section name header

Introduction ⬇

AHFS Class:

Generic Name(s):

Notification

REMS:

FDA approved a REMS for morphine under a shared REMS system (Opioid Analgesic REMS) to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of morphine and consists of the following: medication guide and elements to assure safe use. See the FDA REMS page ([Web]).

Morphine sulfate is a phenanthrene-derivative opioid agonist;1,2,3,4,5,6,7,8,9,10,12,13,757 morphine is the principal alkaloid of opium and considered to be the prototype of the opioid agonists.756,757

Uses ⬆ ⬇

[Section Outline]

Pain !!navigator!!

Morphine sulfate is used in the management of acute or chronic pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.1,2,3,4,5,6,7,8,9,10,12,13,757,758,759 Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, reserve use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products) have not been tolerated (or not expected to be tolerated) or have not provided (or not expected to provide) adequate analgesia.1,2,3,4,5,6,7,8,9,10,12,13 Morphine sulfate should not 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.1,2,3,4,5,8,9,10,12

Morphine sulfate is commercially available in various preparations and formulations.1,2,3,4,5,6,7,8,9,10,12,13 Currently available preparations include immediate-release tablets, oral solution, extended-release tablets, extended-release capsules, rectal suppositories, and injection solutions for IV, IM, epidural, or intrathecal use.1,2,3,4 5 6,7 8 9 10 12,13

Preservative-free injection solutions of morphine sulfate are indicated for IV, epidural, or intrathecal use.5,8,10 Epidural or intrathecal administration can provide pain relief without attendant loss of motor, sensory, or sympathetic function.5 The preservative-free concentrated morphine sulfate injection (Infumorph®) is indicated for use only in continuous microinfusion devices as an epidural or intrathecal infusion; this formulation has been designated an orphan drug by the FDA for intraspinal administration using microinfusion devices in the treatment of intractable chronic pain.10,11

Extended-release oral morphine sulfate preparations may be used in patients with severe and persistent pain requiring extended treatment with a daily opioid analgesic and for which alternative treatment options are inadequate.6,7,13 Extended-release preparations should not be used on an as-needed (“prn”) basis.6,7,13

Pain needs to be appropriately and effectively treated, regardless of whether opioids are part of the treatment regimen.760 Treatment should be individualized, patient-centered, and include multimodal approaches.760 Opioids can be essential in the management of pain but are associated with considerable potential harm, including opioid use disorder and overdose.760 Therefore, safer and more effective treatments should be considered prior to initiating opioid therapy.760 There are multiple nonpharmacologic treatments (e.g., exercise, physical therapy, psychological therapies) and nonopioid drugs (e.g., serotonin and norepinephrine reuptake inhibitors [SNRIs], gabapentinoids, nonsteroidal anti-inflammatory agents [NSAIAs]) that have been shown to be at least as effective as opioids for many types of common pain conditions.760 These nonopioid treatments are generally preferred to opioids in most situations.760 If opioids are used, clinicians should carefully evaluate the risk of opioid-related harms and work with the patient to incorporate appropriate risk-mitigation strategies into the treatment plan, including offering naloxone.760

The Centers for Disease Control and Prevention (CDC) clinical guideline for prescribing opioids for pain provides recommendations for the management of acute (duration <1 month), subacute (duration 1-3 months), and chronic pain (duration >3 months) in adults in the outpatient setting.760 The CDC guideline addresses the following areas: 1) determining whether or not to initiate opioids for pain, 2) selecting opioids and determining opioid dosages, 3) deciding duration of initial opioid prescription and conducting follow-up, and 4) assessing risk and addressing potential harms of opioid use.760

Other clinical practice guidelines provide recommendations for the management of specific types of pain including postoperative pain, cancer-related pain, sickle-cell pain, and pain associated with palliative care; although specific recommendations for the management of opioid therapy vary across the guidelines, common elements include risk mitigation strategies, careful dosage titration, and consideration of risks and benefits.410,414,415,422,423,430,431,432,433,434,758,759,761

Chronic or Subacute Pain

In patients with chronic or subacute pain not associated with active cancer treatment, palliative care, or end-of-life care (also referred to as chronic noncancer pain), nonopioid therapies are preferred.760 There is insufficient evidence to determine the long-term benefits of opioid therapy for chronic pain, and there is an increased risk for serious harms related to long-term opioid therapy that appears to be dose dependent.760 Use of opioid analgesics for the management of chronic noncancer pain increased four-fold in the US from 1999 to 2010, along with a parallel increase in overdose deaths, despite uncertainty over the long-term benefits of such therapy.760 In addition, evidence that opioid analgesics are superior to other pharmacologic or nonpharmacologic treatments for chronic pain generally is lacking.760 Opioid analgesics should be considered only if other pain management strategies (nonpharmacologic [e.g., exercise, physical therapy] and nonopioid drugs [e.g., NSAIAs, select antidepressants or anticonvulsants, gabapentinoids, lidocaine and capsaicin patches for neuropathic pain) have been maximized as appropriate for the specific condition and patient, and the expected benefits of opioid analgesics are anticipated to outweigh the risks.760 If opioid analgesics are used, they should be part of an integrated approach that also includes appropriate nonpharmacologic modalities (e.g., cognitive behavioral therapy, relaxation techniques, biofeedback, functional restoration, exercise therapy, certain interventional procedures) and other appropriate pharmacologic therapies.760 The lowest-effective dosage of an immediate-release preparation should be used.760 Clinicians should work with patients to establish treatment goals and also consider how opioid therapy wll be discontinued if the benefits do not outweigh the risks.760

The benefits and risks of opioid analgesic therapy should be evaluated within 1-4 weeks following initiation of therapy or an increase in dosage, and reevaluated on an ongoing basis throughout therapy.760 Monitoring should include documentation of pain intensity and level of functioning, assessment of progress toward therapeutic goals, presence of adverse effects, and adherence to prescribed therapies.422,423,760 Common opioid-related adverse effects (e.g., constipation, nausea and vomiting, cognitive and psychomotor impairment) should be anticipated and appropriately managed.415,760

If opioids are continued for chronic or subacute pain, clinicians should use caution when prescribing opioids at any dosage and should generally avoid dosage increases when possible.760 Many patients do not experience benefit in pain or function from increasing opioid dosages to ≥50 morphine mg equivalent/day but are exposed to progressive increases in risk as dosage increases.760

