Morphine (Monograph)
Brand names: Astramorph/PF, Avinza, DepoDur, Duramorph, Infumorph,
... show all 9 brands
Drug class: Opiate Agonists
VA class: CN101
CAS number: 6211-15-0
Warning
Risk Evaluation and Mitigation Strategy (REMS):
FDA approved a REMS for morphine to ensure that the benefits outweigh the risk. 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 https://www.accessdata.fda.gov/scripts/cder/rems/.
- FDA drug safety communication (4/13/2023)500
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As part of its ongoing efforts to address the nation’s opioid crisis, FDA is requiring several updates to the prescribing information of opioid pain medicines. The changes are being made to provide additional guidance for safe use of these drugs while also recognizing the important benefits when used appropriately. The changes apply to both immediate-release (IR) and extended-release/long-acting preparations (ER/LA).
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Updates to the IR opioids state that these drugs should not be used for an extended period unless the pain remains severe enough to require an opioid pain medicine and alternative treatment options are insufficient, and that many acute pain conditions treated in the outpatient setting require no more than a few days of an opioid pain medicine.
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Updates to the ER/LA opioids recommend that these drugs be reserved for severe and persistent pain requiring an extended period of treatment with a daily opioid pain medicine and for which alternative treatment options are inadequate.
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A new warning is being added about opioid-induced hyperalgesia (OIH) for both IR and ER/LA opioid pain medicines. This includes information describing the symptoms that differentiate OIH from opioid tolerance and withdrawal.
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Information in the boxed warning for all IR and ER/LA opioid pain medicines will be updated and reordered to elevate the importance of warnings concerning life-threatening respiratory depression, and risks associated with using opioid pain medicines in conjunction with benzodiazepines or other medicines that depress the central nervous system (CNS).
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Other changes will also be required in various other sections of the prescribing information to educate clinicians, patients, and caregivers about the risks of these drugs.
- Standardize 4 Safety
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A standardized concentration for this drug has been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. The drug is included in a standard concentration list which may apply to an IV or oral compounded liquid formulation. For additional information, see the ASHP website [Web].
Warning
- Abuse Potential
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Schedule II controlled substance with abuse liability similar to other opiates.172
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Potential for abuse in a manner similar to other legal or illicit opiates.172 Consider abuse potential when prescribing or dispensing morphine sulfate extended-release capsules (Kadian) in situations where the clinician or pharmacist is concerned about increased risk of misuse, abuse, or diversion.172
- Overdose Risk with Improper Administration of Extended-release (Modified-, Controlled-, or Sustained-release) Products
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Extended-release preparations (Avinza, Kadian, MS Contin, Oramorph SR) are indicated for relief of moderate to severe pain requiring continuous, around-the-clock opiate therapy for an extended period of time.169 170 171 172
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Extended-release formulations are to be swallowed whole;169 170 171 172 alternatively the contents of Avinza or Kadian capsules may be sprinkled on applesauce.171 172
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Extended-release capsules (e.g., Kadian) are not intended for use as an as-needed (“prn”) analgesic.172
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Chewing, crushing, or dissolving any of these extended-release preparations (including capsule beads or pellets) could result in rapid release and absorption of a potentially fatal dose of morphine.169 170 171 172
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Do not consume alcoholic beverages or prescription or nonprescription preparations containing alcohol during therapy with extended-release capsules (Avinza, Kadian).171 195 Consuming alcohol while receiving extended-release capsules could result in rapid release and absorption of a potentially fatal dose of morphine.171 195
- Risk of Medication Errors with Oral Solutions
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Morphine sulfate oral solution is available in concentrations of 10, 20, or 100 mg per 5 mL.234 236 The 100-mg/5-mL preparation is indicated for use only in opiate-tolerant patients.234 235 236
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Use caution to avoid dosing errors resulting from confusion between different concentrations and between mg and mL.182 234 236 Errors may result in inadvertent overdosage and death.182 234 235 236 Ensure appropriate dosage is communicated and dispensed.182 234 236 (See Oral Solutions under Dosage and Administration.)
- Concomitant Use with Benzodiazepines or Other CNS Depressants
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Concomitant use of opiate agonists with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.416 417 418 700 701 702 703
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Reserve concomitant use of opiate analgesics and benzodiazepines or other CNS depressants for patients in whom alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy and monitor closely for respiratory depression and sedation.700 703 (See Specific Drugs under Interactions.)
