Version May 2024
The FDA has issued a drug safety communication to announce safety-related updates to the prescribing information for immediate-release (IR) and extended-release (ER)/long-acting (LA) opioid analgesics, including updates to Boxed Warnings, Indications and Usage, Dosage and Administration, Warnings and Precautions, and the Medication Guide. These safety labeling changes are intended to provide clarity on appropriate patient populations for opioid treatment, appropriate dosage and administration, and updated information on the risks associated with opioid use. The required safety labeling changes include stating:
the risk of overdose increases as the dosage increases for all opioid pain medicines;
IR opioids should not be used for an extended period of time unless a patient's pain remains severe enough to require them and alternative treatment options continue to be inadequate;
many acute pain conditions treated in the outpatient setting require no more than a few days of an opioid pain medicine;
it is recommended to reserve ER/LA opioid pain medicines for severe and persistent pain that requires an extended treatment period with a daily opioid pain medicine and for which alternative treatment options are inadequate; and
a warning about opioid-induced hyperalgesia (OIH), including information on differentiating OIH symptoms from those of opioid tolerance and withdrawal.
Further information may be found at https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescribing-information-all-opioid-pain-medicines-provide-additional-guidance-safe-use.
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 or Infumorph neuraxial administration may result in acute or delayed respiratory depression for up to 24 hours. Monitor patients receiving 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.
Because the use of 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 and reassess all patients regularly for the development of these behaviors and conditions.
Health care providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription.
Serious, life-threatening, or fatal respiratory depression may occur with use of morphine, especially during initiation or following a dose increase. To reduce the risk of respiratory depression, proper dosing and titration of morphine are essential. 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 Mitigo and, as indicated, for the first several days after surgery.
If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome (NOWS), which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery.
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.
Dosage guidance:
Safety: Use lowest effective dose and cautiously titrate, considering benefits and risks of additional opiate exposure; use for shortest duration to meet treatment goals. Neonates may be more susceptible to respiratory depression from morphine; consider frequent or continuous cardiorespiratory monitoring and administer in a setting that permits rapid management of respiratory insufficiency (Ref). Use caution when changing routes of administration; potency differs between some products. To minimize excipient load, use preservative-free formulation when possible.
Analgesia: Note: A multimodal approach (eg, a combination of pharmacologic and non-pharmacologic interventions) should typically be employed for pain control. Pain should be monitored using validated neonatal pain assessment tools (Ref).
Oral: 0.05 to 0.1 mg/kg/dose every 4 to 8 hours as needed (Ref).
IM, IV (preferred), SUBQ: Initial: 0.05 to 0.1 mg/kg/dose every 4 to 8 hours as needed; use lowest effective dose and titrate carefully as clinically indicated (Ref)
Continuous IV infusion: Note: Use caution if patient at risk of hypotension; some experts recommend not using in neonates with GA <27 weeks (Ref).
Preterm and term neonates: Continuous IV infusion: Initial: 0.01 mg/kg/hour (10 mcg/kg/hour); titrate carefully based on patient response and considering benefits and risk of additional opiate exposure; usual range: 0.01 to 0.05 mg/kg/hour (10 to 50 mcg/kg/hour); higher doses may be required in some patients (Ref).
Neonatal opioid withdrawal syndrome: Limited data available; dosing regimens may vary:
Note: In most studies, Finnegan Neonatal Abstinence Scoring tool was utilized to assess severity of withdrawal symptoms; morphine treatment was initiated if 3 consecutive scores were ≥8 or 2 consecutive scores ≥12; doses were increased using these same criteria. Other scoring tools (eg, Eat, Sleep, Console [ESC]) have also been used.
Initial dose and dose escalation for symptom control: Preterm and term neonates: Oral: Initial: 0.03 to 0.05 mg/kg/dose every 3 to 4 hours; higher initial doses may be needed if patient has severe symptoms; if symptoms are not controlled, may increase dose by 0.03 to 0.05 mg/kg/dose as needed; usual maximum dose: 0.2 mg/kg/dose; while a maximum dose is recommended by AAP, generally, there is no consensus or evidenced based maximum; some report using higher doses, while others opt to add adjunctive therapy (Ref). Other studies have reported on a variety of approaches including using the Finnegan score to determine the initial morphine dose and the use of a symptom triggered morphine protocol utilizing the eat, sleep console (ESC) assessment tool (Ref).
Dose weaning after symptom control: Note: Dose and taper schedule should be individualized based on patient response; monitor closely for withdrawal symptoms as well as signs of accumulation (Ref). Weaning of morphine usually occurs after withdrawal symptoms are controlled; typically weaning begins after 24 to 72 hours of stable withdrawal scores (Ref).
Preterm and term neonates: Oral: No standard wean exists; weans are highly variable and patient specific: Decrease dose by 10% to 20% of maximum dose every 24 to 48 hours as tolerated is one weaning approach that has been reported; weaning dose and/or frequency daily has also been reported; see individual studies for weaning details or refer to institutional protocols (Ref).
Dosage guidance:
Safety: Doses should be titrated to appropriate effect; use lowest effective dose for the shortest duration to meet treatment goals. Assess need and discuss availability of naloxone for emergent treatment of opioid overdose with patient and/or caregiver upon initiating and renewing treatment. Dosage forms (parenteral and oral) are available in multiple concentrations; precautions should be taken to avoid confusion between the different concentrations; medication orders (prescriptions) should have the concentration specified as well as the dose clearly represented as milligram (mg) of morphine, not volume (mL). Use caution when changing routes of administration, potency differs between some products.
Acute pain, severe (opioid-naive patients): Note: Repeated SUBQ administration may cause local tissue irritation, pain, and induration. The use of IM injections is no longer recommended, especially for repeated administration due to painful administration, variable absorption, and lag time to peak effect; other routes are more reliable and less painful (Ref).
Infants ≤6 months:
Note: Infants <3 months are more susceptible to respiratory depression and cardiovascular adverse effects; use extra caution and consider frequent or continuous cardiorespiratory monitoring and administer in a setting that permits rapid management of respiratory insufficiency (Ref).
Intermittent dosing: Infants ≤6 months:
Oral: Oral solution (2 mg/mL or 4 mg/mL): Initial: 0.08 to 0.1 mg/kg/dose every 3 to 4 hours (Ref).
IV or SUBQ: Initial: 0.025 to 0.05 mg/kg/dose every 2 to 4 hours (Ref).
Continuous IV infusion: Infants ≤6 months: Initial: 0.008 to 0.02 mg/kg/hour (8 to 20 mcg/kg/hour); titrate carefully to effect (Ref). Higher initial doses of 0.05 mg/kg/hour (50 mcg/kg/hour) have been recommended in critically ill patients in the ICU (Ref).
Infants >6 months, Children, and Adolescents:
Intermittent dosing:
Oral: Infants >6 months, Children, and Adolescents:
Weight <50 kg: Oral: Immediate-release tablets, oral solution: Initial: 0.15 to 0.3 mg/kg/dose every 3 to 4 hours as needed; some experts have recommended higher initial doses of up to 0.5 mg/kg; usual initial maximum dose: 20 mg/dose (Ref).
Weight ≥50 kg: Oral: Immediate-release tablets, oral solution: 10 to 20 mg every 3 to 4 hours as needed (Ref).
IV, SUBQ: Infants >6 months, Children, and Adolescents:
Weight <50 kg: IV, SUBQ: Initial: 0.05 to 0.1 mg/kg/dose every 2 to 4 hours; titrate based on patient response (Ref).
Weight ≥50 kg: IV, SUBQ: Initial: 2 to 5 mg every 2 to 4 hours as needed. Use lower end of the dosing range in opioid naive patients; higher doses have been recommended (5 to 8 mg every 2 to 4 hours as needed) (Ref).
Continuous IV infusion, SUBQ continuous infusion: Note: Patients should have continuous respiratory monitoring (eg, pulse oximetry) and be in a setting that permits rapid management of respiratory insufficiency (Ref).
Infants >6 months, Children, and Adolescents:
Weight <50 kg: Initial: 0.01 mg/kg/hour (10 mcg/kg/hour); titrate carefully to effect; dosage range: 0.01 to 0.04 mg/kg/hour (10 to 40 mcg/kg/hour) (Ref). Higher initial doses of 0.05 mg/kg/hour (50 mcg/kg/hour) have been recommended in critically ill patients in the ICU (Ref).
Weight ≥50 kg: Initial: 1.5 mg/hour; titrate carefully based on clinical response; usual maintenance dose: 0.8 to 3 mg/hour (Ref). Higher initial doses of 2 mg/hour have been recommended in critically ill patients in the ICU (Ref).
Conversion from intermittent IV morphine: Administer the patient's total daily IV morphine dose over 24 hours as a continuous infusion; titrate dose to appropriate effect.
Tapering after prolonged therapy (ie, physical dependence): Note: Do not discontinue morphine abruptly; optimal taper schedule not established; individualize taper based on patient response; use of a withdrawal assessment tool is recommended; manufacturer labeling recommends:
Continuous IV infusion: Infants, Children, and Adolescents: Decrease dose by 25% to 50% every 2 to 4 days; monitor closely for signs and symptoms of withdrawal with each reduction in dose.
Oral solution: Children ≥2 years and Adolescents: Decrease dose by no greater than 10% to 25% of total daily dose every 2 to 4 weeks; monitor closely for signs and symptoms of withdrawal with each reduction in dose. Patients who have been taking opioids for short periods of time may tolerate a more rapid taper.
