GI lumen (eg, esophageal cancer, colon cancer).

• 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). Rapid IV administration may result in chest wall rigidity. Use with caution when injecting IM into chilled areas or in patients with hypotension or shock (impaired perfusion may prevent complete absorption); if repeated injections are administered, an excessive amount may be suddenly absorbed if normal circulation is re-established.

• Infumorph, Mitigo: Should only be used in microinfusion devices; not for IV, IM, or SubQ administration or for single-dose administration. Administer intrathecal doses of 10 and 25 mg/mL to the lumbar area. Monitor closely, especially in the first 24 hours. Inflammatory masses (eg, granulomas), some resulting in severe neurologic impairment, have occurred when receiving Infumorph or Mitigo via indwelling intrathecal catheter; monitor carefully for new neurologic signs/symptoms.

• Product interchange: Improper or erroneous substitution of Infumorph or Mitigo for regular Duramorph is likely to result in serious overdosage, leading to seizures, respiratory depression, and possibly a fatal outcome.

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

Other warnings/precautions:

• Abuse/misuse/diversion: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Other factors associated with increased risk include younger age, concomitant depression (major), and psychotropic medication use (CDC [Dowell 2016]).

• Appropriate use: Chronic pain (outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment) 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 antiseizure medications and antidepressants). If opioid therapy is initiated, it should be combined with nonpharmacologic and nonopioid therapy, as appropriate, and lowest effective dose used. 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 (CDC [Dowell 2016]).

• Naloxone access: Discuss the availability of naloxone with all patients who are prescribed opioid analgesics, as well as their caregivers, and consider prescribing it to patients who are at increased risk of opioid overdose. These include patients who are also taking benzodiazepines or other CNS depressants, have an opioid use disorder (OUD) (current or history of) or substance use disorder, have higher opioid dosages (≥50 morphine milligram equivalents/day orally) (CDC [Dowell 2016]), or have experienced a previous opioid overdose. Additionally, health care providers should consider prescribing naloxone to patients prescribed medications to treat OUD; patients at risk of opioid overdose even if they are not taking an opioid analgesic or medication to treat OUD; and patients taking opioids, including methadone or buprenorphine for OUD, if they have household members, including children, or other close contacts at risk for accidental ingestion or opioid overdose. Inform patients and caregivers on options for obtaining naloxone (eg, by prescription, directly from a pharmacist, a community-based program) as permitted by state dispensing and prescribing guidelines. Educate patients and caregivers on how to recognize respiratory depression, proper administration of naloxone, and getting emergency help.

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

• Surgery: Opioids decrease bowel motility; monitor for decreased bowel motility in postop patients receiving opioids. Use with caution in the perioperative setting; individualize treatment when transitioning from parenteral to oral analgesics. Some dosage forms may be contraindicated after biliary tract surgery, suspected surgical abdomen, or surgical anastomosis.

Warnings: Additional Pediatric Considerations

Prolonged use of any morphine product 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.

It is well known that recurrent exposure to painful stimuli without effective pain management alters the pain pathways in the neonatal brain and results in altered pain perception. There is a growing concern regarding the need to balance pain management with the concern for neuronal apoptosis and potential poor neurodevelopmental outcomes in neonatal patients treated with opiates. In vitro and animal studies show that exposure to morphine induces apoptosis of primary human fetal microglial cells (Attarian 2014; Hu 2002). Clinical evaluations of preterm neonates exposed to morphine have shown impaired cerebellar and cerebral growth but have shown mixed impact on the long-term neurodevelopment outcomes in early childhood (Steinhorn 2015; Zwicker 2016).

Metabolism/Transport Effects

Substrate of OCT1, P-glycoprotein/ABCB1 (major), UGT1A1; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

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

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Alvimopan: Opioid Agonists 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. Risk D: Consider therapy modification

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification

Amphetamines: May enhance the analgesic effect of Opioid Agonists. Risk C: Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Risk C: 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. Risk D: Consider therapy modification

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification

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

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

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

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

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

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

CNS Depressants: May enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists 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. Risk D: Consider therapy modification

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

Desmopressin: Opioid Agonists may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy

DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification

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

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

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

Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Risk C: Monitor therapy

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

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

Eluxadoline: Opioid Agonists may enhance the constipating effect of Eluxadoline. Risk X: Avoid combination

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

Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification

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

Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification

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

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification

Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Risk C: Monitor therapy

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

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

Lumacaftor and Ivacaftor: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may decrease the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors or Inducers). Risk C: Monitor therapy

