Morphine is a strong opioid analgesic medication that is available as an injection, tablets, capsules, and suppositories for moderate to severe pain and perioperatively.

Morphine Uses:

• Acute and chronic pain management:

  • Injection:
    • It is used in management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.
  • Preservative-free solutions only:
    • Duramorph:
      • It can be used in the Epidural or intrathecal management of pain without attendant loss of motor, sensory, or sympathetic function.
      • It should be noted that it is not for use in continuous microinfusion devices.
    • Infumorph, Mitigo:
      • It is also used in continuous micro-infusion 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.
      • It is notable that it is not for single-dose IV, IM, or subcutaneous administration or single-dose neuraxial injection.
  • Oral:
    • Extended release:
      • It is used in management of pain severe enough to require daily, around-theclock, long-term opioid treatment and for which alternative treatment options are inadequate.
    • Immediate release:
      • It can also be used in management of acute and chronic pain 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 patients.
  • Rectal:
    • It is also used in management of acute and chronic pain severe enough to require an opioid analgesic and for which alternative treatments are insufficient.
  • Limitations of use:
    • Its use should be reserved for use in patients for whom alternative treatment options (eg, nonopioid analgesics, opioid combination products) are inadequate, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. ER formulations are not required as as-needed analgesics.

• Off Label Use of Morphine in Adults:

  • It used dor analgesia and sedation in critically ill patients in the ICU.
  • Dyspnea in palliative care patients,

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Morphine Dose in Adults:

 

Morphine Dose in the treatment of moderate to severe pain:

• It is important to note for 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.
• The reccomendations regarding dosing provided is based on typical doses and some patients might require higher or lower doses.
• The dosing abd intervals should be individualized  based on patient-specific factors (eg, comorbidities, severity of pain, concomitant medications, general condition, degree of opioid experience/tolerance) and titrate up to patient specific treatment goals (eg, improvement in function and quality of life, decrease in pain using a validated pain rating scale).
• The lowest effective doseshould be used 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 less than 3 days is often adequate, whereas use more than 7 days is rarely needed.
• Do not use long-acting preparations for treatment of acute pain in opioid-naive patients. Before starting opioid therapy for chronic pain, establish realistic goals for pain and function, and consider how therapy will be stopped if benefits do not outweigh risks.

Morphine Dose in the treatment of Acute pain:

• General dosing:

The dosing presented in this section is for opioid-naive patients. Patients who are opioid-tolerant will likely require higher dosing and soses should be adjusted accordingly.

• Oral: Opioid-naive patients:

  • Immediate release: Oral solution, Tablet:

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

• Initially it is given as 10 mg every 4 hours as required.
• If pain is not relieved, one may increase the dose as tolerated. it can be given up to 30 mg every 4 hours as needed for severe, acute pain in hospitalized patients at low risk for respiratory depression.

• IV: Opioid-naive patients:

  • Intermittent:
    • Initially, it is given as 1 to 4 mg every 1 to 4 hours as required.
    • If pain is not relieved, the dose can be increased as tolerated.
    • It can be given up to 10 mg every 4 hours as needed for severe, acute pain in hospitalized patients at low risk for respiratory depression.
    • For some severe acute pain episodes (eg, trauma), one 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).
    • It should be noted that 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.

  • Patient-controlled analgesia:

IV Patient-Controlled Analgesia: Initial Dose Ranges for Opioid-Naive Patientsa
Usual concentration	1 mg/mL
Demand dose	Usual range: 0.5 to 2.5 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)
aFor use to maintain pain control after initial pain control achieved. May adjust dosing and provide rescue bolus doses (eg, 0.5 to 2.5 mg) if analgesia is inadequate. 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.

• IM (not recommended for routine use):

  • Opioid-naive patients:

    • Initially it is given up to 5 to 10 mg every 3 to 4 hours as needed.
    • If pain is not relieved, the dose can be increased as tolerated.
    • IM administration is generally not preferred due to pain associated with injection, variable absorption, and delayed time to peak effect.

Morphine Dose in the treatment of Acute pain in specific conditions:

• Acute coronary syndrome in refractory ischemic chest pain:

It should be used only in patients with continued ischemic chest pain despite maximally tolerated anti-ischemic medications. 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.

• IV: 2 to 4 mg is given initially, followed by 2 to 8 mg every 5 to 15 minutes as needed OR 1 to 5 mg initially, followed by 1 to 5 mg every 5 to 30 minutes as indicated.

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

  • Oral, IV, SubQ:
    • The usual dose should be given 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.

• Morphine Dose in the Critically ill patients in the ICU (analgesia and sedation) (off-label):

Many 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.

• IV:
  • Loading dose:
    • It is given 2 to 10 mg, followed by maintenance dosing. More than 1 loading dose might be indicated.
    • The 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).
  • Maintenance dosing:
    • It is given as 2 to 4 mg every 1 to 2 hours or 4 to 8 mg every 3 to 4 hours.

• Morphin Dose in the Postoperative pain:

  • Initial pain control in the post-anesthesia care unit:

    • Intravenously it is given as 1 to 3 mg as frequently as every 5 minutes until adequate pain relief or unwanted side effects (eg, respiratory depression, oxygen desaturation, hypotension) occur.
    • A maximum cumulative dose (e.g, 20 mg) prompting a reevaluation of continued morphine use or the dose should be included as part of any medication order intended for short-term use (eg, postanesthesia care unit orders).

  • Ongoing pain control:

    • IV: It is given as 1 to 4 mg every 1 to 4 hours as indicated. One may give up to 10 mg every 2 to 4 hours as required for severe, acute pain in patients at low risk for respiratory depression.
    • If patient-controlled analgesia is needed, refer to Example IV Patient-Controlled Analgesia Initial Dose Ranges for Opioid-Naive Patients table.

• Morphine Dose in the treatment of Sickle cell disease, vaso-occlusive pain :

The dosing which is presented is for patients in the 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 the opioid dose given for a prior episode is known, then choose the initial dose based on the intensity of pain in comparison with the previous episode and the previous effective dose.

• IV:
  • Initially, it's given as 0.1 to 0.15 mg/kg with a maximum initial dose of 10 mg given once within 30 minutes of presentation, reassess pain within 20 minutes.
  • If continued severe pain, repeat with doses of 0.02 to 0.05 mg/kg every 20 to 30 minutes to achieve pain relief.
  • If IV access is difficult, may administer SubQ. If pain relief is not achieved after more than 3 doses, hospitalization for around-the-clock parenteral analgesics is generally indicated.
  • Evaluate the need for long-acting opioids. If the patient usually requires a long-acting opioid at home, the physician might convert it to oral home regimen once IV dose is roughly equivalent to a long-acting opioid dose.

• Morphine Dose in the treatment of chronic pain, including chronic cancer pain:

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 a clinically meaningful improvement in pain and function that outweighs patient safety risks.