Patients should be closely monitored for adverse effects and other risks of therapy, including opioid use disorder.760 Various strategies for managing risks associated with opioid therapy for chronic noncancer pain have been recommended, including written treatment agreements or plans (e.g., “contracts”), urine drug testing, review of state prescription drug monitoring program (PDMP) data, and risk assessment and monitoring tools.414,415,422,423,760 Clinicians should offer or arrange treatment for patients with opioid use disorder.760

Acute Pain

Nonopioid therapies are at least as effective as opioids for many common types of acute pain (e.g., low back pain, neck pain, pain related to other musculoskeletal injuries).760 Use of nonpharmacologic therapies (e.g., ice, heat, elevation, rest, immobilization, exercise) and nonopioid pharmacologic therapies (e.g., topical or oral NSAIAs, acetaminophen) should be maximized as appropriate for the specific condition and patient.760 In the symptomatic treatment of acute pain, opioid analgesics have an important role in the management of pain resulting from traumatic injuries, invasive surgeries, or other severe acute pain when nonopioid alternatives are expected to be ineffective or are contraindicated.760 However, opioid therapy should be considered for acute pain only if the benefits are anticipated to outweigh the risks.760 If opioid therapy is warranted, immediate-release preparations are recommended at the lowest effective dosage.760 The prescribed quantity should be limited to the amount needed for the expected duration of pain severe enough to require opioid analgesia.760 For the treatment of acute pain, opioids should be prescribed only as needed rather than on a scheduled basis.760 Because short-term opioid use can lead to unintended long-term use, clinicians should work with patients to develop a plan for discontinuation as soon as feasible.370,760

When opioid analgesics are used for the management of postoperative pain, opioid therapy should be provided as part of a multimodal regimen that also includes acetaminophen and/or NSAIAs and other pharmacologic and nonpharmacologic therapy as appropriate.371,430 Because of the availability of effective nonopioid analgesics and nonpharmacologic therapies for postoperative pain, it is suggested that clinicians routinely incorporate these therapies into pain management regimens.430,431 Systemic opioids may not be required in all patients.430 If opioid therapy is required, oral administration of a short-acting opioid generally is preferred over IV administration in patients who can tolerate oral therapy.430 Scheduled (around-the-clock) dosing of opioid analgesics frequently is required during the immediate postoperative period or following major surgery.430 When parenteral administration is required, some experts recommend that IV patient-controlled analgesia (PCA) be used for postoperative systemic analgesia.430 Routine use of basal IV infusions of opioids in opioid-naïve patients receiving PCA is not recommended.430 IM administration of analgesics for the management of postoperative pain is discouraged because IM injections can cause pain and are associated with unreliable absorption, which may result in inconsistent analgesia.430

Cancer Pain

The American Society of Clinical Oncology (ASCO) states that opioids should be offered to patients with moderate-to-severe pain associated with cancer or active cancer treatment, unless contraindicated.759 In a recent review of 17 studies of patients receiving oral morphine for cancer pain, 96% of morphine-treated patients (362 of 377) achieved an outcome of no worse than mild pain.759 Prior to initiating opioid therapy, it is useful to assess the mechanism for the pain syndrome (imaging may be required), the response to nonopioid analgesics (e.g., acetaminophen or NSAIAs), and the presence of risk factors such as a history of misuse of alcohol, recreational substances, or prescription drugs.759 Opioids should be initiated as an immediate-release formulation and as needed to establish an effective dosage.759 The lowest possible dosage should be used to achieve acceptable analgesia and patient goals, and patients should be assessed early with frequent dosage titration.759 In patients receiving opioids around the clock, an immediate-release opioid at a dose of 5-20% of the regular morphine equivalent daily dose should be prescribed for breakthrough pain.759 When opioids are no longer indicated, they should be weaned or tapered.759

Sickle Cell Pain

Pain associated with sickle cell disease can manifest as both acute intermittent pain, chronic daily pain, and acute-on-chronic pain.758 Management of acute and chronic pain must be individualized and include multimodal treatment approaches.758 Opioids may potentially be used as part of the treatment regimen to manage acute pain in adults and children with sickle cell disease; selection of an appropriate dosage should consider baseline opioid therapy and prior effective therapy, and the lowest effective dosage should be prescribed.758 For adults and children with emerging and/or recently developed chronic pain related to sickle cell disease, experts suggest against the initiation of chronic opioid therapy unless pain is refractory to multiple other treatments.758 Clinicians should be aware that patients may inadvertently be treated with opioids chronically if episodic pain is frequent.758 Efforts should be made to reduce or eliminate scheduled opioid doses between acute episodic pain events to reduce the likelihood of unintentional chronic opioid therapy.758

Palliative Care

Palliative care is defined as care that provides relief from pain and other symptoms, supports quality of life, and is focused on patients with serious advanced illness and their families.761 Palliative care may begin early in the course of treatment for a serious illness and may be delivered in a number of ways across the continuum of health care settings, including in the home, nursing homes, long-term acute care facilities, acute care hospitals, and outpatient clinics.761

Palliative care guidelines address the use of opioids for pain management in this setting.761 The ongoing care of patients being treated with opioids for physical symptoms, such as pain and dyspnea, includes documentation of treatment goals, ongoing risk assessments for opioid misuse, and frequency of re-assessments.761 The interdisciplinary care team should regularly conduct pain assessments and evaluate the effectiveness of treatments after initiation and upon any changes to the therapeutic regimen.761 The guidelines also recommend that palliative care clinicians receive training on safe and appropriate use of opioids and how to assess risk for opioid use disorder, monitor for signs of opioid abuse and diversion, and manage pain in patients at risk for substance abuse.761

Acute Coronary Syndrome !!navigator!!

Morphine is used to relieve pain and anxiety associated with acute coronary syndrome (ACS).753,754 Because of its ability to alleviate the work of breathing, reduce anxiety, and favorably affect ventricular loading conditions, morphine is considered the analgesic agent of choice in patients with ST-segment-elevation myocardial infarction (STEMI).753 In addition to its potent analgesic and anxiolytic effects, morphine also exhibits favorable hemodynamic effects by causing venodilation and modest reductions in heart rate and systolic blood pressure.753

These properties also may be beneficial in patients with non-ST-segment-elevation ACS (NSTE ACS; unstable angina or non-ST-segment-elevation myocardial infarction [NSTEMI]); although randomized controlled studies specifically evaluating the use of morphine in patients with NSTE ACS have not been conducted, experts state that it may be reasonable to administer IV morphine in such patients who have continued pain despite treatment with maximally tolerated anti-ischemic drugs (e.g., nitrates).754 However, use of morphine should not preclude the use of other anti-ischemic drugs with proven benefit.754

Neonatal Opioid Withdrawal !!navigator!!

