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.
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.
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.
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.
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.
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 of even one dose of morphine, especially by children, can result in a fatal overdose of morphine.
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
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.
Doses should be titrated to appropriate effect; when changing routes of administration in chronically treated patients, please note that oral doses are approximately one-half as effective as parenteral dose; Note: Use preservative-free formulation:
Analgesia: Note: Neonates may be more susceptible to respiratory depression; consider frequent or continuous respiratory monitoring (eg, pulse oximetry) and be in a setting that permits rapid management of respiratory insufficiency (American Pain Society 2016; Berde 2002).
Oral: 0.08 mg/kg/dose every 4 to 6 hours (APA 2012)
IM, IV (preferred), SubQ: Initial: 0.05 to 0.1 mg/kg/dose; usual frequency every 4 to 6 hours, although some neonates may require every 8 hour dosing; titrate carefully to effect; maximum dose: 0.1 mg/kg/dose (Anand 2001; Hegenbarth 2008)
Continuous IV infusion: Initial: 0.01 mg/kg/hour (10 mcg/kg/hour); titrate carefully to effect; maximum: 0.03 mg/kg/hour (30 mcg/kg/hour) (Anand 2001); some have suggested a lower usual maximum infusion rate of 0.015 to 0.02 mg/kg/hour (15 to 20 mcg/kg/hour) due to decreased elimination, increased CNS sensitivity, and adverse effects; Note: Some centers may use slightly higher doses, especially in neonates who develop tolerance.
Endotracheal intubation, nonemergent: IM, IV: 0.05 to 0.1 mg/kg; allow at least 5 minutes for onset of analgesia (Kumar 2010)
Neonatal abstinence syndrome: Limited data available: Note: The lowest concentration of the commercially available oral solution (2 mg/mL) should be utilized if possible; if doses are too small to accurately measure then a dilution of 0.4 mg/mL may be utilized (see Extemporaneous Preparations for dilution details). Oral: Initial: 0.04 mg/kg/dose every 3 to 4 hours; increase by 0.04 mg/kg/dose if symptoms are not controlled; maximum dose: 0.2 mg/kg/dose (Hudak 2012); dose and weaning schedule should be individualized based on signs and symptoms of withdrawal and/or withdrawal scores; once withdrawal symptoms are controlled, maintain dose for 48 to 72 hours; then taper dose usually by 10% to 20% every 2 to 7 days (Burgos 2009; Hudak 2012).
Doses should be titrated to appropriate effect; 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.
Acute pain, moderate to severe: Note: Repeated SubQ administration causes local tissue irritation, pain, and induration. The use of IM injections is no longer recommended, especially for repeated administration due to painful administration, variable absorption, and lag time to peak effect; other routes are more reliable and less painful (American Pain Society 2016).
Infants ≤6 months, nonventilated: Note: Infants <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 (American Pain Society 2016; Berde 2002).
Oral: Oral solution (2 mg/mL or 4 mg/mL): 0.08 to 0.1 mg/kg/dose every 3 to 4 hours (American Pain Society 2008; Berde 2002).
IV or SubQ: 0.025 to 0.03 mg/kg/dose every 2 to 4 hours (American Pain Society 2008; Berde 2002).
Infants ≤6 months, ventilated: Note: Infants <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: Initial: 0.05 mg/kg/dose every 2 to 4 hours; dosing based on experience in postoperative cardiothoracic patients (Penk 2018).
Continuous IV infusion: Initial: 0.008 to 0.02 mg/kg/hour (8 to 20 mcg/kg/hour); titrate carefully to effect (Berde 2002; Lynn 1998); reported dose range following titration: 0.015 to 0.04 mg/kg/hour (15 to 40 mcg/kg/hour); dosing based on studies in postoperative patients, most commonly following cardiac surgery (Koren 1985; Lynn 1998; Penk 2018; Valkenburg 2016). Lower initial doses have been reported in infants following cardiac surgery compared to non-cardiac surgical infants (Lynn 1998); infants with Down Syndrome have been shown to have similar morphine requirements postoperatively as patients without following cardiac surgery (Goot 2018; Valkenburg 2016).
Infants >6 months, Children, and Adolescents:
Oral: Immediate-release tablets, oral solution (2 mg/mL or 4 mg/mL):
Patient weight <50 kg: 0.2 to 0.5 mg/kg/dose every 3 to 4 hours as needed; some experts have recommended an initial dose of 0.3 mg/kg for severe pain; usual initial maximum dose: 15 to 20 mg (American Pain Society 2008; APA 2012; Berde 2002).
Patient weight ≥50 kg: 15 to 20 mg every 3 to 4 hours as needed (American Pain Society 2008; Berde 2002).
IM, IV, or SubQ; intermittent dosing:
Patient weight <50 kg: Opioid naïve: Initial: 0.05 mg/kg/dose; usual maximum initial dose: 1 to 2 mg/dose; higher doses may be required if pain not adequately controlled or if patient is opioid tolerant; usual range: 0.1 to 0.2 mg/kg/dose every 2 to 4 hours as needed; use lower doses in opioid naïve patients; usual maximum dose: Infants: 2 mg/dose; Children 1 to 6 years: 4 mg/dose; Children 7 to 12 years: 8 mg/dose; Adolescents: 10 mg/dose.
Patient weight ≥50 kg: Initial: 2 to 5 mg every 2 to 4 hours as needed; Use lower end of the dosing range in opioid naïve patients; higher doses have been recommended (5 to 8 mg every 2 to 4 hours as needed) and may be needed in tolerant patients (Berde 2002; Kliegman 2011).