Chronic pain:
Note: There is no optimal or maximal dose for morphine in chronic pain. The appropriate dose is one that relieves pain throughout its dosing interval without causing unmanageable side effects. Consider total daily dose, potency, prior opioid use, degree of opioid experience and tolerance, conversion from previous opioid (including opioid formulation), patient's general condition, concurrent medications, and type and severity of pain during prescribing process. Assess need and discuss availability of naloxone for emergent treatment of opioid overdose with patient and/or caregiver upon initiating and renewing treatment.
Oral: Note: A patient's morphine requirement should be established using immediate-release formulations (Ref). Conversion to long-acting products may be considered when chronic, continuous treatment is required. Higher dosages should be reserved for use only in opioid-tolerant patients.
Tablets, extended release (eg, MS Contin): Limited data available: Children and Adolescents able to swallow tablets whole:
Fixed dosing (Ref):
Weight 20 to <35 kg: 10 to 15 mg every 8 to 12 hours; Note: 10 mg strength not available in the United States.
Weight 35 to <50 kg: 15 to 30 mg every 8 to 12 hours.
Weight ≥50 kg: 30 to 45 mg every 8 to 12 hours.
Weight-directed dosing: 0.3 to 0.6 mg/kg/dose every 12 hours (Ref).
Discontinuation of extended-release formulations: In general, gradually titrate dose downward (eg, decrease dose 10% to 25% every 2 to 4 weeks). Do not discontinue abruptly.
Conversion from parenteral morphine or other opioids to extended-release formulation: Substantial interpatient variability exists in relative potency. Therefore, it is safer to underestimate a patient's daily oral morphine requirement rather than overestimate requirements. Consider the parenteral to oral morphine ratio or other parenteral opioids to oral morphine conversions; divide total daily oral morphine dose into the appropriate interval for desired extended-release product.
Conversion from other oral morphine formulations to extended-release formulation: Children and Adolescents who can swallow whole tablets: Total daily oral morphine dose may be administered either in 2 divided doses daily (every 12 hours) or in 3 divided doses (every 8 hours) (Ref).
Continuous IV infusion: Children and Adolescents: Initial: 0.01 to 0.04 mg/kg/hour (10 to 40 mcg/kg/hour) (Ref); opioid-tolerate patients may require higher doses (Ref).
Epidural : Limited data available: Note: Must use preservative-free formulation:
Intermittent: Infants, Children, and Adolescents: Epidural: 0.015 to 0.05 mg/kg/dose (15 to 50 mcg/kg/dose) (Ref); epidural administration can provide pain relief for 12 to 24 hours (Ref). Maximum dose: 0.1 mg/kg (100 mcg/kg) or 5 mg per 24 hours (Ref).
Continuous epidural infusion: Infants >6 months, Children, and Adolescents: Epidural: 0.001 to 0.005 mg/kg/hour (1 to 5 mcg/kg/hour) (Ref).
Palliative care, dyspnea management:
Inhalation (nebulization; preservative-free injection): Note: Dose should be individualized and is dependent upon patient's previous or current systemic opioid exposure; doses not intended to provide analgesic activity; current systemic analgesia should be continued:
Infants, Children, and Adolescents: Very limited data available, efficacy results variable:
Initial dose: Inhalation: Equivalent to patient's 4-hour systemic morphine requirement (eg, IV or oral dose); titrate to effect (Ref); every 4 to 6 hour administration has been suggested (Ref). In the only pediatric case report (end-stage cystic fibrosis, age: 10 years, weight: 20 kg), an initial dose of 2.5 mg was used and the final dose was 10 mg every 4 to 6 hours (Ref).
Oral:
Infants, Children, and Adolescents: Limited data available:
Immediate-release preparations: Oral: Initial: 0.075 to 0.15 mg/kg/dose every 4 hours as needed (Ref); titrate for comfort.
Continuous IV or SUBQ infusion: Note: Use is recommended when oral therapy is ineffective:
Infants, Children, and Adolescents: Limited data available:
Continuous IV or SUBQ infusion: Initial: 0.005 mg/kg/hour (5 mcg/kg/hour); titrate for comfort (Ref); dosing based on palliative management of terminal infants with spinal muscular atrophy (type 1).
Patient-controlled analgesia (PCA), opioid-naive: Note: All patients should receive an initial loading dose of an analgesic (to attain adequate control of pain) before starting PCA for maintenance. Adjust doses, lockouts, and limits based on required loading dose, age, state of health, and presence of opioid tolerance. Assess patient and pain control at regular intervals and adjust settings if needed (Ref):
Children ≥5 years and Adolescents, weighing <50 kg: Note: PCA has been used in children as young as 5 years of age; however, clinicians need to assess children 5 to 8 years of age to determine if they are able to use the PCA device correctly (Ref).
Usual IV concentration: 1 mg/mL.
Demand dose: Usual initial: IV: 0.02 mg/kg/dose; usual range: 0.01 to 0.03 mg/kg/dose.
Lockout: Usual initial: 5 doses/hour.
Lockout interval: Range: 6 to 8 minutes.
Usual basal rate: IV: 0 to 0.03 mg/kg/hour.
Children ≥5 years and Adolescents, weighing ≥50 kg: Note: PCA has been used in children as young as 5 years of age; however, clinicians need to assess children 5 to 8 years of age to determine if they are able to use the PCA device correctly (Ref).
Usual IV concentration: 1 mg/mL.
Demand dose: Usual initial: IV: 1 mg; usual range: 0.5 to 2.5 mg.
Lockout interval: Usual initial: 6 minutes; usual range: 5 to 10 minutes.
Procedural pain and sedation: Infants, Children, and Adolescents: IV: 0.05 to 0.1 mg/kg/dose; consider lowest dose in older children and adolescents; administer 5 minutes before the procedure; maximum dose: 4 mg/dose; may repeat dose in 5 minutes if necessary (Ref).
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: There are no specific dosage adjustments provided in the manufacturer's labeling. In general, the manufacturers recommend starting cautiously with lower doses, titrating slowly while carefully monitoring for side effects. However, the choice of an alternate opioid may be prudent in patients with baseline renal impairment or rapidly changing renal function especially since other analgesics may be safer and reduced initial morphine dosing may result in suboptimal analgesia. Although clearance of morphine is similar to patients with normal renal function, morphine glucuronide metabolites (M3G [inactive as an analgesic; may contribute to CNS stimulation] and M6G [active analgesic]) accumulate in renal impairment resulting in increased sensitivity; patients may experience severe and prolonged respiratory depression which may even be delayed (Ref).
Infants, Children and Adolescents: There are no dosage adjustments provided in manufacturer's labeling. Pharmacokinetics are unchanged in mild liver disease; substantial extrahepatic metabolism may occur. In patients with cirrhosis, the manufacturers recommend starting cautiously with lower doses, titrating slowly while carefully monitoring for adverse effects.
(For additional information see "Morphine: Drug information")
Dosage guidance:
Safety: Consider prescribing naloxone for patients with factors associated with an increased risk for overdose, such as history of overdose or substance use disorder, patients with sleep-disordered breathing, higher opioid dosages (≥50 morphine milligram equivalents [MME]/day orally), and/or concomitant benzodiazepine use (Ref).
Dosing: Dosing provided is based on typical doses; some patients may require higher or lower doses. Dosing should be individualized based on patient-specific factors (eg, comorbidities, severity of pain, degree of opioid experience/tolerance) and titrated 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.
Clinical considerations: Opioids may be part of a comprehensive, multimodal, patient-specific treatment plan for managing moderate to severe pain. Maximize nonopioid analgesia (when appropriate) prior to initiation of opioid analgesia (Ref).
Acute coronary syndrome, refractory ischemic chest pain:
Note: Use only in patients with continued ischemic chest pain despite maximally tolerated anti-ischemic medications (Ref). Routine use in patients with acute coronary syndrome has been associated with worse clinical outcomes, and concomitant use with oral P2Y12 inhibitors may diminish antiplatelet effects (Ref).
IV: 2 to 4 mg initially, followed by 2 to 8 mg every 5 to 15 minutes as needed (Ref) or 1 to 5 mg initially, followed by 1 to 5 mg every 5 to 30 minutes as needed (Ref).
Acute pain in opioid-naive patients:
General dosing: Note: 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 pain severe enough to require opioids. Do not use long-acting preparations for treatment of acute pain in opioid-naive patients (Ref). Dosing presented in this section is for opioid-naive patients. Patients who are opioid-tolerant will likely require higher dosing; adjust doses accordingly (Ref).
Oral: Opioid-naive patients:
Immediate release: Oral solution, Tablet:
Note: Consider the use of other more commonly prescribed oral opioids (eg, oxycodone) instead of morphine (Ref). The 100 mg/5 mL (or 20 mg/mL) concentrated oral solution is not intended for opioid-naive patients.
Initial: 10 mg every 4 hours as needed; if pain is not relieved, may increase dose as tolerated. May give up to 30 mg every 4 hours as needed for severe, acute pain in hospitalized patients at low risk for respiratory depression (Ref).
IV: Opioid-naive patients:
Intermittent: Initial: 1 to 4 mg every 1 to 4 hours as needed; if pain is not relieved, may increase dose as tolerated. May give up to 10 mg every 4 hours as needed for severe, acute pain in hospitalized patients at low risk for respiratory depression (Ref). For some severe acute pain episodes (eg, trauma), may initially give more frequently (eg, every 5 to 15 minutes) if needed and titrate to pain relief; once pain relief is achieved, reduce frequency (eg, every 3 to 4 hours as needed) (Ref).