Introduction
Opiate agonist; phenanthrene derivative.b
Uses for Morphine
Pain (Acute or Chronic)
Strong analgesic used in the relief of severe, acute pain or moderate to severe, chronic pain (e.g., in terminally ill patients).b
Extended-release preparations are used orally for management of moderate to severe pain when a continuous, around-the-clock analgesic is needed for an extended period of time.169 170 171 172 Extended-release preparations are not indicated for relief of acute pain172 or for use on an as-needed (“prn”) basis.171 172
In symptomatic treatment of acute pain, reserve opiate analgesics for pain resulting from severe injuries, severe medical conditions, or surgical procedures, or when nonopiate alternatives for relieving pain and restoring function are expected to be ineffective or are contraindicated.431 432 433 435 Use smallest effective dosage for shortest possible duration since long-term opiate use often begins with treatment of acute pain.411 431 434 435 Optimize concomitant use of other appropriate therapies.432 434 435 (See Managing Opiate Therapy for Acute Pain under Dosage and Administration.)
Generally use opiates for management of chronic pain (i.e., pain lasting >3 months or past the time of normal tissue healing410 411 412 413 ) that is not associated with active cancer treatment, palliative care, or end-of-life care only if other appropriate nonpharmacologic and nonopiate pharmacologic strategies have been ineffective and expected benefits for both pain relief and functional improvement are anticipated to outweigh risks.411 412 413 414 422 429
If used for chronic pain, opiate analgesics 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 (e.g., nonopiate analgesics, analgesic adjuncts such as selected anticonvulsants and antidepressants for certain neuropathic pain conditions).411 412 413 422 429
Available evidence insufficient to determine whether long-term opiate therapy for chronic pain results in sustained pain relief or improvements in function and quality of life411 423 431 432 436 or is superior to other pharmacologic or nonpharmacologic treatments.432 Use is associated with serious risks (e.g., opiate use disorder [OUD], overdose).411 431 436 (See Managing Opiate Therapy for Chronic Noncancer Pain under Dosage and Administration.)
Pain (Severe, Neuraxial Analgesia)
Used epidurally or intrathecally for relief of severe pain (neuraxial analgesia); administration of the drug by these routes reportedly provides pain relief for prolonged periods without attendant loss of motor, sensory, or sympathetic function.b
Chronic epidural or intrathecal analgesia is indicated only when adequate pain relief cannot be obtained with less invasive therapies.b The drug should only be administered epidurally or intrathecally by qualified individuals familiar with the techniques and patient management problems associated with these routes of morphine administration. (See Precautions Associated with Epidural or Intrathecal Administration under Cautions.)
Extended-release liposomal injection (DepoDur) is used epidurally for relief of severe pain following major surgery.192
Pain (Acute Coronary Syndromes [ACS])
Relief of pain and anxiety related to ACS.527 1100
Considered analgesic agent of choice in patients with ST-segment-elevation MI (STEMI).527
Considered reasonable in patients with non-ST-segment-elevation (NSTE) ACS who continue to experience pain despite treatment with maximally tolerated anti-ischemic drugs (e.g., nitrates).1100 However, use of morphine should not preclude use of other anti-ischemic drugs with proven benefit.1100
Patients with acute MI typically exhibit overactivity of the sympathetic nervous system, which adversely increases myocardial oxygen demand via acceleration of heart rate, elevation in arterial blood pressure, augmentation of cardiac contractility, and heightened tendency to develop ventricular tachyarrhythmias.140 Principal objective in these patients is to administer sufficient doses of an analgesic such as morphine to relieve what many patients describe as a feeling of impending doom.140
Analgesia during Labor
Used parenterally for analgesia during labor.b
Acute Pulmonary Edema
Used in patients with acute pulmonary edema for its cardiovascular effects and to allay anxiety.b Should not be used in the treatment of pulmonary edema resulting from a chemical respiratory irritant.b
Neonatal Opiate Withdrawal
Has been used to manage manifestations of opiate abstinence syndrome (i.e., postnatal withdrawal) in neonates† [off-label] exposed to opiates in utero.350 352 353 355 357 359 360
Opiates 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 May add other adjunctive therapy (e.g., clonidine, phenobarbital) if response to opiates is inadequate or add phenobarbital if neonate was exposed to additional substances in utero.350 352 353 355 357 358 359 365 368
Morphine has been used more extensively than other opiates in the management of neonatal opiate abstinence syndrome;352 357 359 360 however, some studies suggest methadone or buprenorphine treatment may be associated with shorter treatment durations and hospital stays.360 361 362 363 Additional study needed to establish optimal dosage schedules and preferred opiates and to evaluate longer-term (e.g., neurodevelopmental) outcomes.351 353 354 355 360