Morphine has been used to manage manifestations of opioid abstinence syndrome (i.e., postnatal withdrawal) in neonates† exposed to opioids in utero.350,352,353,355,357,359,360 Opioids are recommended as first-line pharmacologic therapy when environmental and supportive measures (e.g., minimization of external stimuli, maximization of mother-infant contact [e.g., parental “rooming in”], breast-feeding when not contraindicated, swaddling and gentle handling) are inadequate.350,352,353,355,357,359 Other adjunctive therapy (e.g., clonidine, phenobarbital) may be added if the response to opioids is inadequate; currently, clonidine is recommended over phenobarbital until further study of long-term effects of phenobarbital are known.350,352,353,355,357,358,359,365,368,771 Approximately 60-80% of neonates with opioid abstinence syndrome may require pharmacologic treatment for withdrawal symptoms.352,359 While morphine has been used more extensively than other opioids in the management of neonatal opioid abstinence syndrome, some studies suggest that use of methadone or buprenorphine (an opioid partial agonist) may be associated with shorter treatment durations and hospital stays compared with morphine use,360,361,362,363 but caution is advised if the preparation has a high alcohol content.771 Additional study is needed to establish optimal dosage schedules and preferred opioid drugs and to evaluate longer-term (e.g., neurodevelopmental) outcomes.351,353,354,355,360 Conflicting findings to date may be related in part to differences in study design, nonpharmacologic care, concomitant in utero drug exposures, the stringency of institutional protocols for care, and optimization of dosage schedules.354,360,362

Use of standardized protocols for identification, evaluation, and treatment of neonatal opioid withdrawal syndrome is recommended since use of such protocols has been shown to improve overall response, including shorter hospital stays and durations of pharmacologic treatment.350,352,353,358,359,771 Some evidence suggests that use of a standardized protocol may be more important than use of a specific opioid agonist (e.g., morphine versus methadone) in improving outcomes.352,359,363 Protocols generally utilize assessment tools that were developed to quantify severity of withdrawal in term neonates (e.g., Finnegan or modified Finnegan scoring tools) to facilitate decisions regarding initiation, titration, and tapering of therapy.352,353,355,357,359,771

Dosage and Administration ⬆ ⬇

[Section Outline]

General !!navigator!!

Pretreatment Screening

Patient Monitoring

Dispensing and Administration Precautions

Cautions ⬆ ⬇

[Section Outline]

Contraindications !!navigator!!

Warnings/Precautions !!navigator!!

Warnings

Addiction, Abuse, and Misuse

As an opioid agonist, morphine sulfate exposes users to the risks of addiction, abuse, and misuse.1,2,3,4,5,6,7,8,9,10,12,13 A boxed warning regarding this risk has been included in the prescribing information for morphine.1,2,3,4,5,6,7,8,9,10,12,13 Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed morphine sulfate.1,2,3,4,5,6,7,8,9,10,12,13 Addiction can occur at recommended dosages and if the drug is misused or abused.1,2,3,4,5,6,7,8,9,10,12,13 Because extended-release products deliver the drug over a prolonged period of time, there is a greater risk for overdose and death due to the larger amount of morphine present.6,7,13

Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing morphine sulfate and reassess all patients receiving the drug for the development of these behaviors or conditions.1,2,3,4,5,6,7,8,9,10,12,13 Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression).1,2,3,4,5,6,7,8,9,10,12,13 The potential for these risks should not, however, prevent the proper management of pain in any given patient.1,2,3,4,5,6,7,8,9,10,12,13 Patients at increased risk may be prescribed opioid agonists such as morphine sulfate but use in such patients necessitates intensive counseling about the risks and proper use of the drug along with frequent reevaluation for signs of addiction, abuse, and misuse.1,2,3,4,5,6,7,8,9,10,12,13 Consider prescribing naloxone for the emergency treatment of opioid agonist overdose.1,3,6,13,760

Abuse or misuse of extended-release products (e.g., MS-Contin®) by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of morphine and can result in overdose and death.6,7,13

Opioid agonists are sought for nonmedical use and are subject to diversion from legitimate prescribed use; consider these risks when prescribing or dispensing morphine sulfate.1,2,3,4,5,6,7,8,9,10,12,13 Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during treatment and proper disposal of unused drug.1,2,3,4,5,6,7,8,9,10,12,13 Contact a state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion.1,2,3,4,5,6,7,8,9,10,12,13,760

Life-threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioid agonists, even when used as recommended.1,2,3,4,5,6,7,8,9,10,12,13 A boxed warning regarding this risk has been included in the prescribing information for morphine.1,2,3,4,5,6,7,8,9,10,12,13 Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death.1,2,3,4,5,6,7,8,9,10,12,13 Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status.1,2,3,4,5,6,7,8,9,10,12,13 Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.1,2,3,4,5,6,7,8,9,10,12,13

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of morphine, the risk is greatest during the initiation of therapy or following a dosage increase.1,2,3,4,5,6,7,8,9,10,12,13 Certain morphine sulfate preparations also have an increased risk of serious, life-threatening, or fatal respiratory depression.2,3,5,8,10

Morphine sulfate oral solution 20 mg/mL is for use only in opioid-tolerant adult patients.3 Administration of this formulation may cause fatal respiratory depression when administered to patients who are not tolerant to the respiratory depressant effects of opioid agonists.3

Rapid IV administration of morphine sulfate injection can cause a delay (30 minutes) in the maximum CNS effect and result in overdosing.2,5,12 The respiratory depression may be severe and could require intervention.2,5

Neuraxial administration of morphine as a single dose may result in acute or delayed respiratory depression for periods at least as long as 24 hours.5,8,10 Intrathecal use has been associated with a higher incidence of respiratory depression than epidural use.5,8 Thoracic administration has been shown to dramatically increase the incidence of early and late respiratory depression even at doses of 1 to 2 mg.5,8,10 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.5,10 The facility must be able to resuscitate patients with severe opioid overdosage, and the personnel must be familiar with the use and limitations of specific opioid antagonists (naloxone, naltrexone) in such cases.5,10