Continuous IV infusion, SubQ continuous infusion: Note: Patients should have continuous respiratory monitoring (eg, pulse oximetry) and be in a setting that permits rapid management of respiratory insufficiency (American Pain Society 2016; Berde 2002).
Patient weight <50 kg: Initial: 0.01 mg/kg/hour (10 mcg/kg/hour); titrate carefully to effect; dosage range: 0.01 to 0.04 mg/kg/hour (10 to 40 mcg/kg/hour) (APA 2012; Friedrichsdorf 2007; Golianu 2000).
Patient weight ≥50 kg: 1.5 mg/hour (Berde 2002).
Conversion from intermittent IV morphine: Administer the patient's total daily IV morphine dose over 24 hours as a continuous infusion; titrate dose to appropriate effect.
Epidural: 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) (APA 2012; Henneberg 1993); a trial evaluating pain relief in pediatric patients after abdominal surgery (n=76; age: Newborn to 13 years; median age: 12 months) administered epidural morphine every 8 hours in combination with bupivacaine during the immediate postop period; most children achieved good pain relief with this regimen (Henneberg 1993). Maximum dose: 0.1 mg/kg (100 mcg/kg) or 5 mg/24 hours.
Continuous epidural infusion: Infants >6 months, Children, and Adolescents: 0.001 to 0.005 mg/kg/hour (1 to 5 mcg/kg/hour) (Suresh 2012).
Analgesia for minor procedures/sedation: Infants, Children, and Adolescents: IV: 0.05 to 0.1 mg/kg/dose; administer 5 minutes before the procedure; maximum dose: 4 mg; may repeat dose in 5 minutes if necessary (Cramton 2012; Zeltzer 1990).
Patient-controlled analgesia (PCA), opioid-naïve: Note: All patients should receive an initial loading dose of an analgesic (to attain adequate control of pain) before starting PCA for maintenance. Adjust doses, lockouts, and limits based on required loading dose, age, state of health, and presence of opioid tolerance. Use lower end of dosing range for opioid-naïve. Assess patient and pain control at regular intervals and adjust settings if needed (American Pain Society 2008): IV:
Children ≥5 years and Adolescents, weighing <50 kg: Note: PCA has been used in children as young as 5 years of age; however, clinicians need to assess children 5 to 8 years of age to determine if they are able to use the PCA device correctly (American Pain Society 2008).
Usual concentration: 1 mg/mL.
Demand dose: Usual initial: 0.02 mg/kg/dose; usual range: 0.01 to 0.03 mg/kg/dose.
Lockout: Usual initial: 5 doses/hour.
Lockout interval: Range: 6 to 8 minutes.
Usual basal rate: 0 to 0.03 mg/kg/hour.
Children ≥5 years and Adolescents, weighing ≥50 kg:
Usual concentration: 1 mg/mL.
Demand dose: Usual initial: 1 mg; usual range: 0.5 to 2.5 mg.
Lockout interval: Usual initial: 6 minutes; usual range: 5 to 10 minutes.
Chronic pain: Note: Patients taking opioids chronically may become tolerant and require doses higher than the usual dosage range to maintain the desired effect. Tolerance can be managed by appropriate dose titration. There is no optimal or maximal dose for morphine in chronic pain. The appropriate dose is one that relieves pain throughout its dosing interval without causing unmanageable side effects. Consider total daily dose, potency, prior opioid use, degree of opioid experience and tolerance, conversion from previous opioid (including opioid formulation), patient's general condition, concurrent medications, and type and severity of pain during prescribing process.
Oral: Extended-/controlled-release preparations: A patient's morphine requirement should be established using immediate-release formulations. Conversion to long acting products may be considered when chronic, continuous treatment is required. Higher dosages should be reserved for use only in opioid-tolerant patients.
Capsules, extended release (Kadian): Adolescents ≥18 years: Note: Not intended for use as an initial opioid in the management of pain; use immediate release formulations before initiation. Total daily oral morphine dose may be either administered once daily 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 Adolescent able to swallow tablets whole: Usually not used as an initial opioid in the management of pain; use immediate release formulations to titrate dose. Total daily morphine dose may 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 (Berde 1990).
Alternate dosing; fixed dosing (Berde 2002):
Patient weight 20 to <35 kg: 10 to 15 mg every 8 to 12 hours; Note: 10 mg strength not available in 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 titrate dose downward (eg, every 2 to 4 days). Do not discontinue abruptly.
Conversion from other oral morphine formulations to extended-release formulations:
Kadian: Adolescents ≥18 years: Total daily oral morphine dose may be either administered once daily or in 2 divided doses daily (every 12 hours).
MS Contin: Children and Adolescents: Total daily oral morphine dose may be administered either in 2 divided doses daily (every 12 hours) or in 3 divided doses (every 8 hours).
Conversion from parenteral morphine or other opioids to controlled/extended release formulations: Substantial interpatient variability exists in relative potency. Therefore, it is safer to underestimate a patient's daily oral morphine requirement and provide breakthrough pain relief with immediate-release morphine than to overestimate requirements. Consider the parenteral to oral morphine ratio or other oral or parenteral opioids to oral morphine conversions.