Patient-controlled analgesia (Ref) :
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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 (Buys 2023). | |
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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; Buys 2023). | |
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Usual concentration |
1 mg/mL |
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Demand dose |
Usual range: 0.5 to 2 mg |
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Basal dose |
In general, a continuous (basal) infusion is not recommended in an opioid-naive patient (ISMP 2009)b |
|
Lockout interval |
10 to 20 minutes |
|
Maximum cumulative dose |
30 mg within a 4-hour period |
IM (not recommended for routine use): Opioid-naive patients: Initial: 5 to 10 mg every 3 to 4 hours as needed; if pain is not relieved, may increase dose as tolerated. Note: IM administration is generally not recommended due to pain associated with injection, variable absorption, and delayed time to peak effect (Ref).
Rectal (may be used as an alternative to IV or oral administration): Opioid-naive patients: Initial: 10 mg every 4 hours scheduled or as needed; may increase or decrease the dose as tolerated following the same precautions as oral dosing up to 30 mg every 4 hours scheduled or as needed.
Acute pain (eg, breakthrough cancer pain) in patients on chronic opioid therapy for pain:
Oral, IV, SUBQ: Usual dose: In conjunction with the scheduled long-acting opioid, administer 5% to 20% of the basal daily morphine milligram equivalents (MME) requirement given as needed using an IR formulation with subsequent dosage adjustments based upon response (Ref).
Acute postoperative pain:
Initial pain control in the post-anesthesia care unit: IV: 1 to 3 mg given as frequently as every 5 minutes until adequate pain relief or unwanted side effects (eg, respiratory depression, oxygen desaturation, hypotension) occur. Note: A maximum cumulative dose (eg, 20 mg) prompting reevaluation of continued morphine use and/or dose should be included as part of any medication order intended for short-term use (eg, post-anesthesia care unit orders); refer to institution-specific protocols as appropriate (Ref).
Ongoing pain control: IV: 1 to 4 mg every 1 to 4 hours as needed; may give up to 10 mg every 2 to 4 hours as needed for severe, acute pain in patients at low risk for respiratory depression (Ref). If patient-controlled analgesia is needed, refer to Example IV Patient-Controlled Analgesia Initial Dose Ranges for Opioid-Naive Patients table.
Acute vaso-occlusive pain in sickle cell disease:
Note: Dosing presented is for patients in emergency department and hospital settings (including day hospitals) whose previous opioid dose for prior episodes is unknown or who rarely require opioids for pain management. If opioid dose given for a prior episode is known, choose initial dose based on intensity of pain in comparison with previous episode and previous effective dose (Ref).
IV: Initial: 0.1 to 0.15 mg/kg (maximum initial dose: 10 mg) given once within 30 minutes of presentation, reassess pain within 20 minutes; if continued severe pain, may repeat with doses of 0.02 to 0.05 mg/kg every 20 to 30 minutes to achieve pain relief (Ref). If IV access is difficult, may administer SUBQ (Ref). If pain relief is not achieved after ≥3 doses, hospitalization for around-the-clock parenteral analgesics is generally indicated. Evaluate need for long-acting opioid; if patient usually requires a long-acting opioid at home, may convert to oral home regimen once IV dose is roughly equivalent to long-acting opioid dose (Ref).
Chronic pain, including chronic cancer pain:
Note: 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. 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. Consider opioids, including morphine, only in patients who experience clinically meaningful improvement in pain and function that outweighs patient safety risks (Ref).
Opioid-naive patients: For noncancer pain, morphine requirement should be established using IR formulations (Ref). In patients with cancer pain, may switch to a long-acting formulation earlier in the course of therapy (Ref).
Oral: Immediate release: Oral solution, tablet: Note: The 100 mg/5 mL (or 20 mg/mL) concentrated oral solution is not intended for opioid-naive patients.
Noncancer or cancer pain: Initial: 5 to 15 mg every 4 hours as needed or scheduled around the clock for some patients (eg, cancer pain) (Ref). For chronic noncancer pain, most patients will have pain control with initial doses <50 mg/day (Ref).
IV, SUBQ: Note: Typically reserved for acute exacerbations or those who cannot tolerate oral administration. For progressive illnesses (eg, cancer), a continuous IV or SUBQ infusion, with or without a patient-controlled analgesia option, can also be used as pain requirements increase. In general, SUBQ dose is equivalent to IV dose (Ref). Individualize dose based on patient's previous opioid intake and appropriate opioid analgesic equivalents; titrate further, if needed, based on level of pain.
Noncancer or cancer pain: IV: Initial: 2 to 5 mg every 2 to 4 hours as needed (Ref).
Cancer pain or palliative care: SUBQ: Initial: 2 to 5 mg every 3 to 4 hours as needed (Ref). If a continuous SUBQ infusion is employed, refer to institutional protocols; reported dosing varies greatly and is based on practice and patient needs (Ref).
Titration:
Noncancer pain: Adjust dose according to patient response; if needed, increase the dose slowly in increments of no more than 25% to 50% of the total daily dose (Ref). Note: Dosages ≥50 MME/day are likely to not have increased benefits in pain relief or function relative to overall risks. To reduce risk of overdose in noncancer pain (excluding patients with sickle cell disease and palliative care), readdress pain and reassess evidence of individual benefits and risks when increasing opioid dosage to ≥50 MME/day (Ref).
Cancer pain: Adjust dose according to patient response; if needed, increase the fixed scheduled dose by 30% to 100% of the total dose taken in the prior 24-hour period including total amount of rescue medication used; if pain score decreased and functional assessment improved, continue current effective dosing (Ref).
Opioid-tolerant patients (also refer to the section Dose conversions for pain management):
Oral: Extended release:
Note: Although manufacturer's labeling contains directions for initiating ER morphine products in opioid-naive patients with chronic pain, these preparations should not be used as initial therapy. Instead, treatment should be initiated with an IR preparation to more accurately determine the daily opioid requirement and decrease the risk of overdose. Unless pain is associated with cancer, palliative care, or sickle cell disease, reserve ER opioids for patients who have received IR opioids daily for ≥1 week yet continue to experience severe, continuous pain (Ref).
Capsules, extended release (Kadian): See Dose conversions for pain management: Calculated dose may be administered once daily or in 2 equally divided doses administered every 12 hours; may consider dose reduction with first several doses when converting from IR formulations. Example initial dose: 30 mg once daily or 15 mg every 12 hours. Dose adjustments may be made as frequently as every 1 to 2 days. Note: For generic ER capsules, some products are unique with varying dosing, schedule, and titration recommendations; refer to product labeling for specific ER capsule product information.
Tablets, extended release (Arymo ER, MorphaBond ER, MS Contin): Note: Arymo ER and MorphaBond ER have been discontinued in the United States for >1 year. See Dose conversions for pain management: Calculated dose may be administered in 2 equally divided doses (every 12 hours) or 3 equally divided doses (every 8 hours); may consider dose reduction with first several doses when converting from IR formulations. Example initial dose: 15 mg every 8 or 12 hours. Dose adjustments may be made as frequently as every 1 to 2 days.
Dose conversions for pain management: Note: Equianalgesic conversions serve only as a general guide to estimate opioid dose equivalents. Multiple factors must be considered for safely individualizing conversion of opioid analgesia. In general, for noncancer pain, the decision to convert from an IR to an ER formulation should be individualized and reserved for those with severe continuous pain who have been taking opioids for ≥1 week (Ref).
Converting from oral morphine to parenteral morphine:
Approximate equivalency: 30 mg (oral morphine): 10 mg ( IV/SUBQ morphine) (Ref).
Converting from oral IR morphine to oral ER morphine preparations:
Arymo ER, MorphaBond ER, MS Contin: Total daily oral morphine dose may be administered either in 2 divided doses (every 12 hours) or in 3 divided doses (every 8 hours).
Kadian: Total daily oral morphine dose administered once daily; in patients experiencing inadequate analgesia with once-daily dosing, total daily dose can be administered in 2 divided doses (every 12 hours).
Converting from oral morphine to rectal morphine:
Although the bioavailability of rectal morphine is believed to approximate oral morphine (ie, 1:1), absorption is variable and may be higher or lower than expected. Therefore, when switching from oral to rectal dosing, a reduction in rectal dose may be necessary (Ref).
Converting to/from morphine (parenteral or oral) to/from a different opioid (parenteral or oral):
Refer to published equianalgesic opioid conversion data for guidance (or refer to institutional protocols). Provided conversion ratios are only approximations and substantial interpatient variability exists; therefore, it is safer to underestimate a patient's daily oral requirement and provide breakthrough pain relief with IR formulations rather than risk overestimating daily requirements. When switching to a new opioid (except to/from methadone), reduce the initial daily calculated equianalgesic dose of the new opioid by 25% to 50% to adjust for lack of complete mu receptor cross-tolerance (conversions to/from methadone are highly variable and require extreme caution) (Ref).