• Opioid-naive patients:

  • In general, for noncancer pain, morphine requirements should be established using IR formulations.
  • With cancer pain, may switch to a long-acting formulation earlier in the course of therapy.

  • Oral: Immediate release: Oral solution, Tablet:

Note: The 100 mg/5 mL (or 20 mg/mL) concentrated oral solution is not preferred for opioid-naive patients.

• • • Noncancer or cancer pain:
      • Initially, it is given for 5 to 30 mg every 4 hours as needed or scheduled around the clock for some patients (eg, cancer pain).
      • For chronic non-cancer pain, most patients will have pain control with initial doses <50 mg/day.
    • Titration:
      • For chronic non-cancer pain, one can increase the dose slowly in increments of no more than 25% to 50% of the total daily dose.
      • For chronic cancer pain, the dose might be increased above 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 is decreased, continue current effective dosing. In order to reduce the risk of overdose, caution should be exercised when increasing opioid dosage to more than 50 MME/day and avoid increasing dosage to more than 90 MME/day or carefully justify a decision to titrate dosage to more than 90 MME/day.

  • IV, SubQ:

    • It is typically reserved for acute exacerbations or those who cannot tolerate oral administration.
    • For progressive illnesses like cancer, a continuous IV or SubQ infusion, with or without a patient-controlled analgesia option, can also be used as pain requirements increase.
    • Noncancer or cancer pain:
      • IV: Initially it is given as 2 to 5 mg every 2 to 4 hours as needed.
    • Cancer pain or palliative care:
      • SubQ: Initially it is given 2 to 5 mg every 3 to 4 hours as needed. If a continuous SubQ infusion is employed, to maintain comfort, the SubQ infusion rate should generally not exceed 5 mL/hour.

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

  • Oral: Extended-release:

It should be noted that although literature 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 extended-release opioids should be reserved for patients who have received IR opioids daily for greater than 1 week yet continue to experience severe, continuous pain.

• • Capsules, extended-release (Kadian): See Dose conversions for pain management:
    • The calculated dose may be administered once a day or in 2 equally divided doses administered every 12 hours.
    • One might consider dose reduction with the first several doses when converting from IR formulations. e.g an initial dose of 30 mg once a day or 15 mg every 12 hours. Dose adjustments can be made as frequently as every 1 to 2 days.
  • Tablets, extended-release (Arymo ER, MorphaBond ER, MS Contin): See Dose conversions for pain management:
    • The calculated dose can be administered in 2 equally divided doses (every 12 hours) or 3 equally divided doses (every 8 hours).
    • One might consider dose reductions with the first several doses when converting from IR formulations. For example, an initial dose of 15 mg every 8 or 12 hours. Dose adjustments may be made as frequently as every 1 to 2 days.

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Morphine Dose conversions for pain management:

Equianalgesic conversions serve only as a general guide to estimate opioid dose equivalents. Multiple factors can 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 more than 1 week.

• Converting from oral morphine to parenteral morphine:

  • Approximate equivalency:
    • 30 mg (oral morphine) is equal to 10 mg (IV/SubQ morphine).

• Converting from oral IR morphine to oral ER morphine preparations:

  • Arymo ER, MorphaBond ER, MS Contin:
    • Total daily oral morphine dose can be administered either in 2 divided doses 12 hourly or in 3 divided doses 8 hourly hours.
  • Kadian:
    • The total daily oral morphine dose administered once a day in patients experiencing inadequate analgesia with once-daily dosing.
    • The total daily dose can be administered in 2 divided doses i.e 12 hourly.

• 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 might be higher or lower than expected. Therefore, when switching from oral to rectal dosing, a reduction in rectal dose may be necessary.

• 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 one can refer to institutional protocols.
  • Provided conversion ratios are only approximations and substantial interpatient variability exists.
  • Hence, 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 or 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 and from methadone are highly variable and require extreme caution.

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Discontinuation of pain management therapy:

• When reducing the dose or discontinuing chronic opioid therapy, the dose should be gradually tapered. An optimal tapering schedule has not been established.
• Proposed schedules range from slow (eg, 10% reduction per week) to rapid (eg, 25% to 50% reduction every few days).
• Individualize to minimize withdrawal symptoms while considering patient-specific goals and concerns as well as the opioid’s pharmacokinetics.
• Slower tapers might 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.
• Observe carefully for symptoms of withdrawal.
• If the patient displays withdrawal symptoms, consider slowing the taper schedule.
• Alterations might include increasing the interval between dose reductions, decreasing the amount of daily dose reduction, pausing the taper and restarting when the patient is ready, or coadministration of an alpha-2 agonist like clonidine to blunt withdrawal symptoms.
• Continue to offer nonopioid analgesics as indicated for pain management during the taper.
• Consider nonopioid adjunctive treatments for withdrawal symptoms (eg, GI complaints and muscle spasms) as required.

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Morphine Dose in the treatment of Neuraxial analgesia:

• Epidural:

It is important to note that epidural should be reserved for severe pain (eg, after surgery, cancer pain). It must be administered by health care providers skilled in the care of patients receiving intraspinal opioids. Use a preservative-free (PF) formulation intended for neuraxial use.

• • Single-dose (using 0.5 or 1 mg/mL PF solution): Opioid-naive patients:
    • The usual range is 2 to 3.75 mg.
    • It also depends on patient comorbidities.
  • Continuous infusion (using 0.5 or 1 mg/mL PF solution):
    • Opioid-naive patients: 0.2 to 0.4 mg/hour.
    • It might be given alone or usually in combination with local anesthetics (eg, bupivacaine, ropivacaine).
    • When combined with a local anesthetic, the analgesic effect is increased due to synergism.
  • Continuous microinfusion (using a device intended for continuous microinfusion):
    • It should be used in a 10 mg/mL or 25 mg/mL PF solution (eg, Infumorph); dilution may be required.
    • Initially, it is given as 3.5 to 7.5 mg over 24 hours.

• Intrathecal:

  • Its use is reserved for severe pain (eg, after surgery, cancer pain).
  • It should be administered by health care providers skilled in the care of patients receiving intraspinal opioids.
  • Use a PF formulation intended for neuraxial use.
  • The intrathecal dose is usually one-tenth that of epidural dosage.
  • Single-dose (using 0.5 or 1 mg/mL PF solution):
    • The usual range is 0.1 to 0.2 mg coadministered with a local anesthetic.
    • Repeat doses are not recommended.
    • If pain recurs within 24 hours of administration, the use of an alternative route of administration is preferred.
    • Although product labeling recommends doses up to 1 mg, the risk of adverse effects like nausea, and respiratory depression is higher with doses of more than 0.3 mg.
    • However, some patients with chronic intractable pain (eg, cancer pain) might require doses up to 0.5 mg.
  • Continuous microinfusion (using a device intended for continuous microinfusion):
    • One should  use a 10 mg/mL or 25 mg/mL PF solution (eg, Infumorph).
    • Dilution might be required.
    • Initially, it is given as 0.2 to 1 mg over 24 hours.