Continuous IV infusion, SubQ continuous infusion: Children and Adolescents: 0.01 to 0.04 mg/kg/hour (10 to 40 mcg/kg/hour) (APA 2012; Friedrichsdorf 2007; Golianu 2000); opioid-tolerate patients may require higher doses; in a small study of terminal pediatric oncology patients (n=8; age range: 3 to 16 years), the median required dose was 0.04 to 0.07 mg/kg/hour (40 to 70 mcg/kg/hour); range: 0.025 to 2.6 mg/kg/hour (Miser 1980); another study evaluating subcutaneous continuous infusion in children with cancer (n=17; age range: 22 months to 22 years) had similar findings; median dose: 0.06 mg/kg/hour (60 mcg/kg/hour); range: 0.025 to 1.79 mg/kg/hour (Miser 1983).
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.
Sickle cell disease, acute crisis; opioid naïve patients (APS 1999; NHLBI 2014): Note: Individualize dose; titrate to effect; Infants ≥6 months, Children, and Adolescents:
Patient weight <50 kg: Initial: IV: 0.1 to 0.15 mg/kg every 2 to 4 hours; maximum dose: 7.5 mg/dose.
Patient weight ≥50 kg: Initial: IV: 5 to 10 mg every 2 to 4 hours.
Tetralogy of fallot, hypercyanotic spell (infundibular spasm): Infants and Children: Limited data available: IM, IV, SubQ: 0.1 mg/kg has been used to decrease ventilatory drive and systemic venous return (Hegenbarth 2008).
Palliative care, dyspnea management: Limited data available: Children and Adolescents:
Inhalation (nebulization; preservative-free injection): 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: Initial dose: Equivalent to patient's 4-hour systemic morphine requirement (eg, IV or oral dose); titrate to effect (Golianu 2000); every 4 to 6 hour administration has been suggested (Cohen 2002). In the only pediatric case report (end-stage CF, age: 10 years, weight: 20 kg), an initial dose of 2.5 mg was used and final dose was 10 mg every 4 to 6 hours (Cohen 2002); from experience in adult patients, an initial dose of 5 mg has been used and reported range 2.5 to 30 mg administered up to every 4 hours (Ferraresi 2005; Shirk 2006).
Continuous IV or SubQ infusion (when oral ineffective): Initial: 0.005 mg/kg/hour (5 mcg/kg/hour); titrate for comfort (Garcia-Salido 2015); dosing based on palliative management of terminal infants with spinal muscular atrophy (type 1); intermittent IV maximum doses of 0.4 mg/kg have been reported to control symptoms of dyspnea and pain (di Pede 2018).
Oral: 0.1 mg/kg/dose every 4 hours as needed (Garcia-Salido 2015); titrate for comfort; dosing based on palliative management of terminal infants with spinal muscular atrophy (type 1); maximum doses of 0.4 mg/kg have been reported to control symptoms of dyspnea and pain (di Pede 2018).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Infants, Children and Adolescents: According to the manufacturers' labeling, no specific dosage adjustments are provided (all formulations). In general, the manufacturers recommend starting cautiously with lower doses; titrating slowly while carefully monitoring for side effects. However, the choice of an alternate opioid may be prudent in patients with baseline renal impairment or rapidly changing renal function especially since other analgesics may be safer and reduced initial morphine dosing may result in suboptimal analgesia. Although clearance of morphine is similar to patients with normal renal function, 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 (Lugo 2002; Niscola 2010).
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 adults with cirrhosis, increases in half-life and AUC suggest dosage adjustment required.
(For additional information see "Morphine: Drug information")
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 (CDC [Dowell 2016]; Hill 2018). 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, 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 (APS 2016; CDC [Dowell 2016]). 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 (CDC [Dowell 2016]).
Acute coronary syndrome, refractory ischemic chest pain:
Note: Use only in patients with continued ischemic chest pain despite maximally tolerated anti-ischemic medications (ACC/AHA [Amsterdam 2014]). 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 (Duarte 2019; Kubica 2016; Meine 2005).
IV: 2 to 4 mg initially, followed by 2 to 8 mg every 5 to 15 minutes as needed (ACCF/AHA [O'Gara 2013]; Reeder 2020; Simons 2020) or 1 to 5 mg initially, followed by 1 to 5 mg every 5 to 30 minutes as needed (ACC/AHA [Amsterdam 2014]).
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 (Arnold 2019).
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 (Pino 2022). 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 (APS 2016; Herzig 2019; Pharmacist’s Letter [Cupp 2012]; manufacturer's labeling).
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 (APS 2016; Herzig 2019; Mariano 2019; SCCM [Barr 2013]; manufacturer's labeling). 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) (Lvovschi 2008; Patanwala 2010). 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 (Mariano 2019).
Patient-controlled analgesia (Mariano 2019):
|
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 (APS 2016; Mariano 2019).
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 (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 (Arnold 2019; Azhar 2019; Portenoy 2020).
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 (Aubrun 2012; Alexander 2019; Mariano 2019).
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 (APS 2016; Alexander 2019; Mariano 2019; SCCM [Barr 2013]). 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:
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 (DeBaun 2020).
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 (DeBaun 2020). If IV access is difficult, may administer SUBQ (NIH 2014). 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 (DeBaun 2020).
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 (CDC [Dowell 2016; Dowell 2019]).
Opioid-naive patients: In general, for noncancer pain, morphine requirement should be established using IR formulations (CDC [Dowell 2016]). With cancer pain, may switch to a long-acting formulation earlier in the course of therapy (Portenoy 2020).
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) (Paice 2011; Pharmacist’s Letter [Cupp 2012]; Portenoy 2020; Rosenquist 2019). For chronic noncancer pain, most patients will have pain control with initial doses <50 mg/day (Busse 2017).