Use of standardized protocols for identification, evaluation, and treatment recommended; use of protocols improves overall response, including shorter hospital stays and durations of pharmacologic treatment.350 352 353 358 359 Some evidence suggests that use of a standardized protocol may be more important than use of a specific opiate agonist (e.g., morphine versus methadone) in improving outcomes.352 359 363
Related/similar drugs
gabapentin, acetaminophen, cyclobenzaprine, tramadol, naproxen, oxycodone, Tylenol
Morphine Dosage and Administration
General
Managing Opiate Therapy for Acute Pain
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Optimize concomitant use of other appropriate therapies.432 434 435
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When opiate analgesia required, use conventional (immediate-release) opiates in smallest effective dosage and for shortest possible duration, since long-term opiate use often begins with treatment of acute pain.411 431 434 435
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When sufficient for pain management, use lower-potency opiate analgesics given in conjunction with acetaminophen or an NSAIA on as-needed (“prn”) basis.432
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Consider prescribing naloxone concomitantly for patients who are at increased risk of opiate overdosage411 431 750 or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage.750 (See Respiratory Depression under Cautions.)
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For acute pain not related to trauma or surgery, limit prescribed quantity to amount needed for expected duration of pain severe enough to require opiate analgesia (generally ≤3 days and rarely >7 days).411 433 434 435 Do not prescribe larger quantities for use in case pain continues longer than expected;411 432 instead, reevaluate patient if severe acute pain does not remit.411 431 435
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For moderate to severe postoperative pain, provide opiate analgesic as part of a multimodal regimen that also includes acetaminophen and/or NSAIAs and other pharmacologic (e.g., certain anticonvulsants, regional local anesthetic techniques) and nonpharmacologic therapy as appropriate.430 431 432
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Oral administration of conventional opiate analgesics generally preferred over IV administration in postoperative patients who can tolerate oral therapy.430 431
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Scheduled (around-the-clock) dosing frequently is required during immediate postoperative period or following major surgery.430 432 When repeated parenteral administration is required, IV patient-controlled analgesia (PCA) generally is recommended.430 431
Managing Opiate Therapy for Chronic Noncancer Pain
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Although specific recommendations may vary, common elements in clinical guideline recommendations include risk mitigation strategies, upper dosage thresholds, careful dosage titration, and consideration of risks associated with particular opiates and formulations, coexisting diseases, and concomitant drug therapy.410 411 414 415 423
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Prior to initiating therapy, thoroughly evaluate patient; assess risk factors for misuse, abuse, and addiction;411 412 413 415 422 429 establish treatment goals (including realistic goals for pain and function); and consider how therapy will be discontinued if benefits do not outweigh risks.411 415
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Regard initial opiate therapy for chronic noncancer pain as a therapeutic trial that will be continued only if there are clinically meaningful improvements in pain and function that outweigh treatment risks.411 412 413
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Prior to and periodically during therapy, discuss with patients known risks and realistic benefits and patient and clinician responsibilities for managing therapy.411 412 413 414 415
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Some experts recommend initiating opiate therapy for chronic noncancer pain with conventional (immediate-release) opiate analgesics prescribed at lowest effective dosage.411 415 Individualize opiate selection, initial dosage, and dosage titration based on patient’s health status, prior opiate use, attainment of therapeutic goals, and predicted or observed harms.412 413
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Evaluate benefits and harms within 1–4 weeks following initiation of therapy or dosage increase411 413 and reevaluate on ongoing basis (e.g., at least every 3 months411 ) throughout therapy.411 412 413 Document pain intensity and level of functioning and assess progress toward therapeutic goals, presence of adverse effects, and adherence to prescribed therapies.412 413 422 423 Anticipate and manage common adverse effects (e.g., constipation, nausea and vomiting, cognitive and psychomotor impairment).412 413 415 If benefits do not outweigh harms, optimize other therapies and taper opiate to lower dosage or taper and discontinue opiate.411 412 413 415