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Morphine Dose in the treatment of Dyspnea in palliative care patients (off-label):

• Opioid-naive patients:

  • Moderate dyspnea:

    • Immediate-release (may use 100 mg/5 mL [20 mg/mL] solution): Oral, Sublingual:
      • Initially, it is given as 5 mg every 2 to 4 hours with 2.5 mg every 2 hours as needed or on an “offer, may refuse” basis.
      • Initially, consider lower scheduled doses (eg, 2.5 mg every 2 hours) in patients who are older, frail, or with dyspnea in a setting of heart failure or chronic obstructive pulmonary disease.

  • Severe dyspnea:

    • SubQ, IV:
      • Initially, it is given as 2.5 mg. If dyspnea persists and an initial dose is well tolerated, one can 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 doses can be doubled.

• 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. Morphine equivalents should be calculated.
      • And it is given every 2 hours as needed or on an “offer, may refuse” basis. Consider increasing the regular daily dose by approximately 25% taking into consideration breakthrough doses used in the previous 24 hours.

  • 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, one can give approximately 10% of the current parenteral opioid daily dose.

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Morphine Dose in Children:

Doses should be titrated up to appropriate effect. One should use lower doses in opioid-naive patients. When changing routes of administration in chronically treated patients, please note that oral doses are approximately one-half as effective as parenteral dose.

Morphine Dose in the treatment of moderate to severe acute pain:

Repeated SubQ administration causes local tissue irritation, pain, and induration. The use of intramuscular injections is no longer preferred, especially for repeated administration due to painful administration, variable absorption, and lag time to peak effect. However, other routes are more reliable and less painful.

• Infants ≤6 months, nonventilated:

it is important to note that infants less than 3 months of age are more susceptible to respiratory depression. Lower doses are recommended. Consider frequent or continuous respiratory monitoring (eg, pulse oximetry) and be in a setting that permits rapid management of respiratory insufficiency.

• Oral: Oral solution (2 mg/mL or 4 mg/mL):
  • 0.08 to 0.1 mg/kg/dose every 3 to 4 hours.
• IV or SubQ:
  • 0.025 to 0.03 mg/kg/dose every 2 to 4 hours.

• Infants ≤6 months, ventilated patients:

Infants less than 3 months are more susceptible to respiratory depression. Patients should have continuous respiratory monitoring (eg, pulse oximetry) and be in a setting that permits rapid management of respiratory insufficiency.

• • IV: intermittent dosing:
    • Infants ≥3 months:
      • Initially, it is given as 0.05 mg/kg/dose every 2 to 4 hours. The dosing is based on experience in postoperative cardiothoracic patients.
  • Continuous IV infusion:
    • Initially its given as 0.008 to 0.02 mg/kg/hour (8 to 20 mcg/kg/hour).
    • Titrate-up carefully to effect. The reported dose range following titration is  0.015 to 0.04 mg/kg/hour (15 to 40 mcg/kg/hour).
    • The dosing is based on studies in postoperative patients, most commonly following cardiac surgery. Lower initial doses have been reported in infants following cardiac surgery compared to non-cardiac surgical infants.
    • Infants with Down Syndrome have been reported to have similar morphine requirements postoperatively as patients without following cardiac surgery.

• Infants >6 months, Children, and Adolescents:

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

    • Patient weight <50 kg:
      • It is given as 0.2 to 0.5 mg/kg/dose every 3 to 4 hours as needed.
      • Some clinicians have recommended an initial dose of 0.3 mg/kg for severe pain. The usual initial maximum dose is 15 to 20 mg.
    • Patient weight ≥50 kg:
      • 15 to 20 mg every 3 to 4 hours as needed.

  • IM, IV, or SubQ; intermittent dosing:

    • Patient weight <50 kg: Opioid naïve:
      • Initially, it is given as 0.05 mg/kg/dose.
      • The usual maximum initial dose is 1 to 2 mg/dose.
      • The higher doses might be required if pain not adequately controlled or if the patient is opioid-tolerant.
      • The usual range is  0.1 to 0.2 mg/kg/dose every 2 to 4 hours as needed. Use of lower doses in opioid naïve patients is recommended.
      • The usual maximum dose is Infants: 2 mg/dose. Children 1 to 6 years: 4 mg/dose.
      • For children of 7 to 12 years, it is given as 8 mg/dose and in adolescents, it is given as 10 mg/dose.
    • Patient weight ≥50 kg:
      • Initially, it is given as 2 to 5 mg every 2 to 4 hours as needed.
      • Use of a lower end of the dosing range in opioid naïve patients is preferred.
      • The higher doses have been recommended (5 to 8 mg every 2 to 4 hours as needed) and might be needed in tolerant patients.

  • 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.

• Patient weight <50 kg:
  • Initially its given as 0.01 mg/kg/hour (10 mcg/kg/hour).
  • Titrate up carefully to effect. The dosage range is 0.01 to 0.04 mg/kg/hour (10 to 40 mcg/kg/hour).
• Patient weight ≥50 kg: 5 mg/hour.
• 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.

Morphine Epidural Administration: Astramorph/PF, Duramorph: Limited data available:

Note: Must use preservative-free formulation:

• Intermittent:

  • Infants, Children, and Adolescents:
    • 0.015 to 0.05 mg/kg (15 to 50 mcg/kg).
    • The maximum dose is 0.1 mg/kg (100 mcg/kg) or 5 mg/24 hours.

• Continuous epidural infusion:

  • Infants >6 months, Children, and Adolescents:
    • It is given as 0.001 to 0.005 mg/kg/hour (1 to 5 mcg/kg/hour).

Morphine Dose in the treatment of Analgesia for minor procedures/sedation:

• Infants, Children, and Adolescents:

  • IV: its given as 0.05 to 0.1 mg/kg/dose.
  • Administer the dose 5 minutes before the procedure.
  • The maximum dose is 4 mg. One may repeat the dose in 5 minutes if necessary.

Morphine Dose in the treatment of Patient-controlled analgesia (PCA), opioid-naïve:

It is important to note that all patients should receive an initial loading dose of an analgesic to attain adequate control of pain prior to starting PCA for maintenance. Adjust doses, lockouts, and limits based on required loading dose, age, state of health, and presence of opioid tolerance. Use of lower end of dosing range for opioid-naïve patients is recommended. Assess patient and pain control at regular intervals and adjust settings if needed:

• 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.

• • Usual concentration: 1 mg/mL.
  • Demand dose: Usual initial: 0.02 mg/kg/dose. The usual range is 0.01 to 0.03 mg/kg/dose.
  • Lockout: Usual initial: 5 doses/hour.
  • Lockout interval: Range: 6 to 8 minutes.
  • Usual basal rate: 0 to 0.03 mg/kg/hour.