Discontinuation or tapering of therapy:
When reducing the dose, discontinuing, or tapering long-term opioid therapy, the dose should be gradually tapered. An optimal tapering schedule has not been established. Individualize tapering based on discussions with patient to minimize withdrawal, while considering patient-specific goals and concerns and the opioid’s pharmacokinetics. Proposed initial schedules range from slow (eg, 10% reduction per week or 10% reduction per month depending on duration of long-term therapy) to rapid (eg, 25% to 50% reduction every few days)(Ref). Slower tapers may be appropriate after long-term use (eg, >1 year), whereas more rapid tapers may be appropriate in patients experiencing severe adverse effects. During tapering, patients may be at an increased risk of overdose if they return to their original (or higher) opioid dose or use illicit opioids, due to rapid loss of tolerance; consider prescribing naloxone. 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 autonomic withdrawal symptoms and other adjunctive agents to treat GI symptoms and muscle spasms, as needed. Continue to offer nonopioid analgesics as needed for pain management during the taper (Ref).
Dyspnea in palliative care patients (off-label use):
Opioid-naive patients:
Moderate dyspnea:
Oral, sublingual: Immediate release (may use 100 mg/5 mL [20 mg/mL] solution): Initial: 2 mg every 2 hours as needed or 5 mg every 4 hours with 2.5 mg every 2 hours as needed or on an “offer, may refuse” basis (most patients will not need every dose) (Ref).
SUBQ: Initial: 2 mg every 2 hours as needed or on an “offer, may refuse” basis (most patients will not need every dose) (Ref).
Severe dyspnea: SUBQ, IV: Initial: 2.5 mg; if dyspnea persists and initial dose is well tolerated, may repeat every 30 to 60 minutes (SubQ) or every 15 to 30 minutes (IV). If 2 doses are well tolerated but fail to reduce dyspnea adequately, the dose may be doubled (Ref).
Opioid-tolerant patients: Note: Higher initial doses will likely be needed.
Moderate or severe dyspnea: Immediate release: Oral: Consider giving 10% to 15% of the basal daily opioid requirement (calculated in morphine equivalents) every 2 hours as needed or on an “offer, may refuse” basis. Consider increasing the regular daily dose by ~25% taking into consideration breakthrough doses used in the previous 24 hours (Ref).
Severe dyspnea: SUBQ, IV: Consider giving 5% of the oral basal daily opioid requirement (calculated in morphine equivalents) every 1 hour as needed or on an “offer, may refuse” basis. For breakthrough dyspnea, if already taking a parenteral opioid, may give ~10% of the current parenteral opioid daily dose (Ref).
Neuraxial analgesia:
Epidural:
Note: Reserve use for severe pain (eg, after surgery, cancer pain). Must be administered by health care providers skilled in the care of patients receiving intraspinal opioids. Use a preservative-free formulation intended for neuraxial use. Example regimens and usual doses are provided; specific regimens and doses vary based on type of surgery, comorbidities, and institutional policies and practices.
Single dose (using 0.5 or 1 mg/mL preservative-free solution): Opioid-naive patients: Usual range: 2.5 to 3.75 mg (may depend upon patient comorbidities) (Ref).
Continuous infusion (using 0.5 or 1 mg/mL preservative-free solution): Opioid-naive patients: 0.2 to 0.4 mg/hour (Ref). May be given alone or usually in combination with local anesthetics (eg, bupivacaine, ropivacaine); when combined with a local anesthetic, analgesic effect is increased due to synergy (Ref).
Continuous microinfusion (using a device intended for continuous microinfusion): Note: Must use a 10 or 25 mg/mL preservative-free solution (eg, Infumorph); dilution may be required.
Initial: 3 to 7.5 mg over 24 hours.
Intrathecal:
Note: Reserve use for severe pain (eg, after surgery, cancer pain). Must be administered by health care providers skilled in the care of patients receiving intraspinal opioids. Use a preservative-free formulation intended for neuraxial use. Intrathecal dose is usually one-tenth that of epidural dosage.
Single dose (using 0.5 or 1 mg/mL preservative-free solution): Usual range: 0.1 to 0.3 mg coadministered with a local anesthetic; repeat doses are not recommended. If pain recurs, use of an alternative route of administration is recommended (Ref). Note: Doses vary depending on the clinical scenario and other medications administered as part of multimodal analgesia. Risk of adverse effects (eg, nausea, pruritus, respiratory depression) is higher with doses >0.3 mg; however, some patients with chronic intractable pain (eg, cancer pain) may require doses up to 0.5 mg (Ref).
Continuous microinfusion (using a device intended for continuous microinfusion): Note: Must use a 10 or 25 mg/mL preservative-free solution (eg, Infumorph); dilution may be required.
Initial: 0.2 to 1 mg over 24 hours.
Pain and sedation; critically ill patients in the ICU (off-label use):
Note: Multimodal approaches (eg, a combination of analgesics and techniques) should typically be employed for pain control in this setting. Pain should be monitored using validated scales (eg, behavioral pain scale, critical-care observation tool) in medical, postoperative, or trauma (excluding brain injury) ICU patients who are unable to self-report (Ref).
IV:
Loading dose: 2 to 10 mg, followed by maintenance dosing (Ref). Note: More than 1 loading dose may be needed; onset of action following IV administration is 5 to 10 minutes. Reduce or omit initial loading dose in select patients (eg, older, hypovolemic, at-risk for hemodynamic compromise) (Ref).
Maintenance dosing: 2 to 4 mg every 1 to 2 hours or 4 to 8 mg every 3 to 4 hours (Ref).
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 (Ref). As kidney function deteriorates, M6G accounts for an increasing proportion of the analgesic effect and attainment of steady state is delayed; consequently, patients may experience CNS depression, sedation, and severe and prolonged respiratory depression, which may be delayed in presentation (Ref).
Altered kidney function:
Oral, IM, IV, SUBQ, Rectal:
Note: There are no specific dose adjustments provided in the manufacturer's labeling. ER formulations should preferably be avoided in patients with altered kidney function (Ref). The following suggestions are based on expert opinion and selected references (Ref):
CrCl ≥60 mL/minute: No dosage adjustment necessary.
CrCl 30 to <60 mL/minute: Consider use of an alternative opioid analgesic. If necessary, administer 50% to 75% of usual initial dose; may also consider extending dose interval. Titrate cautiously to response.
CrCl 15 to <30 mL/minute: Avoid use. If necessary, administer 25% to 50% of usual initial dose; may also consider extending dose interval. Titrate cautiously to response.
CrCl <15 mL/minute: Avoid use.
Epidural/intrathecal:
Moderate to severe impairment: There are no specific dose adjustments recommended; however, use with caution and monitor closely. Use of an alternative opioid analgesic may be preferred in patients with more severe impairment.
Hemodialysis, intermittent (thrice weekly): Morphine and M6G are dialyzable, although the extent of removal is not fully quantified (Ref); slow distribution from CNS to plasma may result in prolonged CNS depression even after reduction in plasma levels following dialysis (Ref).
Oral, IM, IV, SUBQ, Rectal:
Note: There are no specific dose adjustments provided in the manufacturer's labeling. ER formulations should preferably be avoided in patients with altered kidney function (Ref). The following suggestions are based on expert opinion and selected references (Ref):
Avoid use; consider alternative opioid analgesic. If necessary, administer 25% to 50% of usual dose; may also consider extending dose interval. Titrate cautiously to response.
Epidural/intrathecal: There are no specific dose adjustments recommended; however, use with caution and monitor closely. Use of an alternative analgesic may be preferred.
Peritoneal dialysis: Avoid use; consider alternative opioid analgesic (Ref). Morphine, M3G, and M6G are not significantly removed by peritoneal dialysis (Ref).
CRRT: Other opioids are preferred (eg, hydromorphone, fentanyl) due to more reliable pharmacokinetic profiles (Ref). Morphine is not significantly removed by hemofiltration or hemodiafiltration (Ref), and the extent of M3G and M6G removal is unknown.
PIRRT (eg, sustained, low-efficiency diafiltration): Other opioids are preferred (eg, hydromorphone, fentanyl) due to more reliable pharmacokinetic profiles. The extent of morphine, M3G, and M6G removal is unknown (Ref).
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.
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 in adult and pediatric patients (Ref).
Mechanism: Dose-related; mediated predominately via the mu-opioid receptor. Activates specific CNS sites (ie, pre-Bötzinger complex and Kölliker-Fuse nucleus) that control respiratory rhythms (Ref).
Onset: Rapid; OIRD reported from 5 minutes to 1.2 hours (Ref).
Risk factors:
• Overdose (but may also occur at therapeutic doses)
• Initiation or dose escalation
• Opioid naive (Ref)
• Opioid misuse/abuse (Ref)
• Respiratory disease (eg, obstructive sleep apnea) (Ref)
• Cardiac disease (Ref)
• Morbid obesity (Ref)
• Older adults
• Kidney and/or liver impairment
• Cachectic or debilitated
• Concurrent benzodiazepines or other CNS depressants
• Rapid IV administration or neuraxial administration
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: Allodynia (opioid-induced hyperalgesia) (FDA Safety Communication 2023), 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).
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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 that require mental alertness (eg, operating machinery or driving). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Some dosage forms may be contraindicated in patients with severe CNS depression.
• Hyperalgesia: Opioid-induced hyperalgesia (OIH) has occurred with short-term and prolonged use of opioid analgesics. Symptoms may include increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily nonpainful stimuli; symptoms may be suggestive of OIH if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Consider decreasing the current opioid dose or opioid rotation in patients who experience OIH.
• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), circulatory shock, or drugs that may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Avoid use in patients with circulatory shock. Some dosage forms may be contraindicated in patients with cardiac arrhythmias or heart failure due to chronic lung disease.