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When repeated dosage increases required, evaluate potential causes and reassess relative benefits and risks.412 413 Although evidence is limited, some experts state that opiate rotation may be considered in patients with intolerable adverse effects or inadequate benefit despite dosage increases.412 413 415
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Higher dosages require particular caution,410 412 415 including more frequent and intensive monitoring or referral to specialist.411 412 413 Greater benefits of high-dose opiates for chronic pain not established in controlled clinical studies; higher dosages associated with increased risks (motor vehicle accidents, overdosage, OUD).411 415 423 424 425 426
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CDC states that primary care clinicians should carefully reassess individual benefits and risks before prescribing morphine sulfate dosages ≥50 mg daily for chronic pain and should avoid dosages ≥90 mg daily or carefully justify decision to prescribe such dosages.411 Other experts recommend consulting a pain management specialist before exceeding a dosage of 80–120 mg daily.423 431 Some states have established opiate dosage thresholds (e.g., maximum daily dosages that can be prescribed, dosage thresholds at which consultation with specialist is mandated or recommended)411 420 421 423 or have mandated risk-management strategies (e.g., review of state prescription drug monitoring program [PDMP] data prior to prescribing).411 419 423
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Recommended strategies for managing risks include written treatment agreements or plans (e.g., “contracts”), urine drug testing, review of state PDMP data, and risk assessment and monitoring tools.410 411 412 413 414 415 422 423 429
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Taper and discontinue opiate therapy if patient engages in serious or repeated aberrant drug-related behaviors or drug abuse or diversion.412 413 415 Offer or arrange treatment for patients with OUD.411 412 413
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Consider prescribing naloxone concomitantly for patients who are at increased risk of opiate overdosage411 431 750 or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage.750 (See Respiratory Depression under Cautions.)
Administration
Administered orallyb 169 170 171 172 or rectally,b by sub-Q, IM, or slow IV injection, or by IV infusion.b 168 173
Administered epidurally or intrathecally (as a preservative-free injection; Astramorph/PF, Duramorph, Infumorph) via intermittent injection or continuous infusion.b Also administered epidurally (as an extended-release liposomal injection; DepoDur) as a single dose.192
IM is preferred to sub-Q injection when repeated parenteral doses are necessary, since repeated sub-Q injection causes local tissue irritation, pain, and induration.173 However, IM administration of opiate analgesics also is discouraged; IM injections can cause pain and are associated with unreliable absorption, resulting in inconsistent analgesia.430 Some experts state that IV injection or continuous IV or sub-Q infusion provides better comfort and reliability and that repeated IM injection should not be used routinely.168
When morphine is administered IV, epidurally, or intrathecally, an opiate antagonist and facilities for administration of oxygen and control of respiration should be available.b
Highly concentrated, conventional, preservative-free morphine sulfate injections intended for continuous epidural or intrathecal infusion via a controlled-microinfusion device (e.g., Infumorph 10 or 25 mg/mL) are not recommended for IV, IM, or sub-Q administration of individual doses of the drug because of the large amount of morphine sulfate contained in each ampul (200 mg/20 mL, 500 mg/20 mL) and the attendant risk of substantial overdosage.b
Handle morphine sulfate injections carefully because of the potency of the injections; accidental cutaneous exposure should be treated by removing any contaminated clothing and rinsing the affected area with water.b
Morphine sulfate injections are subject to substantial risk of overdosage if used inappropriately and to diversion and abuse; therefore, special control measures should be implemented within the institution, including restricted access, rigid accounting, and rigorous control of waste disposal.b
Oral Administration
Administer orally as solution, conventional tablets, or extended-release preparations (Avinza capsules, Kadian capsules, MS-Contin tablets, Oramorph SR tablets).169 170 171 172 b
Extended-release Preparations
Avinza or Kadian extended-release capsules and Oramorph SR extended-release tablets can be administered without regard to food;169 171 172 effect of food on GI absorption of MS-Contin extended-release tablets has not been fully evaluated to date.170
Extended-release preparations should be swallowed intact and should not be broken, crushed, or chewed; intake of a broken, crushed, or chewed tablet may result in too rapid a release of the drug from the preparation and absorption of a potentially toxic dose of morphine sulfate.169 170 171 172 Do not administer extended-release capsules (Avinza, Kadian) with alcohol.171 195 (See Boxed Warning and see Specific Drugs under Interactions.)