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

  • Usual concentration: 1 mg/mL.
  • Demand dose: Usual initial: 1 mg. The usual range is 0.5 to 2.5 mg.
  • Lockout interval: Usual initial: 6 minutes. The usual range is 5 to 10 minutes.

Morphine Dose in the treatment of chronic pain:

Patients taking opioids chronically might become tolerant and require doses higher than the usual dosage range to maintain the desired effect. Tolerance can be managed by appropriate dose titration. There is no optimal or maximal dose for morphine in chronic pain. The appropriate dose is one that relieves pain throughout its dosing interval without causing undesirable side effects. Consider total daily dose, potency, prior opioid use, degree of opioid experience and tolerance, conversion from the previous opioids including opioid formulation, patient's general condition, concurrent medications, and type and severity of pain during the prescribing process.

• Oral: Extended-/controlled-release preparations:

  • A patient's morphine requirement should be established using immediate-release formulations.
  • Conversion to long-acting products might be considered when chronic, continuous treatment is required. Higher dosages should be reserved for use only in opioid-tolerant patients.
  • Capsules, extended-release (Avinza): Adolescents ≥18 years:
    • The daily dose is administered once a day.
    • For best results, administer the dose at the same time each day.
    • Opioid-naive: Initially it is given as 30 mg once a day. Adjust in increments of less than 30 mg daily every 4 days.
  • Capsules, extended-release (Kadian): Adolescents ≥18 years:
    • Its use is not intended for use as an initial opioid in the management of pain.
    • One should use immediate-release formulations before initiation.
    • Total daily oral morphine dose can be either administered once a day or in 2 divided doses daily (every 12 hours).
    • The first dose of Kadian may be taken with the last dose of the immediate-release morphine.
  • Tablets, controlled-release (MS Contin):
    • Children and Adolescents able to swallow tablets whole:
      • It is usually not used as an initial opioid in the management of pain.
      • Use of immediate-release formulations is advised and titrate up the dose.
      • Total daily morphine dose can be administered in 2 divided doses daily (every 12 hours) or in 3 divided doses daily (every 8 hours).
    • Weight-directed dosing:
      • 0.3 to 0.6 mg/kg/dose every 12 hours.
    • Alternate dosing; fixed dosing (Berde 2002):
      • Patient weight 20 to <35 kg:
        • 10 to 15 mg every 8 to 12 hours.
        • It is notable that 10 mg strength not available in the US.
      • Patient weight 35 to <50 kg:
        • 15 to 30 mg every 8 to 12 hours.
      • Patient weight ≥50 kg:
        • 30 to 45 mg every 8 to 12 hours.

    • Discontinuation of extended-release formulations:

      • In general, gradually taper off the dose. (eg, every 2 to 4 days). Do not discontinue abruptly.

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

      • Avinza: Adolescents ≥18 years:
        • Total daily morphine dose administered once a day.
        • The first dose of Avinza can be taken with the last dose of the immediate-release morphine.
        • The maximum daily dose is 1,600 mg/day due to fumaric acid content.
      • Kadian: Adolescents ≥18 years:
        • Total daily oral morphine dose can be either administered once a day or in 2 divided doses daily (every 12 hours).
      • MS Contin: Children and Adolescents:
        • Total daily oral morphine dose can be administered either in 2 divided doses daily (every 12 hours) or in 3 divided doses i.e every 8 hourly.

    • Conversion from parenteral morphine or other opioids to controlled/ extended-release formulations: Substantial interpatient variability exists in relative potency.

      • Hence, it is safer to underestimate a patient's daily oral morphine requirement and provide breakthrough pain relief with immediate-release morphine than to overestimate requirements.
      • Consider the parenteral to oral morphine ratio or other oral or parenteral opioids to oral morphine conversions.

    • Continuous IV infusion, SubQ continuous infusion:

      • Children and Adolescents:
      • It is given as  0.01 to 0.04 mg/kg/hour (10 to 40 mcg/kg/hour).
      • Opioid-tolerant patients do require higher doses.
      • Conversion from intermittent IV morphine:
      • Administer the patient's total daily IV morphine dose over 24 hours as a continuous infusion. Titrate up the dose to appropriate effect.

Morphine Dose in the treatment of acute sickle cell crisis in opioid naïve patients:

Note: Individualize the dose and titrate up to effect.

• Infants ≥6 months, Children, and Adolescents:

  • Patient weight <50 kg:
    • Initially, it is given as IV in 0.1 to 0.15 mg/kg every 2 to 4 hours.
    • The maximum dose is 7.5 mg/dose.
  • Patient weight ≥50 kg:
    • Initially, it is given as IV in 5 to 10 mg every 2 to 4 hours.

Morphine Dose in the treatment of Tetralogy of Fallot, hypercyanotic spell (infundibular spasm):

• Infants and Children: Limited data available:

  • IM, IV, SubQ:
    • It is given as 0.1 mg/kg has been used to decrease ventilatory drive and systemic venous return.

Morphine Dose in the treatment of Palliative care, dyspnea management:

• Children and Adolescents:

  • Inhalation (nebulization, preservative-free injection):
    • The dose should be individualized and is dependent upon the patient's previous or current systemic opioid exposure.
    • Such doses are not intended to provide analgesic activity. Ongoing systemic analgesia should be continued.
    • The initial dose should be equivalent to the patient's 4-hour systemic morphine requirement (eg, IV or oral dose).
    • Titrate to the effect and every 4 to 6 hour administration has been suggested.
  • Continuous IV or SubQ infusion (when oral ineffective):
    • Initially its given as 0.005 mg/kg/hour (5 mcg/kg/hour).
    • Titrate for comfort. The dosing based on palliative management of terminal infants with spinal muscular atrophy (type 1). The intermittent IV maximum doses of 0.4 mg/kg have been reported to control symptoms of dyspnea and pain.
  • Oral:
    • 0.1 mg/kg/dose every 4 hours as needed. Titrate up for comfort.
    • The dosing is based on the palliative management of terminal infants with spinal muscular atrophy (type 1).
    • The recommended maximum doses of 0.4 mg/kg have been reported to control symptoms of dyspnea and pain.