• Phenanthrene hypersensitivity: Use with caution in patients with hypersensitivity reactions to other phenanthrene derivative opioid agonists (codeine, hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone).
Disease-related concerns:
• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.
• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction, infertility, mood disorders, and osteoporosis (Brennan 2013).
• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction or acute pancreatitis; opioids may cause constriction of sphincter of Oddi.
• Cardiovascular conditions: Morphine may cause constipation, which may be problematic in patients with unstable angina and patients post–myocardial infarction.
• CNS depression/coma: Avoid use in patients with impaired consciousness or coma, as these patients are susceptible to intracranial effects of CO2 retention.
• Delirium tremens: Use with caution in patients with delirium tremens. Some dosage forms may be contraindicated in patients with delirium tremens.
• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur. Some dosage forms may be contraindicated in patients with increased intracranial or cerebrospinal pressure, head injuries, or brain tumor.
• Hepatic impairment: Use with caution in patients with severe hepatic impairment.
• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, anxiety disorders, post-traumatic stress disorder) due to potential increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (CDC [Dowell 2022]).
• 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: Use with caution in patients with sleep-related disorders, including sleep apnea, due to increased risk for respiratory and CNS depression. Monitor carefully and titrate dosage cautiously in patients with mild sleep-disordered breathing. Avoid opioids in patients with moderate to severe sleep-disordered breathing (CDC [Dowell 2022]).
• Seizure disorders: Use with caution in patients with seizure disorders; may cause or exacerbate preexisting seizures. Some dosage forms may be contraindicated in patients with seizure disorder.
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.
Concurrent drug therapy issues:
• Benzodiazepines or other CNS depressants: Some dosage forms may be contraindicated in patients with acute alcoholism.
Special populations:
• Older adult: Use opioids with caution in older adults; may be more sensitive to adverse effects. Clearance may also be reduced in older adults (with or without renal impairment), resulting in a narrow therapeutic window and increased adverse effects. Monitor closely for adverse effects associated with opioid therapy (eg, respiratory and CNS depression, falls, cognitive impairment, constipation) (CDC [Dowell 2022]). Consider the use of alternative nonopioid analgesics in these patients when possible.
Dosage form specific issues:
• Infumorph, Duramorph, Mitigo: Neuroaxial administration: Naloxone injection should be immediately available. Thoracic epidural administration has been shown to dramatically increase the risk of early and late respiratory depression. High doses (> 20 mg/day) of neuraxial morphine may produce myoclonic events. Patients with reduced circulating blood volume or impaired myocardial function, or on concomitant sympatholytic drugs should be monitored for orthostatic hypotension, a frequent complication in single-dose neuraxial morphine.
• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.
• Extended-release formulations: Therapy should only be prescribed by health care professionals familiar with the use of potent opioids for chronic pain. Extended-release products are not interchangeable. When determining a generic equivalent or switching from one extended-release product to another, a thorough understanding of the pharmacokinetic properties is important in determining the proper generic equivalent or proper dose of the other extended-release product (review of the manufacturer's label may be necessary).
- Arymo ER: Moistened tablets may become sticky, leading to difficulty in swallowing the tablets; choking, gagging, regurgitation, and tablets getting stuck in the throat may occur. Tablet stickiness and swelling may also predispose patients to intestinal obstruction and exacerbation of diverticulitis. Do not to pre-soak, lick, or otherwise wet tablets prior to placing in the mouth; take one tablet at a time with enough water to ensure complete swallowing. Consider use of an alternative analgesic in patients who have difficulty swallowing and patients at risk for underlying GI disorders resulting in a small GI lumen (eg, esophageal cancer, colon cancer).
• Injections: Products are designed for administration by specific routes (ie, IV, intrathecal, epidural). Use caution when prescribing, dispensing, or administering to use formulations only by intended route(s). Rapid IV administration may result in chest wall rigidity. Use with caution when injecting IM into chilled areas or in patients with hypotension or shock (impaired perfusion may prevent complete absorption); if repeated injections are administered, an excessive amount may be suddenly absorbed if normal circulation is re-established.
• Infumorph, Mitigo: Should only be used in microinfusion devices; not for IV, IM, or SubQ administration or for single-dose administration. Administer intrathecal doses of 10 and 25 mg/mL to the lumbar area. Monitor closely, especially in the first 24 hours. Inflammatory masses (eg, granulomas), some resulting in severe neurologic impairment, have occurred when receiving Infumorph or Mitigo via indwelling intrathecal catheter; monitor carefully for new neurologic signs/symptoms.
• Product interchange: Improper or erroneous substitution of Infumorph or Mitigo for regular Duramorph is likely to result in serious overdosage, leading to seizures, respiratory depression, and possibly a fatal outcome.
• Sulfites: Some dosage forms may contain sulfites that may cause allergic reactions in sulfite sensitive patients.
Other warnings/precautions:
• Abuse/misuse/diversion: Use with caution in patients with a history of substance use disorder; potential for drug dependency exists. Other factors associated with increased risk for misuse include concomitant depression or other mental health conditions, higher opioid dosages, or taking other CNS depressants. Consider offering naloxone prescriptions in patients with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents [MME]/day orally), concomitant benzodiazepine use, and patients at risk for returning to a high dose after losing tolerance (CDC [Dowell 2022]).
• Appropriate use: Outpatient setting: Opioids should not be used as first-line therapy for acute (<1 month duration), subacute (1 to 3 month duration), or chronic pain (>3 month duration [outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment]). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg, nonsteroidal anti-inflammatory drugs, acetaminophen, certain antiseizure medications and antidepressants) as appropriate for the specific condition. If opioid therapy is initiated, it should be combined with nonpharmacologic and nonopioid therapy, as appropriate. Prior to initiation, known risks and realistic benefits of opioid therapy should be discussed with the patient. Therapy should be initiated at the lowest effective dosage using IR opioids (instead of ER/long-acting opioids). For the treatment of acute pain, therapy should only be given for the expected duration of pain severe enough to require opioids and prescribed as needed (not scheduled). For the treatment of subacute and chronic pain, 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. Risk to patients increases with higher opioid dosages. Dosages ≥50 MME/day are likely to not have increased benefit to pain relief or function relative to overall risk to patients; before increasing dosage to ≥50 MME/day, readdress pain and reassess evidence of individual benefits and risks (CDC [Dowell 2022]).
• Naloxone access: Discuss the availability of naloxone with all patients who are prescribed opioid analgesics, as well as their caregivers, and consider prescribing it to patients who are at increased risk of opioid overdose. These include patients who are also taking benzodiazepines or other CNS depressants, have an opioid use disorder (OUD) (current or history of) or substance use disorder, have higher opioid dosages (≥50 morphine milligram equivalents/day orally) (CDC [Dowell 2022]), or have experienced opioid-induced respiratory depression/opioid overdose. Additionally, health care providers should consider prescribing naloxone to patients prescribed medications to treat OUD; patients at risk of opioid overdose even if they are not taking an opioid analgesic or medication to treat OUD; and patients taking opioids, including methadone or buprenorphine for OUD, if they have household members, including children, or other close contacts at risk for accidental ingestion or opioid overdose. Inform patients and caregivers on options for obtaining naloxone (eg, by prescription, directly from a pharmacist, a community-based program) as permitted by state dispensing and prescribing guidelines. Educate patients and caregivers on how to recognize respiratory depression, proper administration of naloxone, and getting emergency help.
• Optimal regimen: An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients; doses should be titrated to pain relief/prevention.
• Surgery: Opioids decrease bowel motility; monitor for decreased bowel motility in postoperative 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.
It is well known that recurrent exposure to painful stimuli without effective pain management alters the pain pathways in the neonatal brain and results in altered pain perception. There is a growing concern regarding the need to balance pain management with the concern for neuronal apoptosis and potential poor neurodevelopmental outcomes in neonatal patients treated with opiates. In vitro and animal studies show that exposure to morphine induces apoptosis of primary human fetal microglial cells (Attarian 2014; Hu 2002). Clinical evaluations of preterm neonates exposed to morphine have shown impaired cerebellar and cerebral growth but have shown mixed impact on the long-term neurodevelopment outcomes in early childhood (Steinhorn 2015; Zwicker 2016).