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

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

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

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Mitapivat: May decrease the serum concentration of UGT1A1 Substrates. Risk C: Monitor therapy

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

Monoamine Oxidase Inhibitors: May enhance the adverse/toxic effect of Morphine (Systemic). Risk X: Avoid combination

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

Nalfurafine: Opioid Agonists may enhance the adverse/toxic effect of Nalfurafine. Opioid Agonists may diminish the therapeutic effect of Nalfurafine. Risk C: Monitor therapy

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

Naltrexone: May diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Risk X: Avoid combination

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

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

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: 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. Risk D: Consider therapy modification

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists 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. Risk D: Consider therapy modification

Opioids (Mixed Agonist / Antagonist): May diminish the analgesic effect of Opioid Agonists. 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. Risk X: Avoid combination

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

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

Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification

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. Risk D: Consider therapy modification

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

Pegvisomant: Opioid Agonists may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy

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

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Morphine (Systemic). Risk C: Monitor therapy

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

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

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

Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

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

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

Ramosetron: Opioid Agonists may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy

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

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification

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

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

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

Samidorphan: May diminish the therapeutic effect of Opioid Agonists. Risk X: Avoid combination

Serotonergic Agents (High Risk): Opioid Agonists may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider therapy modification

Somatostatin Analogs: Opioid Agonists may diminish the analgesic effect of Somatostatin Analogs. Opioid Agonists may enhance the analgesic effect of Somatostatin Analogs. Risk C: Monitor therapy

Succinylcholine: May enhance the bradycardic effect of Opioid Agonists. Risk C: 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. Risk D: Consider therapy modification

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

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

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. Risk D: Consider therapy modification

Food Interactions

Ethanol: Alcoholic beverages or ethanol-containing products may disrupt extended release formulation resulting in rapid release of entire morphine dose. Management: Avoid alcohol. Do not administer Kadian with alcoholic beverages or ethanol-containing prescription or nonprescription products.

Food: Administration of oral morphine solution with food may increase bioavailability (ie, a report of 34% increase in morphine AUC when morphine oral solution followed a high-fat meal). The bioavailability of MorphaBond, MS Contin, or Kadian does not appear to be affected by food. Management: Take consistently with or without meals.

Reproductive Considerations

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

Pregnancy Considerations

Morphine crosses the placenta.

According to some studies, maternal use of opioids may be associated with birth defects (including neural tube defects, congenital heart defects, and gastroschisis), poor fetal growth, stillbirth, and preterm delivery (CDC [Dowell 2016]). Opioids used as part of obstetric analgesia/anesthesia during labor and delivery may temporarily affect the fetal heart rate (ACOG 209 2019).

[US Boxed Warning]: Prolonged use of morphine 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. If chronic opioid exposure occurs in pregnancy, adverse events in the newborn (including withdrawal) may occur (Chou 2009). Symptoms of neonatal abstinence syndrome (NAS) following opioid exposure may be autonomic (eg, fever, temperature instability), gastrointestinal (eg, diarrhea, vomiting, poor feeding/weight gain), or neurologic (eg, high-pitched crying, hyperactivity, increased muscle tone, increased wakefulness/abnormal sleep pattern, irritability, sneezing, seizure, tremor, yawning) (Dow 2012; Hudak 2012). Mothers who are physically dependent on opioids may give birth to infants who are also physically dependent. Opioids may cause respiratory depression and psycho-physiologic effects in the neonate; newborns of mothers receiving opioids during labor should be monitored.

Morphine injection is commonly used for the treatment of pain during labor and immediately postpartum (ACOG 209 2019). Not all dosage forms are appropriate for this use. Agents other than morphine are used to treat chronic non-cancer pain in pregnant women or those who may become pregnant (CDC [Dowell 2016]; Chou 2009).

Breastfeeding Considerations

Morphine is present in breast milk. M6G, the active metabolite of morphine, can also be detected in breast milk (Baka 2002). Reported concentrations of morphine in breast milk are variable.

Morphine has been detected in the urine of a breastfeeding infant following maternal epidural dosing after cesarean delivery (Zakowski 1993) and the serum of an infant following chronic maternal oral use (Robieux 1990).

Nonopioid analgesics are preferred for breastfeeding females who require pain control peripartum or for surgery outside of the postpartum period. However, when a narcotic is needed to treat maternal pain, morphine is one of the preferred agents (ABM [Martin 2018]; ABM [Reece-Stremtan 2017]; Sachs 2013). Analgesics delivered by PCA or administered by the epidural route help limit infant exposure (Sachs 2013). Note: Not all formulations are indicated for intermittent pain control.