---

Morphine Pregnancy Category: D

• The placental barrier is broken by Morphine
• Some studies have shown that opioid use by mothers may be linked to birth defects such as congenital heart defects, neural tube defects, and gastroschisis.
• Temporary effects of opioids used during labor and birth may occur.
• [US Boxed Warning]Neonatal opioid withdrawal syndrome can develop from prolonged use of morphine in pregnancy. This condition is life-threatening and must be treated according to the protocols established by neonatology specialists.
• Pregnant women who are required to use opioids for prolonged periods of time should be advised and treated.
• A pregnant woman who has been exposed to chronic opioids during pregnancy may experience withdrawal symptoms in her newborn.
• Symptoms of neonatal Abstinence Syndrome (NAS) may include autonomic symptoms (eg. fever, temperature instability), gastrointestinal symptoms (eg. diarrhea, vomiting), or neurologic (eg. high-pitched crying and hyperactivity, increased muscle tone/abnormal wakefulness/sleep pattern, irritability/sneezing), seizure/tremor, yawning).
• Opioid-dependent mothers can give birth to babies who are also dependent.
• Opioids can cause respiratory depression in neonates and have psychophysiological side effects. 
• Monitoring should be done for newborns born to mothers who received opioids during labor.
• A common use of Morphine injections is to treat pain immediately after birth and during labor.
• Some dosage forms may not be appropriate for this purpose.
• It is preferable to use agents other than morphine for chronic pain that is not cancerous in pregnant women, or people who may become pregnant.
• Long-term opioid abuse can cause secondary hypogonadism. This could lead to infertility or sexual dysfunction in both men and women.

Morphine use during breastfeeding:

• Breast milk contains Morphine.
• Breast milk can contain M6G, which is the active metabolite for morphine.
• The reported levels of morphine found in breast milk vary widely.
• After cesarean delivery, maternal epidurals were administered to the infant. The serum was also tested for Morphine.
• Breastfeeding women who need pain control postpartum or after surgery are advised to use nonopioid analgesics.
• Morphine is the preferred choice when a narcotic medication is required to relieve maternal pain.
• Infant exposure can be controlled by using analgesics administered via the epidural route or by PCA.
• Not all formulations can be used for intermittent pain relief.
• To limit adverse reactions in mother and baby when opioids are required for breastfeeding, it is important to use the lowest dose of opioids for the shortest time.
• A single, occasional dose of opioid analgesics may be acceptable with breastfeeding.
• Breastfeeding mothers who use opioids to treat postpartum pain and chronic maternal pain should be vigilant for signs of drowsiness, sedation or feeding difficulties in infants.
• When breastfeeding is stopped or maternal use is cut off, withdrawal symptoms can occur.

 

---

 

Morphine dose in Kidney Disease:

• According to the literature, there are no dosage adjustments for any formulation.
• Manufacturers recommend that you start slowly with lower doses and to gradually increase your monitoring for side effects.
• Patients with renal impairment, or rapidly changing renal function may want to consider alternative opioids.
• Other analgesics are safer than morphine and may provide suboptimal pain relief.
• While morphine clearance is comparable in patients with normal renal function and is relatively easy, renal impairment can cause increased sensitivity.
• Patients can also experience prolonged and severe respiratory depression that may be even delayed.

Morphine Dose in Liver disease:

• There are no dosage adjustments provided in the manufacturer's labeling.
• Pharmacokinetics is unchanged in mild liver disease.
• Substantial extrahepatic metabolism does occur.
• In cirrhosis, increases in half-life and AUC suggest dosage adjustment required.

---

Common Side Effects of Morphine:

• Central nervous system:

  • Drowsiness
  • Headache

• Gastrointestinal:

  • Constipation
  • Nausea
  • Vomitting

• Genitourinary:

  • Urinary retention

Less Common Side Effects of Morphine:

• Cardiovascular:

  • Peripheral Edema
  • Chest Pain
  • Atrial Fibrillation
  • Bradycardia
  • Edema
  • Facial Flushing
  • Flushing
  • Hypertension
  • Hypotension
  • Palpitations
  • Syncope
  • Tachycardia
  • Vasodilation

• Central Nervous System:

  • Depression
  • Insomnia
  • Paresthesia
  • Dizziness
  • Anxiety
  • Abnormality In Thinking
  • Confusion
  • Seizure
  • Pain
  • Abnormal Dreams
  • Agitation
  • Amnesia
  • Apathy
  • Ataxia
  • Chills
  • Decreased Cough Reflex
  • Euphoria
  • Hallucination
  • Hypoesthesia
  • Lack Of Concentration
  • Lethargy
  • Malaise
  • Myoclonus
  • Slurred Speech
  • Vertigo
  • Voice Disorder
  • Withdrawal Syndrome

• Dermatologic:

  • Skin Rash
  • Diaphoresis
  • Decubitus Ulcer
  • Pallor
  • Pruritus

• Endocrine & Metabolic:

  • Amenorrhea
  • Decreased Libido
  • Gynecomastia
  • Hyponatremia
  • SIADH

• Gastrointestinal:

  • Abdominal Pain
  • Anorexia
  • Diarrhea
  • Xerostomia
  • Biliary Colic
  • Delayed Gastric Emptying
  • Dyspepsia
  • Dysphagia
  • Gastric Atony
  • Gastroesophageal Reflux Disease
  • Hiccups

• Genitourinary:

  • Impotence
  • Urinary Hesitancy
  • Urine Abnormality

• Hematologic & Oncologic:

  • Anemia
  • Thrombocytopenia
  • Leukopenia

• Neuromuscular & Skeletal:

  • Back Pain
  • Tremor
  • Asthenia
  • Arthralgia
  • Foot-Drop
  • Ostealgia

• Ophthalmic:

  • Amblyopia
  • Blurred Vision
  • Conjunctivitis
  • Diplopia
  • Miosis
  • Nystagmus Disorder

• Respiratory:

  • Dyspnea
  • Flu-Like Symptoms
  • Hypoventilation
  • Asthma
  • Atelectasis
  • Hypoxia
  • Pulmonary Edema
  • Respiratory Depression
  • Respiratory Insufficiency
  • Rhinitis

• Miscellaneous:

  • Accidental Injury
  • Fever
  • Increased Severity Of Condition

Frequency of side effects not defined:

• Cardiovascular:

  • Circulatory Depression
  • Orthostatic Hypotension
  • Peripheral Vascular Insufficiency
  • Phlebitis
  • Presyncope
  • Shock

• Central Nervous System:

  • Abnormal Gait
  • Altered Mental Status
  • Coma
  • Delirium
  • Disorientation
  • Disruption Of Body Temperature Regulation
  • Dysphoria
  • Dyssynergia
  • Fear
  • Feeling Abnormal
  • Increased Catecholamines
  • Increased Intracranial Pressure
  • Mood Changes
  • Nervousness
  • Paradoxical Central Nervous System Stimulation
  • Sedated State
  • Toxic Psychosis

• Dermatologic:

  • Hemorrhagic Urticaria
  • Urticaria
  • Xeroderma

• Endocrine & Metabolic:

  • Antidiuretic Effect
  • Increased Thirst
  • Weight Loss

• Gastrointestinal:

  • Biliary Tract Spasm
  • Decreased Appetite
  • Dysgeusia
  • Gastroenteritis
  • Gastrointestinal Hypermotility
  • Rectal Disease
  • Toxic Megacolon

• Genitourinary:

  • Dysuria
  • Ejaculatory Disorder
  • Erectile Dysfunction
  • Hypogonadism
  • Oliguria
  • Ureteral Spasm

• Hematologic & Oncologic:

  • Granuloma

• Hepatic:

  • Increased Liver Enzymes

• Hypersensitivity:

  • Nonimmune Anaphylaxis

• Local:

  • Erythema At Injection Site
  • Induration At Injection Site
  • Local Irritation
  • Local Swelling
  • Pain At Injection Site
  • Residual Mass At Injection Site

• Neuromuscular & Skeletal:

  • Decreased Bone Mineral Density
  • Laryngospasm
  • Muscle Rigidity
  • Muscle Spasm
  • Muscle Twitching
  • Vesicle Sphincter Spasm

• Ophthalmic:

  • Eye Pain
  • Visual Disturbance

• Respiratory:

  • Apnea

• Miscellaneous:

  • Impaired Physical Performance

---

Contraindications to Morphine:

• An absolute contraindication is hypersensitivity, including anaphylaxis to any component of the formulation.
• Respiratory depression is a serious problem.
• Acute or severe bronchial asthma in an unmonitored setting, or without resuscitative devices.
• Use of monoamine-oxidase inhibitors (MAOIs), or concurrent use within the past 14 days.
• Paralytic ileus, GI obstruction and other gastrointestinal problems are all possible.

There is not much evidence of cross-reactivity between opioids and allergenic opioids. Cross-sensitivity is possible due to similarities in chemical structure or pharmacologic effects. Additional contraindications

• Epidural/intrathecal:
  • Infection at the infusion site
  • Concurrent anticoagulant therapy.
  • Diathesis with uncontrolled bleeding
  • Administration could be made more dangerous if there is any other medical condition or therapy that is being used in conjunction.
  • Obstructive upper airway.

Canadian labeling: Additional contraindications not in US labeling Contraindications can vary by product labeling. Refer also to product labels.

• Suspected surgical abdomen (eg acute appendicitis or pancreatitis).
• Bowel transit disease, suspected or known.
• Chronic obstruction of the airway
• Status asthmaticus
• Acute pain management, including outpatient and day surgery.
• You can manage mild, intermittent or short-term pain with pain medication.
• Acute respiratory depression.
• Hypercarbia, corpulmonale and convulsive disorders include convulsive disorder, delirium, delirium tremens and severe CNS depression.
• Cardiac arrhythmias.
• Pregnancy, pregnancy, delivery and breastfeeding.
• Consumption of alcohol or medication containing alcohol (Kadian product monographs, M-Eslon).
• Toxic psychosis, severe kyphoscoliosis (Kadian product Monograph).
• Severe cirrhosis (Mediat product monograph).
• Hypotension (M.-Eslon product monoograph), emotional instability (Statex product Monograph), and/or suicidal ideastion (Statex product monoograph).
• Surgical anastomosis.

Warnings and precautions

• CNS depression:

  • CNS depression can result, which could lead to mental or physical impairments. 
  • It is important to warn patients about tasks that require mental alertness, such as driving or operating machinery.
  • Patients with severe CNS depression may need to be aware that certain dosage forms might not be appropriate.

• Constipation

  • It can cause constipation, which could be problematic for patients with unstable angina or post-myocardial injury patients.
  • To reduce constipation, consider preventive measures such as stool softener or increased fiber.

• Hypotension

  • It can cause severe hypotension, orthostatic hypotension, and syncope. 
  • Patients with hypovolemia, heart disease (including acute MI), circulatory disorder, and drugs that can exaggerate hypotensive effects (including general anesthetics or phenothiazines) should be cautious.
  • After dose titration or initiation, be aware of hypotension symptoms.
  • Patients with circulatory shock should not use this product.
  • Patients with chronic lung disease or cardiac arrhythmias may need to be cautious about taking certain dosage forms.

• Phenanthrene hypersensitivity:

  • Patients with hypersensitivity reactions to other opioid agonists phenanthrene derivatives (codeine and hydrocodone; hydromorphone; levorphanol; oxycodone; oxymorphone) should be cautious.

• Respiratory depression [US Boxed Warning]

  • It is possible to develop severe, life-threatening or fatal respiratory depression.
  • You should monitor your respiratory health, especially during dose escalation or initiation.
  • You can swallow morphine ER formulas whole or sprinkle the contents on applesauce.
  • Rapid release and absorption can be caused by chewing, crushing, or chewing the ER formulations.
  • The sedating effects of opioids can be exacerbated by carbon dioxide retention due to opioid-induced respiratory depression.

• Conditions abdominales:

  • It could obscure the diagnosis and clinical course for patients suffering from acute abdominal conditions.

• Adrenocortical Insufficiency

  • Patients with adrenal insufficiency (including Addison disease) should exercise caution.
  • Long-term opioid abuse can lead to secondary hypogonadism. This could cause infertility, sexual dysfunction, mood disorders, and osteoporosis.

• Insufficiency of the biliary tract:

  • Patients with acute pancreatitis or biliary dysfunction should be cautious. Opioids can cause constriction to the sphincter.

• CNS depression/coma:

  • Patients with impaired consciousness and coma should not be used as they are more susceptible to the intracranial effects CO2 retention.

• Delirium tremens:

  • Patients with delirium-tremens should exercise caution.
  • Patients with delirium may find certain dosage forms contraindicated.

• Head trauma

  • Patients with intracranial injuries, intracranial lesions or elevated intracranial pressure (ICP) should be used with caution. An exacerbated elevation in ICP could occur.
  • Patients with high intracranial pressure or cerebrospinal tension, brain tumors, head injuries or increased intracranial pressure may need to be cautious about taking certain dosage forms.

• Hepatic impairment

  • Patients with severe hepatic impairment should be cautious.

• Mental health conditions

  • Patients with mental disorders such as depression, anxiety, and post-traumatic stress disorder should be cautious when using opioids for chronic pain. There is a greater risk of opioid overdose or opioid addiction.
  • Keep an eye out for more.

• Obesity:

  • Patients who are severely obese should be taken with caution

• Prostatic hyperplasia/urinary restriction:

  • Patients with prostatic hyperplasia or urinary stricture should be cautious.

• Psychosis:

  • Patients with toxic psychosis should be treated with caution.

• Renal impairment

  • Patients with impaired renal function should be cautious.

• Respiratory disease

  • Patients with severe chronic obstructive lung disease (or cor pulmonale) should be monitored for respiratory depression.
  • Even with therapeutic doses, severe respiratory depression can occur.
  • You might consider using non-opioid analgesics for these patients.