Titration: For chronic noncancer pain, may increase the dose slowly in increments of no more than 25% to 50% of the total daily dose (Rosenquist 2019). 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 (Paice 2011; Portenoy 2020). 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 (CDC [Dowell 2016]).
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 (Anderson 2004). 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 (Portenoy 2020).
Cancer pain or palliative care: SUBQ: Initial: 2 to 5 mg every 3 to 4 hours as needed (Portenoy 2020). If a continuous SUBQ infusion is employed, refer to institutional protocols; reported dosing varies greatly and is based on practice and patient needs (Anderson 2004; Koshy 2005; Portenoy 2020; Walsh 2006).
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 (CDC [Dowell 2016]).
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 (Rosenquist 2019).
Converting from oral morphine to parenteral morphine:
Approximate equivalency: 30 mg (oral morphine): 10 mg (IV/SUBQ morphine) (Pharmacist’s Letter [Cupp 2012]).
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).
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 (Brokjær 2015; Portenoy 2020).
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) (Portenoy 2020).
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 (CDC [Dowell 2016]). 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) (CDC 2015). 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 (CDC [Dowell 2016]). 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 (Berna 2015; CDC [Dowell 2016]). 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 (Berna 2015; Sevarino 2019).
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 (SCCM [Devlin 2018]).
IV:
Loading dose: 2 to 10 mg, followed by maintenance dosing (Tietze 2019). 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) (Tietze 2019).
Maintenance dosing: 2 to 4 mg every 1 to 2 hours or 4 to 8 mg every 3 to 4 hours (SCCM [Barr 2013]; Tietze 2019).
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) (Cancer Care Ontario 2010; Dudgeon 2021; Harman 2021).
SUBQ: Initial: 2 mg every 2 hours as needed or on an “offer, may refuse” basis (most patients will not need every dose) (Harman 2021)
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 (Dudgeon 2021).
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 (Dudgeon 2021; Harman 2021).
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 (Dudgeon 2021; Harman 2021).
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 (APS [Chou 2016]). Use a preservative-free (PF) formulation intended for neuraxial use.
Single dose (using 0.5 or 1 mg/mL PF solution): Opioid-naive patients: Usual range: 2 to 3.75 mg (may depend upon patient comorbidities) (Bujedo 2012; Lanz 1985; Mariano 2019; Palmer 2000).
Continuous infusion (using 0.5 or 1 mg/mL PF solution): Opioid-naive patients: 0.2 to 0.4 mg/hour (Bujedo 2012). 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 (Bujedo 2012; Manion 2011).
Continuous microinfusion (using a device intended for continuous microinfusion): Note: Must use a 10 or 25 mg/mL PF 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 (APS [Chou 2016]). Use a PF formulation intended for neuraxial use. Intrathecal dose is usually one-tenth that of epidural dosage (APS 2016).
Single dose (using 0.5 or 1 mg/mL PF solution): Usual range: 0.1 to 0.2 mg coadministered with a local anesthetic; repeat doses are not recommended. If pain recurs within 24 hours of administration, use of an alternative route of administration is recommended (APS 2008; Mariano 2019). Note: Although product labeling recommends doses up to 1 mg, the risk of adverse effects (eg, nausea, 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 (PACC [Deer 2017]; Rathmell 2005).
Continuous microinfusion (using a device intended for continuous microinfusion): Note: Must use a 10 or 25 mg/mL PF 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.
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 (Osborne 1993). 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 (Klimas 2014; Koncicki 2017; Lugo 2002; Niscola 2010).
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 (Tawfic 2015). The following suggestions are based on expert opinion and selected references (Aronoff 2007; Golightly 2013):
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 (Angst 2000; Bastani 1997); slow distribution from CNS to plasma may result in prolonged CNS depression even after reduction in plasma levels following dialysis (Angst 2000).
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 (Tawfic 2015). The following suggestions are based on expert opinion and selected references (Aronoff 2007; Golightly 2013):
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 (Slater 2019). Morphine, M3G, and M6G are not significantly removed by peritoneal dialysis (Hanna 1993; Osborne 1993; Pauli-Magnus 1999).
CRRT: Other opioids are preferred (eg, hydromorphone, fentanyl) due to more reliable pharmacokinetic profiles (expert opinion). Morphine is not significantly removed by hemofiltration or hemodiafiltration (Jamal 1998), 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 (expert opinion).
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.