Improper or erroneous substitution of concentrated morphine sulfate injection (Infumorph® 200 or 500 [10 or 25 mg/mL, respectively]) for conventional morphine injection (e.g., Duramorph® 0.5 or 1 mg/mL) is likely to result in serious overdosage, leading to seizures, respiratory depression, and death.10

Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases.2,4,9,12 To reduce the risk of respiratory depression, proper dosing and titration of morphine are essential.2,4,9,12,13

Overestimating the dosage when converting patients from another opioid agonist product can result in a fatal overdose with the first dose.1,2,3,4,5,6,7,8,9,10,12,13

Accidental ingestion of even one dose of morphine sulfate, especially by children, can result in respiratory depression and death due to an overdose of morphine.1,3,4,6,7,13 Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or seeking emergency medical assistance immediately in the event of a known or suspected overdose.1,3,13

Opioid agonists can cause sleep-related breathing disorders including central sleep apnea and sleep-related hypoxemia.1,2,3,8,9,12,13 Opioid use increases the risk of central sleep apnea in a dose-dependent fashion.1 In patients who present with central sleep apnea, consider decreasing the opioid agonist dosage using best practices for opioid taper.1,2,3,8,9,10,12,13

Patient Access to Naloxone for Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid agonist overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with morphine sulfate preparations.1,3,13,760 Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).1,3,13 Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or seeking emergency medical help, even if naloxone is administered.1,3,13

Consider prescribing naloxone, based on the patient's risk factors for overdose, such as concomitant use of CNS depressants, history of opioid use disorder, or prior opioid agonist overdose.1,3,13 The presence of risk factors for overdose should not prevent the proper management of pain in any given patient.1,3,13 Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.1,3 If naloxone is prescribed, educate patients and caregivers on use of the drug.1,3,13

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from concomitant use of morphine with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids).1,2,3,4,5,6,7,8,9,10,12,13 A boxed warning regarding this risk has been included in the prescribing information for morphine.1,2,3,4,5,6,7,8,9,10,12,13 Because of these risks, reserve concomitant prescribing of these drugs for patients in whom alternative treatment options are inadequate.1,2,3,4,5,6,7,8,9,10,12,13

Use of neuroleptics in conjunction with neuraxial administration of morphine may increase the risk of respiratory depression.5,8

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone.1,2,3,4,5,6,7,8,9,10,12,13 Because of similar pharmacological properties, it is reasonable to expect similar risk with concomitant use of other CNS depressant drugs with opioid analgesics.1,2,3,4,5,6,7,8,9,10,12,13

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use.1,2,3,4,5,6,7,8,9,10,12,13 In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response.1,2,3,4,5,6,7,8,9,10,12,13 If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dosage of the opioid analgesic, and titrate based on clinical response.1,2,3,4,5,6,7,8,9,10,12,13 In clinical settings, monitor patients closely for signs and symptoms of respiratory depression and sedation.2,5,8,10 For ambulatory use, inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).1,3,4,6,7,13 If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose.1,3,4,6,7,13

Advise both patients and caregivers about the risks of respiratory depression and sedation when morphine is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs).1,2,3,4,6,7,8,9,12,13 Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined.1,2,3,4,6,7,8,9,12,13 Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs.1,2,3,4,6,7,8,9,12,13

Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while receiving treatment with morphine sulfate extended-release capsules.13 The concomitant use of alcohol with morphine sulfate extended-release capsules may result in increased plasma levels and a potentially fatal overdose of morphine.13

Neonatal Opioid Withdrawal Syndrome

Use of morphine for an extended period during pregnancy can result in withdrawal in the neonate.1,2,3,4,5,6,7,8,9,10,12,13 A boxed warning regarding this risk has been included in the prescribing information for morphine.1,2,3,4,5,6,7,8,9,10,12,13 Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts.1,2,3,4,5,6,7,8,9,10,12,13 Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly.1,2,3,4,5,6,7,8,9,10,12,13 Advise pregnant women using opioids for an extended period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.1,2,3,4,5,6,7,8,9,10,12,13

Risk of Accidental Overdose and Death due to Medication Errors

Dosing errors can result in accidental overdose and death.3,5 A boxed warning regarding this risk has been included in the prescribing information for morphine.3,5 Avoid dosing errors that may result from confusion between mg and mL and confusion with morphine sulfate oral solutions of different concentrations, when prescribing, dispensing, and administering morphine sulfate oral solution.3 Ensure that the dose is communicated clearly and dispensed accurately.3

Instruct patients and caregivers on how to measure and take or administer the correct dose of morphine sulfate oral solution and to use extreme caution when measuring the dose.3 Instruct patients and caregivers to always use a graduated oral syringe when administering the oral solution to ensure the dose is measured and administered accurately.3 Instruct patients to never use a household teaspoon or tablespoon to measure a dose because these are not adequate measuring devices.3

Parenteral administration of narcotics in patients receiving epidural or intrathecal morphine may result in overdosage.5

Other Warnings and Precautions

Opioid-Induced Hyperalgesia and Allodynia

Opioid-induced hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain; however, this condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect.1,2,3,5,10,13 Symptoms of OIH may include increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia).1,2,3,5,10,13 Evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior should be ruled out to suggest a diagnosis of OIH based on these symptoms.1,2,3,5,10,13

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics.1,2,3,5,10,13 Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated.1,2,3,5,10,13 There is evidence suggesting a strong biologic plausibility between opioid analgesics and OIH and allodynia.1,2,3,5,10,13 If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or safely switch the patient to a different opioid drug.1,2,3,5,10,13

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of morphine sulfate in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.1,2,3,4,5,6,7,8,9,10,12,13

Patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression receiving morphine sulfate are at increased risk of decreased respiratory drive including apnea, even at recommended dosages.1,2,3,4,5,6,7,8,9,10,12,13 Life-threatening respiratory depression is also more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.1,2,3,4,5,6,7,8,9,10,12,13

Regularly evaluate or monitor patients, particularly when initiating and titrating morphine sulfate and when morphine sulfate is given concomitantly with other drugs that depress respiration.1,2,3,4,5,6,7,8,9,10,12,13 Alternatively, consider the use of non-opioid analgesics in these patients.1,3,4,7,8,12,13

Interaction with Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, including respiratory depression, coma, and confusion.1,2,3,4,5,6,7,8,9,10,12,13 Morphine sulfate should not be used in patients taking MAOIs or within 14 days of stopping such treatment.1,2,3,4,5,6,7,8,9,10,12,13 (See Drug Interactions.)

Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, generally after more than 1 month of use.1,2,3,4,5,6,7,8,9,10,12,13 Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.1,2,3,4,5,6,7,8,9,10,12,13

If adrenal insufficiency is suspected, confirm the diagnosis as soon as possible.1,2,3,4,5,6,7,8,9,10,12,13 If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids.1,2,3,4,5,6,7,8,9,10,12,13 Wean the patient from the opioid to allow adrenal function to recover and continue corticosteroid treatment until recovery.1,2,3,4,5,6,7,8,9,10,12,13 Use of opioids other than morphine may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency.1,2,3,4,5,6,7,8,9,10,12,13 Current evidence does not identify any particular opioid as being more likely to be associated with adrenal insufficiency.1,2,3,4,5,6,7,8,9,10,12,13

Severe Hypotension

Morphine may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients.1,2,3,4,5,6,7,8,9,10,12,13 There is increased risk in patients whose ability to maintain blood pressure has already been compromised by reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines, general anesthetics).1,2,3,4,5,6,7,8,9,10,12,13 Regularly evaluate patients for signs of hypotension after initiating or titrating the dosage of morphine sulfate.1,2,3,4,5,6,7,8,9,10,12 In patients with circulatory shock, morphine may cause vasodilation that can further reduce cardiac output and blood pressure; avoid use in such patients.1,2,3,4,5,6,7,8,9,10,12,13

In ambulatory patients with reduced circulating blood volume, impaired myocardial function, or on sympatholytic drugs receiving single-dose neuraxial morphine, monitor for orthostatic hypotension.5,8,10

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), morphine may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure.1,2,3,4,5,6,7,8,9,10,12,13 Monitor patients for signs of sedation and respiratory depression, particularly when initiating therapy.1,2,3,4,5,6,7,8,9,10,12,13 Opioids may also obscure the clinical course in patients with head injuries.1,2,3,4,5,6,7,8,9,10 13 Avoid the use of morphine in patients with impaired consciousness or coma.1,2,3,4,5,6,7,8,9,10,12,13

Risks in Patients with GI Conditions

Morphine is contraindicated in patients with GI obstruction, including paralytic ileus, as the drug may cause spasm of the sphincter of Oddi.1,2,3,4,5,6,7,8,9,10,12,13 Opioids may cause increases in serum amylase.1,2,3,4,5,6,7,8,9,10,12,13 Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.1,2,3,4,5,6,7,8,9,10,12,13

Risk of Seizures

Morphine may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures occurring in other clinical settings associated with seizures.1,2,3,4,5,6,7,8,9,10,12,13 Regularly evaluate patients with a history of seizure disorders for worsened seizure control during morphine therapy.1,2,3,4,5,6,7,8,9,10,12,13

Excitation of the CNS, resulting in convulsions, may accompany high doses of morphine given by IV administration.2,5,8,12

Withdrawal

Do not abruptly discontinue morphine in a patient physically dependent on opioids, but rather gradually taper the dosage.1,2,3,4,5,6,7,8,9,10,12,13 Rapid tapering in a physically dependent patient may lead to withdrawal symptoms and return of pain.1,2,3,4,5,6,7,8,9,10,12,13

Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients receiving a full opioid agonist analgesic, such as morphine.1,2,3,4,5,6,7,8,9,10,12,13 In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.1,2,3,4,5,6,7,8,9,10,12,13

Risks of Driving and Operating Machinery

Morphine may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.1,2,3,4,6,7,9,10,12,13 Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of morphine and know how they will react to the medication.1,2,3,4,6,7,9,10,12,13

Risk of Tolerance and Myoclonic Activity

Patients sometimes manifest unusual acceleration of neuraxial morphine requirements, which may cause concern regarding systemic absorption and the hazards of large doses; these patients may benefit from hospitalization and detoxification.5,8,10 Myoclonic-like spasm of the lower extremities in patients receiving more than 20 mg/day of intrathecal morphine have been reported.5,8,10 After detoxification, it might be possible to resume treatment at lower doses, and some patients have been successfully switched from continuous epidural morphine to continuous intrathecal morphine.5,8,10 Repeat detoxification may be indicated at a later date.5,8,10 The upper daily dosage limit for each patient during continuous treatment must be individualized.5,8,10

Cardiovascular Instability

While low doses of IV administered morphine have little effect on cardiovascular stability, high doses are excitatory, resulting from sympathetic hyperactivity and increase in circulatory catecholamines.2,9,12 Ensure that naloxone and resuscitative equipment are immediately available for use in case of life-threatening or intolerable side effects and whenever IV morphine is being initiated.2,9,12

Risks with Neuraxial Administration

In the case of epidural or intrathecal administration, morphine sulfate injection should be administered by or under the direction of a physician experienced in the techniques and familiar with the patient management problems associated with epidural or intrathecal drug administration.5,8,10 The physician should be familiar with patient conditions such as infection at the injection site, bleeding diathesis, and anticoagulant therapy, which require special evaluation of benefit versus risk.5,8,10

Because epidural administration has been associated with less potential for immediate or late adverse effects than intrathecal administration, the epidural route should be used whenever possible.5,8 Administration of morphine sulfate injection by the epidural or intrathecal routes should be limited to the lumbar area.5,8,10 Thoracic epidural administration has been shown to dramatically increase the incidence of early and late respiratory depression even with doses of 1 to 2 mg.5,8

Chest Wall Rigidity

Rapid IV administration of morphine sulfate may result in chest wall rigidity.5,8

Risks in Patients with Urinary System Disorders

Urinary retention, which may persist 10 to 20 hours following a single epidural or intrathecal administration, is frequently associated with neuraxial opioid administration and must be anticipated, more frequently in male than female patients.5,8,10 Urinary retention may also occur during the first several days of hospitalization for the initiation of continuous intrathecal or epidural morphine therapy.5,8,10 Early recognition of difficulty in urination and prompt intervention in cases of urinary retention is indicated.5,8,10 Patients who develop urinary retention have responded to cholinomimetic treatment and/or judicious use of catheters.5,8,10

CNS Toxicity

Dysphoric reactions may occur after any size dose and toxic psychoses have been reported with use of morphine.9