• Sleep-related disorders

  • Dose-dependent, opioid use can increase the risk of sleep-related disorders such as central sleep apnea [CSA], and hypoxemia.
  • Patients with sleep-disordered or heart disease should be cautious about chronic pain.
  • Patients who have CSA should be considered for dose reduction.
  • Patients with severe or moderate sleep-disordered breathing should avoid opioids

• Seizure disorders:

  • Patients with seizure disorders should be cautious; it may cause or exacerbate existing seizures.
  • Patients with seizure disorders may need to be aware that certain dosage forms might not be appropriate.

• Thyroid dysfunction:

  • Patients with thyroid dysfunction should be cautious.

Morphine: Drug Interaction

Risk Factor C (Monitor therapy)
Alfuzosin	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Alizapride	May enhance the CNS depressant effect of CNS Depressants.
Amphetamines	May enhance the analgesic effect of Opioid Agonists.
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.
Blood Pressure Lowering Agents	May enhance the hypotensive effect of HypotensionAssociated Agents.
Brimonidine (Topical)	May enhance the CNS depressant effect of CNS Depressants.
Brimonidine (Topical)	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Bromopride	May enhance the CNS depressant effect of CNS Depressants.
Cannabidiol	May enhance the CNS depressant effect of CNS Depressants.
Cannabis	May enhance the CNS depressant effect of CNS Depressants.
Chlorphenesin Carbamate	May enhance the adverse/toxic effect of CNS Depressants.
Desmopressin	Opioid Agonists may enhance the adverse/toxic effect of Desmopressin.
Diazoxide	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Dimethindene (Topical)	May enhance the CNS depressant effect of CNS Depressants.
Diuretics	Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics.
Dronabinol	May enhance the CNS depressant effect of CNS Depressants.
DULoxetine:	Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine.
Erdafitinib	May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
Esmolol	Morphine (Systemic) may increase the serum concentration of Esmolol.
Gabapentin	May enhance the CNS depressant effect of Morphine (Systemic). Morphine (Systemic) may increase the serum concentration of Gabapentin.
Gastrointestinal Agents (Prokinetic)	Opioid Agonists may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic).
Herbs (Hypotensive Properties)	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Hypotension-Associated Agents	Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents.
Kava Kava	May enhance the adverse/toxic effect of CNS Depressants.
Levodopa-Containing Products	Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products.
Lofexidine	May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Lumacaftor	May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
Magnesium Sulfate	May enhance the CNS depressant effect of CNS Depressants.
MetyroSINE	CNS Depressants may enhance the sedative effect of MetyroSINE.
Minocycline (Systemic)	May enhance the CNS depressant effect of CNS Depressants.
Molsidomine	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Nabilone	May enhance the CNS depressant effect of CNS Depressants.
Naftopidil	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Nicergoline	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Nicorandil	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Nitroprusside	Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside.
Pegvisomant	Opioid Agonists may diminish the therapeutic effect of Pegvisomant.
Pentoxifylline	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
P-glycoprotein/ABCB1 Inducers	May decrease the serum concentration of Pglycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.).
P-glycoprotein/ABCB1 Inhibitors	May increase the serum concentration of Pglycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.).
Phosphodiesterase 5 Inhibitors	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Piribedil	CNS Depressants may enhance the CNS depressant effect of Piribedil.
Pramipexole	CNS Depressants may enhance the sedative effect of Pramipexole.
Prostacyclin Analogues	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Quinagolide	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Ramosetron	Opioid Agonists may enhance the constipating effect of Ramosetron.
Ranolazine	May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
RifAMPin	May decrease the serum concentration of Morphine (Systemic).
ROPINIRole	CNS Depressants may enhance the sedative effect of ROPINIRole.
Rotigotine	CNS Depressants may enhance the sedative effect of Rotigotine.
Rufinamide	May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced.
Selective Serotonin Reuptake Inhibitors	CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced.
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.
Succinylcholine	May enhance the bradycardic effect of Opioid Agonists.
Tetrahydrocannabinol	May enhance the CNS depressant effect of CNS Depressants.
Tetrahydrocannabinol and Cannabidiol	May enhance the CNS depressant effect of CNS Depressants.
Risk Factor D (Consider therapy modification)
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.
Amifostine	Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered.
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 antiischemic/analgesic therapies (eg, beta-blockers, nitroglycerin) in patients with acute coronary syndromes treated with a P2Y12 inhibitor when possible. The risks associated with other opioids are unknown. Exceptions: Cangrelor.
Blonanserin	CNS Depressants may enhance the CNS depressant effect of Blonanserin.
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.
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.
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. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Flunitrazepam	CNS Depressants may enhance the CNS depressant effect of Flunitrazepam.
HYDROcodone	CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.
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.
Methotrimeprazine	CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established.
Nalmefene	May diminish the therapeutic effect of Opioid Agonists. Management: Avoid the concomitant use of nalmefene and opioid agonists. Discontinue nalmefene 1 week prior to any anticipated use of opioid agonistss. If combined, larger doses of opioid agonists will likely be required.
Naltrexone	May diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations.
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.
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.
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.
Perampanel	May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination.
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.
Sodium Oxybate	May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated.
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.
Tapentadol	May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.
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 Factor X (Avoid combination)
Azelastine (Nasal)	CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal).
Bromperidol	Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents.
Bromperidol	May enhance the CNS depressant effect of CNS Depressants.
Eluxadoline	Opioid Agonists may enhance the constipating effect of Eluxadoline.
Lasmiditan	May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
Monoamine Oxidase Inhibitors	May enhance the adverse/toxic effect of Morphine (Systemic).
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.
Orphenadrine	CNS Depressants may enhance the CNS depressant effect of Orphenadrine.
Oxomemazine	May enhance the CNS depressant effect of CNS Depressants.
Paraldehyde	CNS Depressants may enhance the CNS depressant effect of Paraldehyde.
Thalidomide	CNS Depressants may enhance the CNS depressant effect of Thalidomide.

 

Monitoring parameters:

• Controlling pain, breathing and mental health
• Blood pressure
• Signs of abuse, misuse, and addiction
• Signs and symptoms of hypogonadism/hypoadrenalism

Alternate suggestions:

• Chronic pain is long-term treatment that does not include end-of life or palliative care. It can also be active cancer treatment, sickle cells disease or medication-assisted opioid abuse disorder treatment.
  • Assess the benefits and risks of opioid therapy within one to four weeks after treatment initiation. Dose increases are also considered.
  • Patients at higher risk for overdose or those with opioid addiction should reevaluate the benefits and risks every three months.
  • It is recommended that urine drug testing be done before initiating treatment. Re-checking should also be considered at least once a year (includes prescription drugs and illegal drugs of abuse).
  • Clinicians should review state prescription drug monitoring program data (PDMP) prior to initiation, and periodically during therapy (frequency ranging between every prescription to every three months).

Critically ill

• Patients who can self-report their pain should use the Numeric Rating Scale.
• Patients who cannot self-report pain can use the Behavioral Pain Score and the Critical Care Pain Observational tool.