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 brilliant blue fcf (fd&c blue #1)]
Kadian: 10 mg [DSC] [contains brilliant blue fcf (fd&c blue #1), corn starch]
Kadian: 20 mg [DSC] [contains corn starch, fd&c yellow #10 (quinoline yellow)]
Kadian: 20 mg [DSC] [contains fd&c yellow #10 (quinoline yellow)]
Kadian: 30 mg [DSC] [contains brilliant blue fcf (fd&c blue #1)]
Kadian: 30 mg [DSC] [contains brilliant blue fcf (fd&c blue #1), corn starch]
Kadian: 40 mg [DSC] [contains brilliant blue fcf (fd&c blue #1), corn starch, fd&c yellow #10 (quinoline yellow)]
Kadian: 40 mg [DSC] [contains brilliant blue fcf (fd&c blue #1), fd&c yellow #10 (quinoline yellow)]
Kadian: 50 mg [DSC] [contains brilliant blue fcf (fd&c blue #1), corn starch, fd&c red #40]
Kadian: 50 mg [DSC] [contains brilliant blue fcf (fd&c blue #1), fd&c red #40]
Kadian: 60 mg [DSC] [contains brilliant blue fcf (fd&c blue #1), corn starch, fd&c red #40]
Kadian: 60 mg [DSC] [contains brilliant blue fcf (fd&c blue #1), fd&c red #40]
Kadian: 80 mg [DSC] [contains brilliant blue fcf (fd&c blue #1), corn starch, fd&c red #40, fd&c yellow #6 (sunset yellow)]
Kadian: 80 mg [DSC] [contains brilliant blue fcf (fd&c blue #1), fd&c red #40, fd&c yellow #6 (sunset yellow)]
Kadian: 100 mg [DSC] [contains brilliant blue fcf (fd&c blue #1), corn starch, fd&c yellow #10 (quinoline yellow)]
Kadian: 100 mg [DSC] [contains brilliant blue fcf (fd&c blue #1), fd&c yellow #10 (quinoline yellow)]
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); 20 mg/mL (30 mL, 118 mL, 120 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 brilliant blue fcf (fd&c blue #1), fd&c red #40, fd&c yellow #6 (sunset yellow)]
MorphaBond ER: 30 mg [DSC] [contains fd&c blue #2 (indigotine), fd&c red #40]
MorphaBond ER: 60 mg [DSC] [contains fd&c red #40, fd&c yellow #6 (sunset yellow)]
MorphaBond ER: 100 mg [DSC] [contains fd&c blue #2 (indigotine), fd&c red #40, 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 brilliant blue fcf (fd&c blue #1)]
MS Contin: 60 mg [contains fd&c yellow #10 (quinoline yellow)]
MS Contin: 100 mg
MS Contin: 200 mg [contains brilliant blue fcf (fd&c blue #1), fd&c yellow #10 (quinoline yellow)]
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])
May be product dependent
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 brilliant blue fcf (fd&c blue #1), corn starch, fd&c red #40]
M-Ediat: 30 mg [contains corn starch, fd&c blue #2 (indigotine), fd&c yellow #10 (quinoline yellow)]
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 (1 mL, 4 mL); 50 mg/mL (1 mL, 5 mL, 10 mL, 50 mL)
Solution, Oral:
Statex: 50 mg/mL ([DSC])
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)
Solution, Oral, as sulfate:
Statex: 20 mg/mL ([DSC])
Suppository, Rectal, as sulfate:
Statex: 5 mg ([DSC]); 10 mg ([DSC]); 20 mg ([DSC]); 30 mg (10 ea)
Syrup, Oral:
Doloral 1: 1 mg/mL (10 mL, 250 mL, 500 mL)
Doloral 5: 5 mg/mL (10 mL, 250 mL, 500 mL)
Statex: 1 mg/mL ([DSC]); 5 mg/mL ([DSC]); 10 mg/mL ([DSC])
Generic: 1 mg/mL ([DSC]); 5 mg/mL ([DSC]); 10 mg/mL ([DSC]); 20 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 aluminum lake, fd&c blue #2 (indigotine), fd&c yellow #10 aluminum lake]
MS Contin: 30 mg [contains fd&c blue #1 aluminum lake]
MS Contin: 60 mg [contains fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]
MS Contin: 100 mg [contains fd&c blue #1 aluminum lake]
MS Contin: 200 mg [contains fd&c blue #2 (indigotine), fd&c yellow #6 aluminum lake]
Generic: 15 mg, 30 mg, 60 mg, 100 mg, 200 mg
Arymo ER and MorphaBond ER have been discontinued in the United States for >1 year.
C-II
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Arymo ER: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208603s005lbl.pdf#page=34
Kadian: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/020616s065lbl.pdf#page=36
MorphaBond ER: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/206544s012lbl.pdf#page=38
MS Contin: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/019516s057lbl.pdf#page=29
Oral solution: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/201517s017lbl.pdf#page=29 or https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022195s019lbl.pdf#page=29
Oral tablet: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022207s010lbl.pdf#page=26
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; prescriptions should have the concentration specified as well as the dose clearly represented as milligram (mg) of morphine, not volume (mL). The enclosed calibrated oral syringe should always be used to administer the concentrated oral solution to ensure the dose is measured and administered accurately. The concentrated oral solution (20 mg/mL) should only be used in opioid-tolerant patients (adults taking ≥60 mg/day of morphine or equivalent for ≥1 week).
Extended/controlled release products: Do not chew, crush, break, or dissolve extended and controlled release products; swallow whole. Kadian capsules may be opened and contents sprinkled on a small amount of applesauce and eaten immediately without chewing; rinse mouth with water and swallow to ensure all beads have been ingested; do not chew, crush, or dissolve beads or pellets from capsule as it can result in a rapid release and absorption of a potentially fatal dose of morphine. Kadian capsules may be opened and contents sprinkled into ~10 mL of water, then flushed while swirling through a prewetted 16-French gastrostomy tube fitted with a funnel at the port end; flush with water to transfer all pellets and flush the tube; do not attempt to administer via NG tube.
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.
IV push: Administer undiluted or diluted solution over 4 to 5 minutes (Gahart 2014); 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. In pediatric patients, limited data is available; for adults, Infumorph was developed for use in continuous microinfusion devices only; it may require dilution before use, as determined by the individual patient's dosage requirements and the characteristics of the continuous microinfusion device; not recommended for single dose IV, IM, or SubQ administration; filter through ≤5 micron microfilter before injecting into microinfusion device. Astramorph/PF may be administered as a continuous infusion via the epidural route only. Duramorph is not for use in continuous microinfusion devices.