When opioids are needed in breastfeeding women, the lowest effective dose for the shortest duration of time should be used to limit adverse events in the mother and breastfeeding infant. In general, a single occasional dose of an opioid analgesic may be compatible with breastfeeding (WHO 2002). Breastfeeding women using opioids for postpartum pain or for the treatment of chronic maternal pain should monitor their infants for drowsiness, sedation, feeding difficulties, or limpness (ACOG 209 2019). Withdrawal symptoms may occur when maternal use is discontinued, or breastfeeding is stopped.

Dietary Considerations

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

Monitoring Parameters

Pain control, respiratory and mental status; blood pressure; signs of misuse, abuse, and addiction; signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013)

Alternate recommendations: Chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment): Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of treatment initiation and with dose increases. Re-evaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder. Urine drug testing is recommended prior to initiation and 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]).

Critically ill: The Numeric Rating Scale should be used in patients who are able to self-report pain. In patients who are unable to self-report pain, the Behavioral Pain Scale and the Critical-Care Pain Observational Tool can be used in intubated or nonintubated patients (SCCM [Devlin 2018]).

Epidural/intrathecal: 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 or Mitigo via microinfusion device, patient may be observed, as appropriate, for the first several days after catheter implantation.

Alternative monitoring recommendations (Bujedo 2012a): 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.

Mechanism of Action

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

Pharmacokinetics

Onset of action (patient dependent; dosing must be individualized): Oral (immediate release): ~30 minutes; IV: 5 to 10 minutes.

Duration (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 2012a).

Suppository: 3 to 7 hours.

Absorption: Variable.

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

Preterm neonates: 2.04 ± 1.01 L/kg (range: 0.6 to 3.68 L/kg) (Chay 1992).

Term neonates: 2.07 ± 1.26 L/kg (range: 0.24 to 3.34 L/kg) (Chay 1992).

Children with cancer (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).

Protein binding: Premature infants: 18% to 22% (Bhat 1990); Adults: 20% to 35%.

Metabolism: Hepatic via conjugation with glucuronic acid primarily to morphine-6-glucuronide (M6G) (active analgesic) 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. Due to immature hepatic enzyme development, neonates exhibit at least a 50% lower glucuronidation rate than older children (Cravero 2019).

Bioavailability: Oral: 17% to 33% (first-pass effect limits oral bioavailability); Nebulization: 5.5 ± 3.2% (Masood 1996).

Half-life elimination:

Pediatric: Note: Values listed are based on IV dosing (IV bolus and/or continuous IV infusion):

Preterm neonates: 10.6 ± 2.7 hours (range: 5.5 to 13.3 hours) (Chay 1992).

Term neonates: 7.6 ± 2.6 hours (range: 4.5 to 11 hours) (Chay 1992).

Infants 1 to 3 months: Median: 6.2 hours (range: 5 to 9.9 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 (Olkkola 1995).

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

Adults: Immediate-release forms: 2 to 4 hours; Kadian: 11 to 13 hours.

Time to peak:

Plasma:

Tablets, oral solution, epidural: 1 hour.

Extended release tablets: 3 to 4 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).

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 (Olkkola 1995).

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 (Olkkola 1995).

Children with cancer (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.

Pharmacokinetics: Additional Considerations

Pediatric: Increased pharmacokinetic variability in neonates likely due to immaturity of hepatic glucuronidation, alterations in hepatic blood flow during acute illness, and blood shunting away from the liver by the ductus venosus (Bhat 1990).

Pricing: US

Capsule ER 24 Hour Therapy Pack (Morphine Sulfate ER Beads Oral)

30 mg (per each): $5.73

45 mg (per each): $8.50

60 mg (per each): $11.13

75 mg (per each): $14.16

90 mg (per each): $16.73

120 mg (per each): $19.74

Capsule ER 24 Hour Therapy Pack (Morphine Sulfate ER Oral)

10 mg (per each): $4.73

20 mg (per each): $5.23

30 mg (per each): $5.69

50 mg (per each): $9.50

60 mg (per each): $11.37

80 mg (per each): $15.15

100 mg (per each): $19.01

Solution (Infumorph 200 Injection)

200 MG/20ML (10 mg/mL) (per mL): $12.48

Solution (Infumorph 500 Injection)

500 MG/20ML (25 mg/mL) (per mL): $21.22

Solution (Mitigo Injection)