Exposure, Hypothermia, Immersion and Shock

Caution must be used when injecting any opioid intramuscularly into chilled areas or in patients with hypotension or shock, since impaired perfusion may prevent complete absorption; if repeated injections are administered, an excessive amount may be suddenly absorbed if normal circulation is re-established.9

Risk of Inflammatory Masses

Inflammatory masses such as granulomas, some of which have resulted in serious neurologic impairment including paralysis, have been reported to occur in patients receiving continuous infusion of opioid analgesics including morphine sulfate injection (Infumorph®) via indwelling intrathecal catheters.10 Patients receiving continuous infusion of morphine sulfate injection (Infumorph®) via an indwelling intrathecal catheter should be carefully monitored for new neurologic signs or symptoms.10 Further assessment or intervention should be based on the clinical condition of the individual patient.10

Patient-controlled Analgesia (PCA)

Although self-administration of opioids by PCA may allow each patient to individually titrate to an acceptable level of analgesia, PCA administration has resulted in adverse outcomes and episodes of respiratory depression.12 Healthcare providers and family members monitoring patients receiving PCA analgesia should be instructed in the need for appropriate monitoring for excessive sedation, respiratory depression, or other adverse effects of opioid medications.12

Specific Populations

Pregnancy

There are no available data with morphine use in pregnant women to inform a drug-associated risk for major birth defects and miscarriage.1,2,3,4,5,6,7,8,9,10,12,13 Clinical studies of morphine use during pregnancy have not reported a clear association between morphine and major birth defects.1,2,3,4,5,6,7,8,9,10,12,13 Based on findings from animal studies, advise pregnant women of the potential risk to a fetus.1,2,3,4,5,6,7,8,9,10,12,13

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates.1,2,3,4,5,6,7,8,9,10,12,13 An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate.1,2,3,4,5,6,7,8,9,10,12,13 Morphine is not recommended for use in women during and immediately prior to labor, when use of shorter-acting analgesics or other analgesic techniques are more appropriate.1,2,3,4,5,6,7,8,9,10,12,13 Opioid analgesics, including morphine, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions.1,2,3,4,5,6,7,8,9,10,12,13 However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which may shorten labor.1,2,3,4,5,6,7,8,9,10,12,13 Monitor neonates exposed to opioid analgesics during labor for signs of excessive sedation and respiratory depression.1,2,3,4,5,6,7,8,9,10,12,13

Use of opioid analgesics for an extended period during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.1,2,3,4,5,6,7,8,9,10,12,13 Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.1,2,3,4,5,6,7,8,9,10,12,13 Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly.1,2,3,4,5,6,7,8,9,10,12,13

Lactation

Morphine should be used with caution in nursing women, since the drug has been reported to distribute into human milk.1,2,3,4,5,6,7,8,9,10,12,13

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for morphine and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.1,2,3,4,5 7,8,9,10,12,13 Because of the potential for serious adverse reactions, including excessive sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with morphine sulfate extended-release capsules or tablets.6,7,13

Monitor infants exposed to morphine through breast milk for excess sedation and respiratory depression.1,2,3,4,5,6,7,8,9,10,12,13 Withdrawal symptoms can occur in breastfed infants when maternal administration of morphine is stopped, or when breastfeeding is stopped.1,2,3,4,5,6,7,8,9,10,12,13

Females and Males of Reproductive Potential

Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential.1,2,3,4,5,6,7,8,9,10,12,13 It is not known whether these effects on fertility are reversible.1,2,3,4,5,6,7,8,9,10 In animal studies, morphine sulfate administration adversely effected fertility and reproductive endpoints in male rats and prolonged estrus cycle in female rats.1,2,3,4,5,6,7,8,9,10,12,13

Pediatric Use

Safety and effectiveness of morphine in pediatric patients vary based on the route of administration and characteristics of the preparation.1,2,3,4,5,6,7,8,9,10,12,13

The safety and effectiveness of immediate-release morphine sulfate tablets administered orally have been established for the management of pediatric patients weighing at least 50 kg with acute pain severe enough to require an opioid analgesic when alternative treatments are inadequate.1 Use of the immediate-release tablets in this age group is supported by clinical evidence in adults and supportive data from an open-label, safety and pharmacokinetic study in pediatric patients 2 through 17 years of age with postoperative acute pain.1 The safety and effectiveness of immediate-release morphine sulfate tablets have not been established in pediatric patients weighing less than 50 kg because the recommended dosage cannot be achieved with available tablet strengths.1 Consider use of another morphine sulfate product in patients who cannot swallow oral tablets or who weigh less than 50 kg.1

The safety and effectiveness of morphine sulfate oral solution (2 mg/mL and 4 mg/mL) have been established for the management of pediatric patients 2 to 17 years of age with acute pain severe enough to require an opioid analgesic when alternative treatments are inadequate.3 The safety and effectiveness of the oral solution have not been established in pediatric patients younger than 2 years of age.3 The safety and effectiveness of morphine sulfate oral solution 20 mg/mL have not been established in pediatric patients.3 The safety and effectiveness of morphine sulfate oral solution have not been established for the management of pediatric patients 2 years of age and older with chronic pain severe enough to require an opioid analgesic when alternative treatments are inadequate.3

The safety and effectiveness of continuous IV infusion of morphine have been established for the management of pain in pediatric patients of all age groups.2 Such use is supported by evidence from randomized controlled studies in pediatric patients.2 Monitor cardiorespiratory function in children younger than 3 months of age.2 Adjust the infusion rate based on clinical signs of inadequate pain relief and/or increased somnolence.2 For premature infants and former premature infants with chronic lung disease and up to 5 to 6 months of age, careful monitoring for depressed hypoxic drive is required following continuous IV infusion of the opioid.2

Safety and efficacy of morphine sulfate suppositories in pediatric patients have not been established.4

Safety and efficacy of epidural or intrathecal injection of morphine in pediatric patients have not been established and such injections are not recommended.5,8,10 Safety and efficacy of patient-controlled analgesia (PCA) have not been established in pediatric patients.12

Safety and efficacy of morphine sulfate extended-release capsules in children younger than 18 years of age have not been established.13 In addition, the manufacturers state that commercially available strengths of morphine sulfate extended-release capsules are not appropriate for children and that the contents of the capsules should not be sprinkled onto applesauce for administration to children.13

Safety and efficacy of morphine sulfate extended-release tablets in children have not been established.6,7