Inhalation: Limited data available; utilize preservative free parenteral morphine and further dilute prior to administration (Cohen 2002; Ferraresi 2005; Shirk 2006)
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 (Lloret-Linares 2014).
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 (Pasero 1999).
SUBQ continuous infusions: Change site every 3 to 7 days or when erythema occurs (Anderson 2004). To maintain comfort, the SUBQ infusion rate should generally not exceed 5 mL/hour (Portenoy 2019).
IV infusion: 0.1 mg/mL
IV infusion: 0.1 mg/mL, 0.5 mg/mL, or 1 mg/mL
Parenteral: Store intact vials at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Do not freeze. Store in carton until use. Protect from light. Degradation depends on pH and presence of oxygen; relatively stable in pH ≤4. Darkening of solutions indicate degradation. Do not heat-sterilize. Once diluted may store NS preparations at room temperature 20°C to 25°C (68°F to 77°F) or in refrigerator 2°C to 8°C (36°F to 46°F) for up to 14 days; D5W preparations may be stored at room temperature 20°C to 25°C (68°F to 77°F) for up to 72 hours or in refrigerator 2°C to 8°C (36°F to 46°F) for up to 14 days.
Oral:
Extended release: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect capsules from light and moisture.
Immediate release: Store at 20°C to 25°C (68°F to 77°F). Protect from moisture.
Suppositories: Store at 20°C to 25°C (68°F to 77°F).
Oral:
Immediate release formulations (oral solution and tablets): Management of moderate to severe acute and chronic pain (FDA approved in ages ≥18 years and adults); has also been used for treatment of neonatal abstinence syndrome, iatrogenic opioid withdrawal, and palliative care management of dyspnea
Controlled and extended release products (eg, Kadian, MS Contin): Management of moderate to severe chronic pain when continuous, around-the-clock opioid analgesia is required for an extended amount of time (FDA approved in ages ≥18 years and adults); Note: Not intended for use as a PRN analgesic or for treatment of mild pain, acute pain, pain that is not expected to persist for an extended period of time, or for immediate postoperative pain (within 12-24 hours after surgery) unless the patient is already receiving chronic opioid therapy prior to surgery or if postoperative pain is expected to be moderate to severe and persist for an extended period of time
Parenteral:
Intravenous: Management of severe acute pain; preanesthetic sedative [FDA approved in pediatric patients (age not specified) and adults]; has also been used for management of hypercyanotic spells associate with tetralogy of Fallot; and for palliative care management of dyspnea (including nebulization)
Epidural (at the lumbar level): Management of pain unresponsive to nonopioid analgesics (Astramorph/PF, Duramorph: FDA approved in adults); treatment of intractable chronic pain as an epidural infusion via microinfusion device (Infumorph: FDA approved in adults)
Intrathecal (at lumbar level): Management of pain unresponsive to nonopioid analgesics (Astramorph/PF, Duramorph: FDA approved in adults); treatment of intractable chronic pain as a continuous infusion via microinfusion device (Infumorph: FDA approved in adults)
Rectal: Suppositories: Management of severe acute and chronic pain (FDA approved in adults)
Morphine may be confused with 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
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.
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.
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)
Serious, life-threatening, or fatal opioid-induced respiratory depression (OIRD) may occur with use of morphine (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
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 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)
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
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)
Concerns related to adverse effects:
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Some dosage forms may be contraindicated in patients with severe CNS depression.
• Constipation: May cause constipation which may be problematic in patients with unstable angina and patients post-myocardial infarction. Consider preventive measures (eg, stool softener, increased fiber) to reduce the potential for constipation.
• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), circulatory shock, or drugs 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).
• Respiratory depression: [US Boxed Warning]: Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely for respiratory depression, especially during initiation or dose escalation. Swallow morphine ER formulations whole (or may sprinkle the contents of the capsule on applesauce and swallow without chewing); crushing, chewing, or dissolving the ER formulations can cause rapid release and absorption of a potentially fatal dose of morphine. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Patients and caregivers should be educated on how to recognize respiratory depression and the importance of getting emergency assistance immediately (eg, calling 911) in the event of known or suspected overdose.
Disease-related concerns:
• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.
• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction, infertility, mood disorders, and osteoporosis (Brennan 2013).
• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction or acute pancreatitis; opioids may cause constriction of sphincter of Oddi.
• CNS depression/coma: Avoid use in patients with 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: [US Boxed Warning]: Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of morphine and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosage and durations to the minimum required and follow patients for signs and symptoms of respiratory depression and sedation. Some dosage forms may be contraindicated in patients with acute alcoholism. Consider prescribing naloxone for emergency treatment of opioid overdose in patients taking benzodiazepines or other CNS depressants concomitantly with opioids.
• Ethanol use: Extended-release capsules: [US Boxed Warning]: Patients should not consume alcoholic beverages or medication containing ethanol while taking ER capsules; ethanol may increase morphine plasma levels, resulting in a potentially fatal overdose.
Special populations:
• Cachectic or debilitated patients: Use with caution in cachectic or debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.
• Elderly: Use with caution in elderly patients; may be more sensitive to adverse effects, including life-threatening respiratory depression. Decrease initial dose. In the setting of chronic pain, monitor closely due to an increased potential for risks, including certain risks such as falls/fracture, cognitive impairment, and constipation. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increasing the risk for respiratory depression or overdose (CDC [Dowell 2016]). Consider the use of alternative nonopioid analgesics in these patients.