200 MG/20ML (10 mg/mL) (per mL): $12.49

500 MG/20ML (25 mg/mL) (per mL): $21.24

Solution (Morphine Sulfate (Concentrate) Oral)

100 mg/5 mL (per mL): $0.75 - $0.84

Solution (Morphine Sulfate (PF) Injection)

0.5 mg/mL (per mL): $0.82

1 mg/mL (per mL): $0.90

2 mg/mL (per mL): $3.44

4 mg/mL (per mL): $3.44

5 mg/mL (per mL): $3.44

8 mg/mL (per mL): $3.53

10 mg/mL (per mL): $3.66

Solution (Morphine Sulfate (PF) Intravenous)

1 mg/mL (per mL): $0.56

2 mg/mL (per mL): $2.56 - $4.25

4 mg/mL (per mL): $2.34 - $4.28

8 mg/mL (per mL): $2.29

10 mg/mL (per mL): $2.29 - $5.04

Solution (Morphine Sulfate Injection)

2 mg/mL (per mL): $3.44

4 mg/mL (per mL): $3.44

Solution (Morphine Sulfate Intravenous)

1 mg/mL (per mL): $0.48

4 mg/mL (per mL): $2.41 - $3.00

8 mg/mL (per mL): $3.38 - $3.39

10 mg/mL (per mL): $3.06

50 mg/mL (per mL): $0.77

Solution (Morphine Sulfate Oral)

10 mg/5 mL (per mL): $0.33

20 mg/5 mL (per mL): $0.18

Suppository (Morphine Sulfate Rectal)

5 mg (per each): $5.00

10 mg (per each): $6.25

20 mg (per each): $7.50

30 mg (per each): $9.38

Tablet, controlled release (Morphine Sulfate ER Oral)

15 mg (per each): $0.39 - $1.87

30 mg (per each): $0.73 - $3.38

60 mg (per each): $1.40 - $6.21

100 mg (per each): $2.12 - $9.20

200 mg (per each): $3.88 - $18.38

Tablet, controlled release (MS Contin Oral)

15 mg (per each): $5.05

30 mg (per each): $9.60

60 mg (per each): $18.73

100 mg (per each): $27.73

200 mg (per each): $50.79

Tablets (Morphine Sulfate Oral)

15 mg (per each): $0.49 - $0.91

30 mg (per each): $0.84 - $1.54

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Analfin (CR, DO, GT, HN, NI, PA, SV);
  • Anamorph (AU);
  • Contalgin (DK, IS);
  • Depolan (FI, SE);
  • Dimorf (BR);
  • Dimorf SP (PY);
  • Dolcontin (FI, SE);
  • Dolcontin Depottab (NO);
  • Doltard (DK, EE, LV);
  • Graten (CR, DO, GT, HN, NI, PA, SV);
  • Kadian (BM);
  • Kapanol (AU);
  • M-Eslon (CL, CO, EC, NZ, PE);
  • M.I.R. (IL);
  • Malfin (NO);
  • MCR (IL);
  • Morfex (BD);
  • Morgesic XR (BD);
  • Morin (PH);
  • Morphgesic (TR);
  • Morphgesic SR (GB, MT);
  • Morphiprex (EG);
  • Moscontin (FR);
  • MS Contin (AU, BE, CN, IT, LU, NL, VE, VN);
  • MS Contin CR (KR);
  • MS Mono (AU);
  • MSP (IL);
  • MST (PT);
  • MST Continus (AE, AR, BF, BG, BH, BJ, CI, CY, CZ, EE, EG, ES, ET, GB, GH, GM, GN, HK, HR, ID, IE, IQ, IR, JO, KE, KW, LB, LR, LY, MA, ML, MR, MT, MU, MW, MY, NE, NG, OM, PH, PK, PL, QA, RO, SA, SC, SD, SG, SK, SL, SN, SY, TH, TN, TR, TW, TZ, UG, YE, ZA, ZM, ZW);
  • MST Continus Retard (CH);
  • Mundidol Retard (AT);
  • MXL (TW);
  • Oramorph (BE, ES, FR, GB, HR, IE, IL, IT, LU, NL, PT);
  • P Guard (JP);
  • Pacif (JP);
  • Painbreak (DE);
  • Rumorf (IN);
  • S-Morphine (KR);
  • Sevredol (AU, CH, CZ, DE, HR, IE, NZ, RO, SI, SK, TR);
  • SRM-Rhotard (ZA);
  • Statex (SG);
  • Vendal (AT, UY);
  • Vendal Retard (LV);
  • Vermor (LK)


For country code abbreviations (show table)
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