Geriatric Use

Patients 65 years of age or older may have increased sensitivity to morphine.1,2,3,4,5,6,7,8,9,10,12,13 In general, use caution when selecting dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.1,2,3,4,5,6,7,8,9,10,12,13

Respiratory depression is the main risk for geriatric patients treated with opioids and has occurred after administration of large initial doses in patients who were not opioid-tolerant or when opioids were co-administered with other drugs that depress respiration.1,2,3,4,5,6,7,8,9,10,12,13 Titrate the dosage of morphine sulfate slowly in geriatric patients and frequently reevaluate the patient for signs of CNS and respiratory depression.1,2,3,4,5,6,7,8,9,10,12,13

Morphine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.1,2,3,4,5,6,7,8,9,10,12,13 Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection; regular evaluation of renal function should occur.1,2,3,4,5,6,7,8,9,10,12,13

Hepatic Impairment

Morphine pharmacokinetics have been reported to be significantly altered in patients with cirrhosis.1,2,3,4,5,6,7,8,9,10,12,13 Initiate treatment in these patients with a lower than usual dosage and titrate slowly while regularly evaluating for signs of respiratory depression, sedation, and hypotension.1,2,3,4,5,6,7,8,9,10,12,13

Renal Impairment

Morphine pharmacokinetics are altered in patients with renal failure.1,2,3,4,5,6,7,8,9,10,12,13 Initiate treatment in these patients with a lower than usual dosage and titrate slowly while regularly evaluating for signs of respiratory depression, sedation, and hypotension.1,2,3,4,5,6,7,8,9,10,12,13

Common Adverse Effects !!navigator!!

Common adverse effects reported in adults receiving morphine include constipation, nausea, somnolence, lightheadedness, dizziness, sedation, vomiting, headache, and sweating.1,2,3,4,5,6,7,8,9,10,12,13 Serious adverse effects include apnea, circulatory depression, respiratory depression or arrest, shock, and cardiac arrest.5,8,9 10,12

Common adverse effects reported in pediatric patients (>5%) receiving morphine include nausea, vomiting, constipation, decreased oxygen saturation, and flatulence.1,3

Drug Interactions ⬆ ⬇

[Section Outline]

Morphine is not significantly metabolized by cytochrome P-450 (CYP) isoenzyme 3A4; the drug does not induce or inhibit CYP enzymes.773 Morphine is a substrate of the efflux transporter P-glycoprotein (P-gp).1,2,3,4,5,6,7,8,9,10 Morphine is mainly metabolized by UDP-glucuronosyltransferases (UGTs) with a specific affinity for the UGT2B7 isoenzyme.773

Drugs Affecting or Affected by Transport Systems !!navigator!!

Concomitant use of morphine and P-gp inhibitors (e.g., quinidine, verapamil) can increase exposure to morphine by two-fold and can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.1,2,3,4,5,6,7,8,9,10,12,13 Evaluate patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate tablets and/or the P-gp inhibitor as necessary.1,2,3,4,5,6,7,8,9,10,12,13

Studies have shown that drugs that inhibit the UGT2B7 pathway may alter the amount of metabolites available from morphine metabolism.757 Drugs that are the most potent inhibitors of this pathway include tamoxifen, diclofenac, naloxone, carbamazepine, tricyclic and heterocyclic antidepressants, and benzodiazepines.757

Alcohol !!navigator!!

Concomitant use of alcohol with morphine sulfate extended-release capsules can result in increased morphine plasma levels and potentially fatal overdose.13 Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while receiving the extended-release capsules.13

Anticholinergic Drugs !!navigator!!

Concomitant use of morphine and anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.1,2,3,4,5,6,7,8,9,10,12,13 Evaluate patients for signs of urinary retention or reduced gastric motility when these drugs are used concomitantly.1,2,3,4,5,6,7,8,9,10,12,13

Benzodiazepines and Other CNS Depressants !!navigator!!

Due to additive pharmacologic effect, concomitant use of morphine with benzodiazepines or other CNS depressants (other sedatives/hypnotics, anxiolytics, tranquilizers and muscle relaxants, general anesthetics, antipsychotics, other opioids, and alcohol) can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.1,2,3,4,5,6,7,8,9,10,12,13

Reserve concomitant use for patients for whom alternative treatment options are inadequate.1,2,3,4,5,6,7,8,9,10,12,13 Limit dosages and durations to the minimum required.1,2,3,4,5,6,7,8,9,10,12,13 Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).1,2,3,4,5,6,7,8,9,10,12,13

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose.1,2,3,4,5,6,7,8,9,10,12,760,13

Cimetidine !!navigator!!

Concomitant use of morphine and cimetidine has been reported to precipitate apnea, confusion, and increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.1,2,3,4,5,6,7,8,9,10,12,13 Monitor patients for increased respiratory and CNS depression when morphine is used concomitantly with cimetidine and decrease dosage of the drugs as necessary.1,2,3,4,5,6,7,8,9,10,12,13

Diuretics !!navigator!!

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.1,2,3,4,5,6,7,8,9,10,12,13 Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.1,2,3,4,5,6,7,8,9,10,12,13

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics !!navigator!!

Mixed agonist/antagonist and partial agonist opioid analgesics (butorphanol, nalbuphine, pentazocine, buprenorphine) may reduce the analgesic effect of morphine and/or precipitate withdrawal symptoms.1,2,3,4,5,6,7,8,9,10,12,13 Avoid concomitant use.1,2,3,4,5,6,7,8,9,10,12,13

Monamine Oxidase (MAO) Inhibitors !!navigator!!

Interactions between opioids and MAO inhibitors (e.g., phenelzine, tranylcypromine, linezolid, IV methylene blue) may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).1,2,3,4,5,6,7,8,9,10,12,13 Do not use morphine in patients taking MAOIs or within 14 days of stopping such treatment.1,2,3,4,5,6,7,8,9,10,12,13

Muscle Relaxants !!navigator!!

Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants (e.g., cyclobenzaprine, metaxalone) and produce an increased degree of respiratory depression.1,2,3,4,5,6,7,8,9,10,12,13 Because respiratory depression may be greater than otherwise expected, decrease the dosage of morphine and/or the muscle relaxant as necessary.1,2,3,4,5,6,7,8,9,10,12,13 Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose.1,2,3,4,5,6,7,8,9,10,12,13

P2Y12 Inhibitors !!navigator!!