• Neonates: Neonatal withdrawal syndrome: [US Boxed Warning]: Prolonged maternal use of opioids during pregnancy can cause neonatal withdrawal syndrome in the newborn, which may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. If prolonged opioid therapy is required in a pregnant woman, ensure treatment is available and warn patient of risk to the neonate. Signs and symptoms include irritability, hyperactivity, abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.
• Pediatric: Infants <3 months of age, especially if premature, are more susceptible to respiratory depression and/or apnea; use with caution and generally in reduced doses in this age group (APS 2008).
Dosage form specific issues:
• Infumorph, Duramorph, Mitigo: Neuroaxial administration: [US Boxed Warning]: 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 for the first several days after catheter implantation. 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).
• Oral solution: Risk of medication errors: [US Boxed Warning]: 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. The 100 mg per 5 mL (20 mg/mL) is for use in opioid-tolerant adults only.
• Injections: [US Boxed Warning]: 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. 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:
• Abrupt discontinuation/withdrawal: Abrupt discontinuation in patients who are physically dependent on opioids has been associated with serious withdrawal symptoms, uncontrolled pain, attempts to find other opioids (including illicit), and suicide. Use a collaborative, patient-specific taper schedule that minimizes the risk of withdrawal, considering factors such as current opioid dose, duration of use, type of pain, and physical and psychological factors. Monitor pain control, withdrawal symptoms, mood changes, suicidal ideation, and for use of other substances; provide care as needed. 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.
• Abuse/misuse/diversion: [US Boxed Warning]: Morphine exposes patients and other users to the risks of addiction, abuse, and misuse, potentially leading to overdose and death. Assess each patient's risk prior to prescribing; monitor all patients regularly for development of these behaviors or conditions. Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Other factors associated with increased risk include younger age, concomitant depression (major), and psychotropic medication use. Consider offering naloxone prescriptions in patients with factors associated with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents/day orally), and concomitant benzodiazepine use (CDC [Dowell 2016]).
• Accidental exposure: [US Boxed Warning]: Accidental ingestion of even one dose, especially in children, can result in a fatal overdose of morphine.
• Appropriate use: Chronic pain (outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-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. 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 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.
• Risk Evaluation and Mitigation Strategy (REMS): [US Boxed Warning]: 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.
• 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.
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.
For postoperative tonsillectomy (with/without adenoidectomy) pain management in pediatric patients, morphine has been shown to have a higher risk of adverse effects compared to other analgesics without additional analgesic benefit; patient-specific risk factors for these adverse events are not fully defined (Biesiade 2014; Jimenez 2012; Kelly 2015; Ragjavendran 2010; Sadhasivam 2012). Data is preliminary and large-scale population-based generalizations and recommendations for practice have not been made. However, racial differences in adverse effects have been observed. A statistically significant higher incidence of adverse effects (pruritus, emesis) was reported in Latino children and adolescents following perioperative morphine administration than the comparative non-Latino Caucasian cohort (Jimenez 2012). In another trial, Caucasian children and adolescents receiving peri/postoperative morphine showed a higher incidence of postoperative pruritus and emesis than African-American patients (Sadhasivam 2012). The observed risk for respiratory depression between racial groups has been variable, with some data showing no racial difference in risk between Latino and non-Latino Caucasians or between Caucasians and African-American patients, while other data shows a higher risk in African-American pediatric patients compared to Caucasians (Biesiada 2014; Jimenez 2012; Sadhasivam 2012). Regardless of race, an overall higher and clinically significant incidence of respiratory depression has been observed in patients with sleep disturbances requiring tonsillectomy procedure (eg, obstructive sleep apnea); a lower initial dose has been suggested in these patients (Ragjavendran 2010). Current guidelines recommend that children and adolescents receive intravenous dexamethasone intraoperatively and effective therapy for postoperative tonsillectomy pain; NSAIDs (except ketorolac) can be used safely (AAO-HNS [Baugh 2011]).
Substrate of P-glycoprotein/ABCB1 (major), UGT1A1; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
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
Asciminib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
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
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
Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Esmolol: Morphine (Systemic) may increase the serum concentration of Esmolol. Risk C: Monitor therapy
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
Gilteritinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). 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
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
Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). 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
Mitapivat: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). 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
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
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
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.
Morphine may cause GI upset; take with food if GI upset occurs. Be consistent when taking morphine with or without meals.
Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction or infertility in men and women (Brennan 2013).
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).
Respiratory rate; oxygen saturation; mental status; blood pressure; heart rate; pain relief; signs of misuse, abuse, and addiction; level of sedation; signs or symptoms of hypogonadism or hypoadrenalism with long term use (Brennan 2013)
Chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-assisted treatment for opioid use disorder): Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of treatment initiation and with dose increases. Re-evaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder. Urine drug testing is recommended prior to initiation and with consideration for re-checking at least yearly (includes controlled prescription medications and illicit drugs of abuse). State prescription drug monitoring program (PDMP) data should be reviewed by clinicians prior to initiation and periodically during therapy (frequency ranging from every prescription to every 3 months) (Dowell [CDC 2016]).
Astramorph/PF, Duramorph, Infumorph: Patients should be observed in a fully equipped and staffed environment for at least 24 hours following initiation, and as appropriate for the first several days after catheter implantation. Naloxone injection should be immediately available. Patient should remain in this environment for at least 24 hours following the initial dose. For patients receiving Infumorph via microinfusion device, patient may be observed, as appropriate, for the first several days after catheter implantation.