Arymo ER and MorphaBond ER have been discontinued in the United States for >1 year.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule Extended Release 24 Hour, Oral, as sulfate:
Kadian: 10 mg [DSC] [contains corn starch, fd&c blue #1 (brilliant blue)]
Kadian: 10 mg [DSC] [contains fd&c blue #1 (brilliant blue)]
Kadian: 20 mg [DSC] [contains corn starch, quinoline yellow (d&c yellow #10)]
Kadian: 30 mg [DSC] [contains corn starch, fd&c blue #1 (brilliant blue)]
Kadian: 40 mg [DSC] [contains corn starch, fd&c blue #1 (brilliant blue), quinoline yellow (d&c yellow #10)]
Kadian: 50 mg [DSC], 60 mg [DSC] [contains corn starch, fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye)]
Kadian: 80 mg [DSC] [contains corn starch, fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), fd&c yellow #6 (sunset yellow)]
Kadian: 100 mg [DSC] [contains corn starch, fd&c blue #1 (brilliant blue), quinoline yellow (d&c yellow #10)]
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); 50 mg/mL (20 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 [preservative free]:
Generic: 1 mg/mL (30 mL); 2 mg/mL (1 mL); 4 mg/mL (1 mL); 8 mg/mL (1 mL); 10 mg/mL (1 mL); 50 mg/mL (20 mL [DSC], 50 mL)
Solution, Oral, as sulfate:
Generic: 10 mg/5 mL (5 mL, 100 mL, 500 mL); 20 mg/5 mL (5 mL [DSC], 100 mL [DSC], 500 mL [DSC]); 10 mg/0.5 mL (1 ea); 20 mg/mL (15 mL, 30 mL, 118 mL, 120 mL [DSC], 240 mL); 100 mg/5 mL (15 mL, 30 mL, 120 mL, 240 mL)
Suppository, Rectal, as sulfate:
Generic: 5 mg (12 ea); 10 mg (12 ea); 20 mg (12 ea); 30 mg (12 ea)
Tablet, Oral, as sulfate:
Generic: 15 mg, 30 mg
Tablet ER 12 Hour Abuse-Deterrent, Oral, as sulfate:
MorphaBond ER: 15 mg [DSC] [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), fd&c yellow #6 (sunset yellow)]
MorphaBond ER: 30 mg [DSC] [contains fd&c blue #2 (indigotine,indigo carmine), fd&c red #40 (allura red ac dye)]
MorphaBond ER: 60 mg [DSC] [contains fd&c red #40 (allura red ac dye), fd&c yellow #6 (sunset yellow)]
MorphaBond ER: 100 mg [DSC] [contains fd&c blue #2 (indigotine,indigo carmine), fd&c red #40 (allura red ac dye), fd&c yellow #6 (sunset yellow)]
Tablet Extended Release, Oral, as sulfate:
MS Contin: 15 mg [contains fd&c blue #2 (indigotine,indigo carmine)]
MS Contin: 30 mg [contains fd&c blue #1 (brilliant blue)]
MS Contin: 60 mg [contains quinoline yellow (d&c yellow #10)]
MS Contin: 100 mg
MS Contin: 200 mg [contains fd&c blue #1 (brilliant blue), quinoline yellow (d&c yellow #10)]
Generic: 15 mg, 30 mg, 60 mg, 100 mg, 200 mg
Tablet Extended Release Abuse-Deterrent, Oral, as sulfate:
Arymo ER: 15 mg (100 ea [DSC]); 30 mg (100 ea [DSC]) [contains fd&c blue #2 (indigotine,indigo carmine)]
Arymo ER: 60 mg (100 ea [DSC])
May be product dependent
Capsule ER 24 Hour Therapy Pack (Morphine Sulfate ER Beads Oral)
30 mg (per each): $5.73
45 mg (per each): $8.50
60 mg (per each): $11.13
75 mg (per each): $14.16
90 mg (per each): $16.73
120 mg (per each): $19.74
Capsule ER 24 Hour Therapy Pack (Morphine Sulfate ER Oral)
10 mg (per each): $4.73
20 mg (per each): $5.23
30 mg (per each): $5.69
50 mg (per each): $9.50
60 mg (per each): $11.37
80 mg (per each): $15.15
100 mg (per each): $19.01
Solution (Infumorph 200 Injection)
200 MG/20ML (10 mg/mL) (per mL): $12.48
Solution (Infumorph 500 Injection)
500 MG/20ML (25 mg/mL) (per mL): $21.22
Solution (Mitigo Injection)
200 MG/20ML (10 mg/mL) (per mL): $12.49
500 MG/20ML (25 mg/mL) (per mL): $21.24
Solution (Morphine Sulfate (Concentrate) Oral)
100 mg/5 mL (per mL): $0.75 - $0.84
Solution (Morphine Sulfate (PF) Injection)
0.5 mg/mL (per mL): $0.99
1 mg/mL (per mL): $1.09
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 - $5.15
4 mg/mL (per mL): $2.34 - $5.18
8 mg/mL (per mL): $2.77
10 mg/mL (per mL): $2.77 - $6.10
Solution (Morphine Sulfate Injection)
2 mg/mL (per mL): $3.44
4 mg/mL (per mL): $3.44
50 mg/mL (per mL): $1.03
Solution (Morphine Sulfate Intravenous)
4 mg/mL (per mL): $2.41 - $3.00
8 mg/mL (per mL): $3.38 - $3.39
10 mg/mL (per mL): $3.06
50 mg/mL (per mL): $0.79
Solution (Morphine Sulfate Oral)
10 mg/5 mL (per mL): $0.33
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): $0.26 - $1.87
30 mg (per each): $0.47 - $3.38
60 mg (per each): $0.89 - $6.21
100 mg (per each): $0.91 - $9.20
200 mg (per each): $2.34 - $18.38
Tablet, controlled release (MS Contin Oral)
15 mg (per each): $5.05
30 mg (per each): $9.60
60 mg (per each): $18.73
100 mg (per each): $27.73
200 mg (per each): $50.79
Tablets (Morphine Sulfate Oral)
15 mg (per each): $0.49 - $0.91
30 mg (per each): $0.84 - $1.54
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule, Oral:
M-Ediat: 5 mg [DSC] [contains corn starch, fd&c blue #2 (indigotine,indigo carmine)]
M-Ediat: 10 mg [DSC] [contains corn starch]
M-Ediat: 20 mg [DSC] [contains corn starch, fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye)]
M-Ediat: 30 mg [DSC] [contains corn starch, fd&c blue #2 (indigotine,indigo carmine), quinoline yellow (d&c yellow #10)]
Capsule Extended Release 12 Hour, Oral:
M-Eslon: 10 mg, 15 mg, 30 mg, 60 mg, 100 mg, 200 mg
Capsule Extended Release 24 Hour, Oral, as sulfate:
Kadian: 20 mg, 50 mg, 100 mg
Kadian SR: 10 mg
Solution, Injection:
Generic: 1 mg/mL ([DSC])
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); 50 mg/mL (1 mL, 5 mL, 10 mL, 50 mL)
Solution, Intravenous, as sulfate:
Generic: 100 mg /100 mL in NaCl 0.9% (100 mL)
Suppository, Rectal, as sulfate:
Statex: 5 mg ([DSC]); 10 mg ([DSC]); 20 mg ([DSC]); 30 mg ([DSC])
Syrup, Oral:
Doloral 1: 1 mg/mL (225 mL, 500 mL) [contains alcohol, usp, fd&c blue #1 (brilliant blue), fd&c yellow #5 (tartrazine), methylparaben, propylparaben]
Doloral 5: 5 mg/mL (10 mL, 250 mL, 500 mL)
Tablet, Oral:
MS/IR: 5 mg, 10 mg, 20 mg
Statex: 5 mg, 10 mg, 25 mg [DSC], 50 mg [DSC]
Tablet, Oral, as sulfate:
MS/IR: 30 mg
Tablet Extended Release, Oral, as sulfate:
MS Contin: 15 mg [contains fd&c blue #1 (brill blue) aluminum lake, fd&c blue #2 (indigotine,indigo carmine), quinoline (d&c yellow #10) aluminum lake]
MS Contin: 30 mg [contains fd&c blue #2 (indigo carm) aluminum lake, fd&c yellow #6(sunset yellow)alumin lake]
MS Contin: 60 mg [contains fd&c yellow #6(sunset yellow)alumin lake, quinoline (d&c yellow #10) aluminum lake]
MS Contin: 100 mg [contains fd&c blue #2 (indigo carm) aluminum lake]
MS Contin: 200 mg [contains fd&c yellow #6(sunset yellow)alumin lake]
Generic: 15 mg, 30 mg, 60 mg, 100 mg, 200 mg
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.
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.
C-II
Oral: Administer with food.
Immediate release: Oral solution: Available in multiple strengths, including a concentrated oral solution (20 mg/mL). Precautions should be taken to avoid confusion between the different concentrations; medication orders (prescriptions) should have the concentration specified as well as the dose clearly represented as milligram (mg) of morphine, not volume (mL). Administer with an accurate measuring device (calibrated oral syringe or measuring cup); do not use a household teaspoon or tablespoon to measure dose (overdosage may occur).
Concentrated oral solution: Only use in opioid-tolerant patients (eg, adults taking ≥60 mg/day of morphine or equivalent for ≥1 week). Administer only using the calibrated oral syringe provided with the concentrated oral solution to ensure the dose is measured and administered accurately.
Extended-/controlled-release products: Do not chew, crush, break, or dissolve extended- and controlled-release products as it can result in uncontrolled delivery and can lead to overdose or death; swallow whole.
Parenteral: Note: Solutions for injection should be visually inspected for particulate matter and discoloration prior to administration. Do not use if contains a precipitate or is darker in color than pale yellow or discolored in any other way. Precautions should be taken to avoid confusion between the different concentrations; medication orders (prescriptions) should have the concentration specified as well as the dose clearly represented as milligram (mg) of morphine, not volume (mL).
IV push: Administer undiluted or diluted solution over 4 to 5 minutes (Ref); rapid IV administration may increase adverse effects. For neonates, IV boluses may be administered over 5 to 15 minutes via a syringe pump (Ref).
Intermittent IV infusion: Further dilute and administer over 15 to 30 minutes.
Continuous IV infusion: Administer as a continuous infusion via an infusion pump.
Epidural and intrathecal: Use only preservative-free injections.