Co-administration of oral P2Y12 inhibitors (e.g., clopidogrel, prasugrel, ticagrelor) and IV morphine sulfate can decrease the absorption and peak concentration of the P2Y12 inhibitor and delay the onset of the antiplatelet effect.2,5,8,9,10,12 Consider the use of a parenteral antiplatelet agent in the setting of acute coronary syndrome (ACS) requiring co-administration of IV morphine sulfate.2,5,8,9,10,12

Serotonergic Drugs !!navigator!!

Concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system (e.g., selective serotonin reuptake inhibitors [SSRIs], serotonin and norepinephrine reuptake inhibitors [SNRIs], tricyclic antidepressants [TCAs], triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system [e.g., mirtazapine, trazodone, tramadol]) has resulted in serotonin syndrome.1,2,3,4,5,6,7,8,9,10,12,13 If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment.1,2,3,4,5,6,7,8,9,10,12,13 Discontinue morphine therapy if serotonin syndrome is suspected.1,2,3,4,5,6,7,8,9,10,12,13

Other Information ⬆ ⬇

Description

Morphine is a phenanthrene-derivative opioid agonist.757 The drug is the principal alkaloid of opium and considered to be the prototype of the opioid agonists.757 Morphine is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses.1

The principal therapeutic action of morphine is analgesia.1,3 Like all full opioid agonists, there is no ceiling effect for analgesia with morphine.1,3 Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.1 The precise mechanism of the analgesic action is unknown.1,3 However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of the drug.1,3

Morphine sulfate is about two-thirds absorbed from the GI tract.1,3 The oral bioavailability of morphine is 20-40% but exhibits large inter-individual variability due to extensive pre-systemic metabolism.1,3,7 The extent of absorption from immediate-release and extended-release oral preparations is essentially the same, but time to peak plasma concentrations is longer and peak plasma concentrations are lower with extended-release preparations.6,7,13 Food may decrease the rate of GI absorption of morphine sulfate administered orally as either immediate-release or extended-release preparations, but extent of absorption is unchanged.1 Peak plasma concentrations of morphine are achieved 5-30 minutes after IM injection,9 30 minutes after conventional tablet administration,1 60 minutes after rectal administration,4 about 90 minutes after administration of extended-release preparations,757 and within 5-10 minutes after epidural or intrathecal administration.5,8,10 Although the primary site of action is the CNS, only about 40-50% of the dose crosses the blood-brain barrier due to poor lipid solubility, protein binding, rapid conjugation with glucuronic acid, and ionization of the drug at a physiologic pH.1,757,768 Morphine is metabolized by demethylation and glucuronidation; glucuronidation is the predominant mode of metabolism, producing morphine-6 glucuronide (M6G), morphine-3 glucuronide (M3G), and a demethylated normorphine metabolite.3,7,757 M6G has been shown to have analgesic activity but crosses the blood-brain barrier poorly, while M3G has no significant analgesic activity.3 Protein binding is low and reported to be 20-36%.2,13 Morphine is generally excreted in the urine as M3G and M6G, with smaller amounts excreted unchanged.10,757 Elimination half-life in patients with normal renal function is 1.5 to 2 hours.1,2,9,757

Advice to Patients

Preparations ⬆ ⬇

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule II (C-II) drug.

Morphine Sulfate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, extended-release (containing pellets)

30 mg*

Morphine Sulfate Extended-release Capsules ( C-II )

45 mg*

Morphine Sulfate Extended-release Capsules ( C-II )

60 mg*

Morphine Sulfate Extended-release Capsules ( C-II )

75 mg*

Morphine Sulfate Extended-release Capsules ( C-II )

90 mg*

Morphine Sulfate Extended-release Capsules ( C-II )

120 mg*

Morphine Sulfate Extended-release Capsules ( C-II )

Solution

10 mg/5 mL*

Morphine Sulfate Oral Solution ( C-II )

20 mg/5 mL*

Morphine Sulfate Oral Solution ( C-II )

100 mg/5 mL*

Morphine Sulfate Oral Solution ( C-II; with graduated oral syringe)

Tablets

15 mg*

Morphine Sulfate Tablets ( C-II; scored)

30 mg*

Morphine Sulfate Tablets ( C-II; scored)

Tablets, extended-release, film-coated

15 mg*

Morphine Sulfate Tablets ER ( C-II )

MS Contin® ( C-II )

Rhodes

30 mg*

Morphine Sulfate Tablets ER ( C-II )

MS Contin® ( C-II )

Rhodes

60 mg*

Morphine Sulfate Tablets ER ( C-II )

MS Contin® ( C-II )

Rhodes

100 mg*

Morphine Sulfate Tablets ER ( C-II )

MS Contin® ( C-II )

Rhodes

200 mg*

Morphine Sulfate Tablets ER ( C-II )

MS Contin® ( C-II )

Rhodes

Parenteral

Injection, for IV or IM use

2 mg/mL*

Morphine Sulfate Injection ( C-II )

4 mg/mL*

Morphine Sulfate Injection ( C-II )

5 mg/mL*

Morphine Sulfate Injection ( C-II )

8 mg/mL*

Morphine Sulfate Injection ( C-II )

10 mg/mL*

Morphine Sulfate Injection ( C-II )

Injection, for epidural, intrathecal, or IV use

0.5 mg/mL*

Duramorph® ( C-II )

Hikma

Preservative-free Morphine Sulfate Injection ( C-II )

1 mg/mL*

Duramorph® ( C-II )

Hikma

Preservative-free Morphine Sulfate Injection ( C-II )

Injection, for epidural or intrathecal use via continuous microinfusion device only

10 mg/mL

Infumorph® ( C-II )

Hikma

25 mg/mL*

Infumorph® ( C-II )

Hikma

Morphine Sulfate Injection (C-II)

Injection, for IV infusion via compatible patient-controlled infusion device only

1 mg/mL*

Morphine Sulfate Preservative-free Injection ( C-II )

Injection, for IV infusion

50 mg/mL*

Morphine Sulfate Injection ( C-II )

Rectal

Suppositories

5 mg*

Morphine Sulfate Suppositories ( C-II )

10 mg*

Morphine Sulfate Suppositories ( C-II )

20 mg*

Morphine Sulfate Suppositories ( C-II )

30 mg*

Morphine Sulfate Suppositories ( C-II )

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Copyright ⬆ ⬇

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions August 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References ⬆

Only references cited for selected revisions after 1984 are available electronically.

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