Alternative monitoring recommendations (Bujedo 2012): Epidural: Note: All patients receiving neuraxial opioids should be monitored for adequate ventilation (eg, respiratory rate, depth of respiration [without disturbing patient]), oxygenation (eg, pulse oximetry when appropriate), and level of consciousness.
Single dose: Monitor patient for a minimum of 24 hours after administration with a frequency of at least once per hour for the first 12 hours after administration, followed by at least once every 2 hours for the next 12 hours (ie, from 12 to 24 hours after administration). After 24 hours, frequency dictated by overall clinical condition and concurrent medications.
Continuous infusion or patient controlled epidural analgesia (PCEA): Monitor patient during the entire duration of the infusion with a frequency of at least once per hour for the first 12 hours, followed by at least once every 2 hours for the next 12 hours (ie, from 12 to 24 hours after administration). After 24 hours, monitor at least once every 4 hours. After discontinuation of infusion or PCEA, frequency dictated by overall clinical condition and concurrent medications.
Note: Also refer to institution specific protocols as appropriate
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
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 2012)
Suppository: 3 to 7 hours
Absorption: Variable
Distribution: Distributes to skeletal muscle, liver, kidneys, lungs, intestinal tract, spleen and brain; Vd:
Cancer patients (children age: 1.7 to 18.7 years): Median: 5.2 L/kg; a significantly higher Vd was observed in children <11 years (median: 7.1 L/kg) versus >11 years (median: 4.7 L/kg) (Hunt 1999)
Adults: 1 to 6 L/kg; binds to opioid receptors in the CNS and periphery (eg, GI tract)
Protein binding: Premature Infants: <20%; 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
Bioavailability: Oral: 17% to 33% (first-pass effect limits oral bioavailability); Nebulization: 5.5 ± 3.2% (Masood 1996)
Half-life elimination:
Preterm: 10 to 20 hours
Neonates: 7.6 hours (range: 4.5 to 13.3 hours)
Infants 1 to 3 months: Median: 6.2 hours (range: 5 to 10 hours) (McRorie 1992)
Infants 3 to 6 months: Median: 4.5 hours (range: 3.8 to 7.3 hours) (McRorie 1992)
Infants 6 months to Children 2.5 years: Median: 2.9 hours (range: 1.4 to 7.8 hours) (McRorie 1992)
Preschool Children: 1 to 2 hours
Children with sickle cell disease (age: 6 to 19 years): ~1.3 hours (Dampier 1995)
Adults: Immediate-release forms: 2 to 4 hours; 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
Neonates 1 to 7 days: Median: 5.5 mL/minute/kg (range: 3.2 to 8.4 mL/minute/kg) (McRorie 1992)
Neonates 8 to 30 days: Median: 7.4 mL/minute/kg (range: 3.4 to 13.8 mL/minute/kg) (McRorie 1992)
Infants 1 to 3 months: Median: 10.5 mL/minute/kg (range: 9.8 to 20.1 mL/minute/kg) (McRorie 1992)
Infants 3 to 6 months: Median: 13.9 mL/minute/kg (range: 8.3 to 24.1 mL/minute/kg) (McRorie 1992)
Infants 6 months to Children 2.5 years: Median: 21.7 mL/minute/kg (range: 5.8 to 28.6 mL/minute/kg) (McRorie 1992)
Preschool Children: 20 to 40 mL/minute/kg
Cancer patients (Children age 1.7 to 18.7 years): Median: 23.1 mL/minute/kg; a significantly higher clearance was observed in children <11 years (median: 37.4 mL/minute/kg) versus >11 years (median: 21.9 mL/minute/kg) (Hunt 1999)
Children with sickle cell disease (age: 6 to 19 years): ~36 mL/minute/kg (range: 6 to 59 mL/minute/kg) (Dampier 1995)
Adults: 20 to 30 mL/minute/kg
Equianalgesic doses: Codeine: 120 mg IM = morphine 10 mg IM = single dose oral morphine 60 mg or chronic dosing oral morphine 15 to 25 mg
Kadian capsules contain extended release pellets that are polymer-coated; this product is intended for every 12- or 24-hour dosing. Kadian capsules also contain talc; parenteral abuse may result in local tissue necrosis, infection, pulmonary granulomas, endocarditis, and valvular heart injury.
0.4 mg/mL (400 mcg/mL) Oral Solution (ASHP 2017)
A 0.4 mg/mL oral solution may be made using the 2 mg/mL oral morphine solution. Measure 10 mL (20 mg) of the 2 mg/mL oral morphine solution and transfer to a plastic amber bottle. Measure 40 mL of sterile water for irrigation and add to bottle containing the morphine. Shake to mix. Store at room temperature. Stable for 60 days.
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): $5.22
30 mg (per each): $5.68
50 mg (per each): $9.49
60 mg (per each): $11.36
80 mg (per each): $15.14
100 mg (per each): $18.99
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 - $4.05
4 mg/mL (per mL): $2.34 - $4.16
8 mg/mL (per mL): $2.29
10 mg/mL (per mL): $2.29 - $4.89
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 - $2.73
8 mg/mL (per mL): $3.08
50 mg/mL (per mL): $0.77
Solution (Morphine Sulfate Oral)
10 mg/5 mL (per mL): $0.12
20 mg/5 mL (per mL): $0.14
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
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