Inhalation: Limited data available; utilize preservative free parenteral morphine and further dilute prior to administration (Ref)
Oral: Do not crush, chew, or dissolve ER formulations; swallow whole. Cutting, breaking, crushing, chewing, or dissolving ER formulations may result in uncontrolled delivery of morphine, leading to overdose and death.
Arymo ER: Swallow tablets whole, one tablet at a time, with enough water to ensure complete swallowing immediately after placing in the mouth; do not pre-soak, lick, or wet tablets prior to placing in the mouth.
Kadian: Capsules may be opened and sprinkled on applesauce and eaten immediately without chewing; do not crush, dissolve, or chew the beads, as it can result in a rapid release of a potentially fatal dose of morphine. Ensure all pellets have been swallowed by rinsing mouth. Contents of capsules may be opened and sprinkled over 10 mL water and flushed through prewetted 16F gastrostomy tube; do not administer through gastric/nasogastric tubes.
Bariatric surgery: Tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. ER tablet should be swallowed whole. Do not break, crush, cut, chew, dissolve, presoak, wet, or split as this will result in uncontrolled delivery of morphine that can lead to overdose or death. Take one abuse deterrent dose at a time and with sufficient water to avoid tablet becoming sticky and difficult to swallow. IR tablet, oral solution, and rectal suppository are available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery; however, clinicians should be advised that oral morphine has been shown to have significantly increased Cmax and decreased Tmax in the immediate (1 to 2 weeks) and long-term (6 months) periods after bariatric surgery (Ref).
IV: Administer single-use prefilled syringes/cartridges via slow IV push over 4 to 5 minutes (rapid administration may result in chest wall rigidity). Concentrated vials are available for preparation of continuous IV infusion or PCA; refer to indication-specific infusion rates in dosing for detailed recommendations.
Epidural, intrathecal: Use only preservative-free solutions indicated for intrathecal or epidural use; refer to indication-specific infusion rates in dosing for detailed recommendations.
Rectal: Remove suppository from plastic packet and moisten suppository with water to avoid irritation. Gently insert (rounded end first) approximately a finger's length into rectum, angling it toward the umbilicus, and placing it against the rectal wall; after suppository is inserted, hold buttocks together until urge to expel ceases (Ref).
SUBQ continuous infusions: Change site every 3 to 7 days or when erythema occurs (Ref). To maintain comfort, the SUBQ infusion rate should generally not exceed 5 mL/hour (Ref).
IV infusion: 0.04 mg/mL, 0.1 mg/mL, 0.5 mg/mL, or 1 mg/mL.
IV infusion: 0.04 mg/mL, 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).
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/2023/019516s058lbl.pdf#page=32
Oral solution: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/022195s021lbl.pdf#page=23
Oral tablet: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/022207s011lbl.pdf#page=29
Oral:
Immediate-release formulations (oral solution and tablets): Management of severe acute pain for which alternative treatment options are inadequate (eg, nonopioid analgesics) (immediate-release tablets: FDA approved in pediatric patients ≥50 kg and adults; oral solution [2 mg/mL, 4 mg/mL]: FDA approved in ages ≥2 years and adults); management of severe chronic pain for which alternative treatment options are inadequate (immediate-release tablets: FDA approved in adults; oral solution [2 mg/mL, 4 mg/mL]: FDA approved in ages ≥18 years and adults); management of acute and chronic pain in opioid-tolerant patients (oral solution [20 mg/mL]: 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 severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate (FDA approved in ages ≥18 years and adults).
Parenteral:
Intravenous: Management of severe acute pain when opioid treatment is required and for which alternative treatment options are inadequate (FDA approved in all ages); 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: Management of pain unresponsive without attendant loss of motor, sensory, or sympathetic function. Note: Not for use in continuous microinfusion devices (Duramorph: FDA approved in adults); treatment of intractable chronic pain severe enough to require an opioid analgesic as an epidural infusion via microinfusion device and for which less invasive means of controlling pain are inadequate (Infumorph, Mitigo: FDA approved in adults).
Intrathecal: Management of pain without attendant loss of motor, sensory, or sympathetic function. Note: Not for use in continuous microinfusion devices (Duramorph: FDA approved in adults); treatment of intractable chronic pain severe enough to require an opioid analgesic as a continuous infusion via microinfusion device and for which less invasive means of controlling pain are inadequate (Infumorph, Mitigo: FDA approved in adults).
Rectal: Suppositories: Management of severe acute and chronic pain when opioid treatment is required and for which alternative treatment options are inadequate (FDA approved in adults).
Limitations of use: Because of the risks of substance use disorder, abuse, and misuse with opioids, which may occur at any dosage or duration, reserve morphine for use in patients for whom alternative treatment options (eg, nonopioid analgesics, opioid combination products) have not been tolerated, or are not expected to be tolerated, have not provided adequate analgesia, or are not expected to provide adequate analgesia. Immediate-release formulations are not intended to be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. Extended-release formulations are not indicated as as-needed analgesics.
Morphine may be confused with diamorphine, HYDROmorphone, methadone
Morphine sulfate may be confused with magnesium sulfate
Kadian may be confused with Kapidex [DSC]
MS Contin may be confused with OxyCONTIN
MSO4 and MS are error-prone abbreviations (mistaken as magnesium sulfate)
Roxanol may be confused with OxyFast, Roxicet, Roxicodone Intensol
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.
Avinza [Puerto Rico] may be confused with Evista brand name for raloxifene [US, Canada, and multiple international markets] and Invanz brand name for ertapenem [US, Canada, Qatar]
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.
Substrate of OCT1, P-glycoprotein/ABCB1 (major), UGT1A1; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Alvimopan: Opioid Agonists may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider therapy modification
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification
Amphetamines: May enhance the analgesic effect of Opioid Agonists. Risk C: Monitor therapy
Anticholinergic Agents: May enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Risk C: Monitor therapy
Antiplatelet Agents (P2Y12 Inhibitors): Morphine (Systemic) may diminish the antiplatelet effect of Antiplatelet Agents (P2Y12 Inhibitors). Morphine (Systemic) may decrease the serum concentration of Antiplatelet Agents (P2Y12 Inhibitors). Management: Consider alternative anti-ischemic/analgesic therapies (eg, beta-blockers, nitroglycerin) in patients with acute coronary syndromes treated with a P2Y12 inhibitor when possible. The risks associated with other opioids are unknown. Risk D: Consider therapy modification
Arginine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. 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
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Risk C: Monitor therapy
DroPERidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy
Eluxadoline: Opioid Agonists may enhance the constipating effect of Eluxadoline. Risk X: Avoid combination
Esmolol: Morphine (Systemic) may increase the serum concentration of Esmolol. Risk C: Monitor therapy
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
Gastrointestinal Agents (Prokinetic): Opioid Agonists may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Risk C: Monitor therapy
Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Ixabepilone: May enhance the CNS depressant effect of CNS Depressants. 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
Landiolol: Morphine (Systemic) may enhance the therapeutic effect of Landiolol. Risk C: Monitor therapy
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-Foslevodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Foslevodopa. Risk C: Monitor therapy
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lumacaftor and Ivacaftor: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may decrease the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors or Inducers). Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Mitapivat: May decrease the serum concentration of UGT1A1 Substrates. Risk C: Monitor therapy
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors: May enhance the adverse/toxic effect of Morphine (Systemic). Risk X: Avoid combination
Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nalfurafine: Opioid Agonists may enhance the adverse/toxic effect of Nalfurafine. Opioid Agonists may diminish the therapeutic effect of Nalfurafine. Risk C: Monitor therapy
Nalmefene: May diminish the therapeutic effect of Opioid Agonists. Management: Avoid the concomitant use of oral nalmefene and opioid agonists. Discontinue oral nalmefene 1 week prior to any anticipated use of opioid agonists. If combined, larger doses of opioid agonists will likely be required. Risk D: Consider therapy modification
Naltrexone: May diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Risk X: Avoid combination
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy
Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Risk D: Consider therapy modification
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Opioids (Mixed Agonist / Antagonist): May diminish the analgesic effect of Opioid Agonists. Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Risk X: Avoid combination
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Pegvisomant: Opioid Agonists may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Morphine (Systemic). Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Ramosetron: Opioid Agonists may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy
RifAMPin: May decrease the serum concentration of Morphine (Systemic). Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Samidorphan: May diminish the therapeutic effect of Opioid Agonists. Risk X: Avoid combination
Serotonergic Agents (High Risk): Opioid Agonists may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Silodosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. 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
Zuranolone: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. 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.
Chronic opioid use may cause hypogonadism and hyperprolactinemia which may decrease fertility in patients of reproductive potential. Menstrual cycle disorders (including amenorrhea), erectile dysfunction, and impotence have been reported. The incidence of hypogonadism may be increased with the use of opioids in high doses or long-acting opioid formulations. It is not known if the effects on fertility are reversible. Monitor patients on long-term therapy (de Vries 2020; Gadelha 2022).
Consider family planning, contraception, and the effects on fertility prior to prescribing opioids for chronic pain to patients who could become pregnant (ACOG 2017; CDC [Dowell 2022]).
Morphine crosses the placenta.
Maternal use of opioids may be associated with poor fetal growth, stillbirth, and preterm delivery (CDC [Dowell 2022]). Opioids used as part of obstetric analgesia/anesthesia during labor and delivery may temporarily affect the fetal heart rate (ACOG 2019).