Epidural/intrathecal:

• Patients should be monitored in a well-equipped and staffed environment for at most 24 hours after initiation and for several days thereafter.
• Naloxone injection should be immediately available.
• After the first dose, patient should stay in this area for at least 24 hours.
• Patients receiving Infumorph and Mitigo via microinfusion devices may be monitored for several days following catheter implantation.

Alternative monitoring recommendations (Bujedo 2012: Epidural)

Notice:Patients receiving neuraxial opioids must be monitored for adequate ventilation (eg., respiratory rate, depth [without disturbing patient]), oxygenation, pulse oximetry, and level of consciousness).

• Single-dose:
  • Monitor patient for at least 24 hours following administration. For the first 12 hours, monitor at least once an hour, then every two hours for the next twelve hours.
  • Frequency will be determined by the overall clinical condition and any concurrent medications after 24 hours.
• Continuous infusion (PCEA) or patient controlled epidural pain relief (CIP).
  • Monitor patient throughout the infusion. Infuse at least once an hour for the first 12 hrs, then at least once every two hours for the 12 - 24 hours.
  • Monitor at least once every four hours after 24 hours.
  • The frequency of infusions or PCEA should be discontinued after the patient is stable and has not taken any concurrent medication.

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How to administer Morphine?

Oral:

• Do not chew, crush, or disintegrate ER formulations. Instead, swallow them whole.
• Uncontrolled delivery of morphine can be caused by cutting, breaking, crushing or chewing ER formulations. This could lead to overdose and even death.

Arymo ER:

• Take one tablet at a moment and swallow it whole with enough water. Do not soak, lick or wet the tablets before placing them in your mouth.

Kadian

• Capsules can be opened and sprinkled onto applesauce.
• Do not chew, crush, dissolve or chew them as this could result in rapid release of potentially fatal amounts of morphine.
• Rinse the mouth to ensure that all pellets are swallowed.
• You can open capsules and sprinkle them over 10 mL of water before flushing through a 16F gastrostomy tube.
• Do not give gastric/nasogastric tube.

IV:

• Single-use prefilled Syringes/Cartridges should be administered via slow IV push for 4 to 5 minutes. Rapid administration can cause chest wall rigidity.
• For continuous IV infusions or PCA, concentrated vials can be purchased.
• It is also a good idea to consult local guidelines

Intrathecal and epidural:

• Only use preservative-free solutions for intrathecal and epidural use. Refer to the indication-specific infusion rate in dosing for more information.

Rectal:

• To avoid irritation, remove the suppository and moisten it with water.
• Gently insert the round end of the finger approximately one-finger long into the rectum. Then, angle it towards the umbilicus and place it against the rectal wall.
• Once the suppository has been inserted, keep your buttocks closed until you feel the urge to expel.

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Mechanism of action of Morphine:

It binds to opioid receptors within the CNS, inhibiting ascending pain pathways and altering the perception and response to pain. It causes generalized CNS depression

The beginning of action(Patient dependent; Dosing must be individualized)

• Oral (immediate release). 30 minutes
• IV: 5-10 minutes

Time(Patient dependent; Dosing must be individualized): Pain relief

• Instant-release formulations (tablets, oral solution, injections): 3 to 4 hours
• Extended-release tablet and capsule: 8 to 24 hours (formulation dependent).
• Intrathecal or epidural: One dose for up to 24 hours.
• Supppository: 3-7 hours

Absorption:

• Variable

Distribution:

• Distributes to skeletal muscle, liver, kidneys, lungs, intestinal tract, spleen, and brain.

Protein binding:

• Premature Infants: <20%.
• In 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 an analgesic; may contribute to CNS stimulation.
• Minor metabolites include morphine-3-6-diglucuronide; other minor metabolites include normorphine (active) and morphine 3-ethereal sulfate

Bioavailability:

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

Half-life elimination:

• Preterm:
  • 10 to 20 hours
• Neonates:
  • 7.6 hours (range: 4.5 to 13.3 hours)
• Infants 1 to 3 months: Median:
  • 6.2 hours (range: 5 to 10 hours)
• Infants 3 to 6 months: Median:
  • 4.5 hours (range: 3.8 to 7.3 hours)
• Infants 6 months to Children 2.5 years: Median:
  • 2.9 hours (range: 1.4 to 7.8 hours)
• Preschool Children:
  • 1 to 2 hours
• Children with sickle cell disease (age: 6 to 19 years):
  • ~1.3 hours
• 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).

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).

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International Brand Names of Morphine:

• Arymo ER
• Duramorph
• Infumorph 200
• Infumorph 500
• Kadian
• Mitigo
• MorphaBond ER
• MS Contin
• BAR-Morphine SR
• Doloral 1
• Doloral 5
• Kadian
• Kadian SR
• M-Ediat
• M-Eslon
• Morphine Extra Forte
• Morphine Forte
• Morphine HP
• Morphine LP Epidural
• Morphine SR
• Morphine Sulfate SDZ
• Morphine-Epd
• MOS SR
• MOS-Sulfate
• MS Contin
• MS/IR
• RATIO-Morphine
• Ratio-Morphine
• SANDOZ Morphine SR
• Statex
• TEVA-Morphine SR
• Analfin
• Anamorph
• Contalgin
• Depolan
• Dimorf
• Dimorf SP
• Dolcontin
• Dolcontin Depottab
• Doltard
• Graten
• Kadian
• Kapanol
• La Morph
• M-Eslon
• I.R.
• Malfin
• MCR
• Morfex
• Morficontin
• Morgesic XR
• Morphanton
• Morphgesic
• Morphgesic SR
• Morphiprex
• Moscontin
• MS Contin
• MS Contin CR
• MS Mono
• MSP
• MST
• MST Continus
• MST Continus Retard
• Mundidol Retard
• MXL
• Oramorph
• P Guard
• Pacif
• RA-Morph
• Rumorf
• S-Morphine
• Sevredol
• Statex
• Vendal
• Vendal Retard
• Vermor
• Zomorph

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Morphine Brand Names in Pakistan:

Morphine Injection 10 mg/ml in Pakistan
Morfscot	Scotmann Pharmaceuticals

 

Morphine Injection 15 Mg/Ml in Pakistan
Morphine	Lahore Chemical & Pharmaceutical Works (Pvt) Ltd

 

Morphine Injection 20 Mg/Ml in Pakistan
Morfscot	Scotmann Pharmaceuticals

 

Morphine Injection 30 Mg/Ml in Pakistan
Morfscot	Scotmann Pharmaceuticals

 

Morphine Tablets 10 Mg in Pakistan
Qonza	Wilshire Laboratories (Pvt) Ltd.

 

Morphine Capsules 10 Mg in Pakistan
Magnus Mr	AGP(Private) Ltd.

 

Morphine Capsules 30 Mg in Pakistan
Magnus Mr	AGP (Private) Ltd.