Neonatal abstinence syndrome (NAS)/neonatal opioid withdrawal syndrome (NOWS) may occur following prolonged in utero exposure to opioids (CDC [Dowell 2022]). NAS/NOWS may be life-threatening if not recognized and treated and requires management according to protocols developed by neonatology experts. Presentation of symptoms varies by opioid characteristics (eg, immediate release, sustained release), time of last dose prior to delivery, drug metabolism (maternal, placental, and infant), net placental transfer, as well as other factors (AAP [Hudak 2012]; AAP [Patrick 2020]). Clinical signs characteristic of withdrawal following in utero opioid exposure include excessive crying or easily irritable, fragmented sleep (<2 to 3 hours after feeding), tremors, increased muscle tone, or GI dysfunction (hyperphagia, poor feeding, feeding intolerance, watery or loose stools) (Jilani 2022). NAS/NOWS occurs following chronic opioid exposure and would not be expected following the use of opioids at delivery (AAP [Patrick 2020]).
Monitor infants of mothers on long-term/chronic opioid therapy for symptoms of withdrawal. Symptom onset reflects the half-life of the opioid used. Monitor infants for at least 3 days following exposure to immediate-release opioids; monitor for at least 4 to 7 days following exposure to sustained-release opioids (AAP [Patrick 2020]; CDC [Dowell 2022]). Monitor newborns for excess sedation and respiratory depression when opioids are used during labor.
When opioids are needed to treat acute pain in pregnant patients, the lowest effective dose for only the expected duration of pain should be prescribed (CDC [Dowell 2022]).
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. Opioid use for pain following vaginal or cesarean delivery should be made as part of a shared decision-making process. A stepwise, multimodal approach to managing postpartum pain is recommended. A low-dose, low-potency, short-acting opioid such as morphine can be used to treat acute pain associated with delivery when needed (ACOG 2021).
Opioids are not preferred for the treatment of chronic noncancer pain during pregnancy; consider strategies to minimize or avoid opioid use. Advise pregnant patients requiring long-term opioid use of the risk of NAS/NOWS and provide appropriate treatment for the neonate after delivery. NAS/NOWS is an expected and treatable condition following chronic opioid use during pregnancy and should not be the only reason to avoid treating pain with an opioid in pregnant patients (ACOG 2017; CDC [Dowell 2022]). Do not abruptly discontinue opioids during pregnancy; taper prior to discontinuation when appropriate, considering the risks to the pregnant patient and fetus if maternal withdrawal occurs (CDC [Dowell 2022]).
Respiratory rate; oxygen saturation; blood pressure; heart rate; pain relief (if used for analgesia) using a pain scale appropriate to patient age and clinical condition; abstinence scoring system (if used for neonatal abstinence syndrome); level of sedation and mental status; monitor for bowel sounds, abdominal distention, constipation, and urinary retention; signs of misuse, abuse, and substance use disorder; 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) (CDC [Dowell 2016]).
Astramorph/PF, Duramorph, Infumorph, Mitigo: 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 morphine via microinfusion device, patient may be observed, as appropriate, for the first several days after catheter implantation.
Alternative monitoring recommendations (Bujedo 2012a): Epidural: Note: All patients receiving neuraxial opioids should be monitored for adequate ventilation (eg, respiratory rate, depth of respiration [without disturbing patient]), oxygenation (eg, pulse oximetry when appropriate), and level of consciousness.
Single dose: Monitor patient for a minimum of 24 hours after administration with a frequency of at least once per hour for the first 12 hours after administration, followed by at least once every 2 hours for the next 12 hours (ie, from 12 to 24 hours after administration). After 24 hours, frequency dictated by overall clinical condition and concurrent medications.
Continuous infusion or patient controlled epidural analgesia (PCEA): Monitor patient during the entire duration of the infusion with a frequency of at least once per hour for the first 12 hours, followed by at least once every 2 hours for the next 12 hours (ie, from 12 to 24 hours after administration). After 24 hours, monitor at least once every 4 hours. After discontinuation of infusion or PCEA, frequency dictated by overall clinical condition and concurrent medications.
Note: Also refer to institution specific protocols as appropriate.
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 2012a).
Suppository: 3 to 7 hours.
Absorption: Variable.
Distribution: Distributes to skeletal muscle, liver, kidneys, lungs, intestinal tract, spleen and brain; Vd:
Preterm neonates: 2.04 ± 1.01 L/kg (range: 0.6 to 3.68 L/kg) (Chay 1992).
Term neonates: 2.07 ± 1.26 L/kg (range: 0.24 to 3.34 L/kg) (Chay 1992).
Children with cancer (age: 1.7 to 18.7 years): Median: 5.2 L/kg; a significantly higher Vd was observed in children <11 years (median: 7.1 L/kg) versus >11 years (median: 4.7 L/kg) (Hunt 1999).
Adults: 1 to 6 L/kg; binds to opioid receptors in the CNS and periphery (eg, GI tract).
Protein binding: Premature infants: 18% to 22% (Bhat 1990); Adults: 20% to 35%.
Metabolism: Hepatic via conjugation with glucuronic acid primarily to morphine-6-glucuronide (M6G) (active analgesic) morphine-3-glucuronide (M3G) (inactive as analgesic; may contribute to CNS stimulation [Lugo 2002]); minor metabolites include morphine-3-6-diglucuronide; other minor metabolites include normorphine (active) and morphine 3-ethereal sulfate. Due to immature hepatic enzyme development, neonates exhibit at least a 50% lower glucuronidation rate than older children (Cravero 2019).
Bioavailability: Oral: 17% to 33% (first-pass effect limits oral bioavailability); Nebulization: 5.5 ± 3.2% (Masood 1996).
Half-life elimination:
Pediatric: Note: Values listed are based on IV dosing (IV bolus and/or continuous IV infusion):
Preterm neonates: 10.6 ± 2.7 hours (range: 5.5 to 13.3 hours) (Chay 1992).
Term neonates: 7.6 ± 2.6 hours (range: 4.5 to 11 hours) (Chay 1992).
Infants 1 to 3 months: Median: 6.2 hours (range: 5 to 9.9 hours) (McRorie 1992).
Infants 3 to 6 months: Median: 4.5 hours (range: 3.8 to 7.3 hours) (McRorie 1992).
Infants 6 months to Children 2.5 years: Median: 2.9 hours (range: 1.4 to 7.8 hours) (McRorie 1992).
Preschool children: 1 to 2 hours (Olkkola 1995).
Children with sickle cell disease (age: 6 to 19 years): ~1.3 hours (Dampier 1995).
Adults: Immediate-release forms: 2 to 4 hours; Kadian: 11 to 13 hours.
Time to peak:
Plasma:
Tablets, oral solution, epidural: 1 hour.
Extended release tablets: 3 to 4 hours; Kadian: ~10 hours.
Suppository: 20 to 60 minutes.
SUBQ: 50 to 90 minutes.
IM: 30 to 60 minutes.
IV: 20 minutes.
Cerebrospinal fluid: After an oral dose of controlled release morphine concentrations peak at 8 hours for both normal and reduced renal function; morphine-6-glucuronide (active analgesic) and morphine-3-glucuronide distribution into the CNS may be delayed peaking at 12 hours in patients with normal renal function or up to 24 hours in patients with ESRD (peak level of morphine-6-glucuronide is ~15 times higher than patients with normal renal function) (D'Honneur 1994).
Excretion: Urine (primarily as morphine-3-glucuronide, neonates: 3% to 15%; adults: ~2% to 12% excreted unchanged); feces (~7% to 10%). It has been suggested that accumulation of morphine-6-glucuronide might cause toxicity with renal insufficiency. All of the metabolites (ie, morphine-3-glucuronide, morphine-6-glucuronide, and normorphine) have been suggested as possible causes of neurotoxicity (eg, myoclonus).
Clearance: Note: In pediatric patients, adult values are reached by 6 months to 2.5 years of age (McRorie 1992).
Preterm: 0.5 to 3 mL/minute/kg (Olkkola 1995).
Neonates 1 to 7 days: Median: 5.5 mL/minute/kg (range: 3.2 to 8.4 mL/minute/kg) (McRorie 1992).
Neonates 8 to 30 days: Median: 7.4 mL/minute/kg (range: 3.4 to 13.8 mL/minute/kg) (McRorie 1992).
Infants 1 to 3 months: Median: 10.5 mL/minute/kg (range: 9.8 to 20.1 mL/minute/kg) (McRorie 1992).
Infants 3 to 6 months: Median: 13.9 mL/minute/kg (range: 8.3 to 24.1 mL/minute/kg) (McRorie 1992).
Infants 6 months to Children 2.5 years: Median: 21.7 mL/minute/kg (range: 5.8 to 28.6 mL/minute/kg) (McRorie 1992).
Preschool children: 20 to 40 mL/minute/kg (Olkkola 1995).
Children with cancer (age: 1.7 to 18.7 years): Median: 23.1 mL/minute/kg; a significantly higher clearance was observed in children <11 years (median: 37.4 mL/minute/kg) versus >11 years (median: 21.9 mL/minute/kg) (Hunt 1999).
Children with sickle cell disease (age: 6 to 19 years): ~36 mL/minute/kg (range: 6 to 59 mL/minute/kg) (Dampier 1995).
Adults: 20 to 30 mL/minute/kg.
Pediatric: Increased pharmacokinetic variability in neonates likely due to immaturity of hepatic glucuronidation, alterations in hepatic blood flow during acute illness, and blood shunting away from the liver by the ductus venosus (Bhat 1990).
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