Alternatively, the entire contents of Avinza or Kadian capsules may be sprinkled on a small amount of applesauce, at room temperature or cooler, immediately prior to administration; subdividing the contents of a capsule is not recommended.171 172 The beads or pellets should not be crushed, chewed, or dissolved.171 172 The patient should swallow the entire mixture and then drink a glass of water to rinse the mouth and ensure that the beads or pellets are swallowed.171 172 The mixture of applesauce and beads or pellets should not be stored for future use.171 172 (See Boxed Warning.)
Manufacturer of Kadian states that the contents of the extended-release capsules should not be administered through a nasogastric tube, but can be administered through a 16 French (16F) gastrostomy tube; consult manufacturer’s information.172
Oral Solutions
Morphine sulfate oral solutions are commercially available in various concentrations, which generally are expressed in terms of mg of drug per mL (mg/mL) or per 5 mL (mg/5 mL) of solution.182 234 Serious adverse events and deaths have occurred as a result of inadvertent overdosage of concentrated morphine oral solutions.182 234 235 In most of these cases, morphine sulfate oral solutions prescribed in mg were mistakenly interchanged for mL of the concentrated preparation, resulting in 20-fold overdoses.182 234 235
The 100-mg/5-mL concentration is indicated for use only in patients who are opiate tolerant (i.e., individuals who have been receiving ≥60 mg of oral morphine sulfate daily, ≥30 mg of oral oxycodone daily, ≥12 mg of hydromorphone hydrochloride daily, or an equianalgesic dosage of another opiate daily for ≥1 week) and have been titrated to a stable analgesic dosage using a preparation containing a lower concentration of morphine sulfate.234 235 236
A graduated oral syringe is supplied by the manufacturer with the 100-mg/5-mL oral solution; always use this oral syringe to ensure that the dose is measured and administered accurately.234 235 236
To avoid medication errors, write a prescription for morphine sulfate oral solution by clearly specifying the concentration of morphine sulfate oral solution to be dispensed and, in the directions for use, indicating the intended dose of morphine in mg along with the corresponding volume in mL (in parentheses).182 234
It is important that the prescription be filled with the proper concentration of morphine sulfate oral solution to prevent potential medication errors; if the specified morphine sulfate oral solution is unavailable, pharmacists should contact the prescriber.182 234
Provide careful instructions to patients receiving morphine oral solutions.236 (See Morphine Oral Solution under Advice to Patients.)
Rectal Administration
Administered rectally as suppositories.b
Administer carefully according to manufacturer’s instructions.b
IV Administration
For solution and drug compatibility information, see Compatibility under Stability.
Administer by direct IV injection or IV infusion.b Also administered IV via a controlled-delivery device for PCA.191 200
For IV injection, morphine sulfate should be injected slowly with the patient in the recumbent position.b Rapid IV injection may result in an increased frequency of opiate-induced adverse effects; severe respiratory depression, apnea, hypotension, peripheral circulatory collapse, chest wall rigidity, cardiac arrest, and anaphylactoid reactions have occurred following rapid IV injection.b
Dilution
For continuous IV infusion, morphine sulfate has been diluted to a concentration of 0.1–1 mg/mL in 5% dextrose and administered via a controlled-infusion device; more concentrated solutions have been used in patients whose fluid intake was restricted and/or dosage requirements were high.b
Morphine sulfate injections containing 25 or 50 mg/mL are intended for preparation of IV infusion solutions and should not be administered IV without prior dilution.196 b
For continuous sub-Q infusion† [off-label], the drug has been diluted to an appropriate concentration in 5% dextrose and administered via a portable, controlled, sub-Q infusion device.b
Rate of Administration
The rate of continuous IV infusion of the drug must be individualized according to the response and tolerance of the patient.b
Rate of IV infusion in neonates generally should not exceed 0.015–0.02 mg/kg per hour.b
Epidural and Intrathecal Administration
Appropriate morphine sulfate solutions (e.g., solutions that do not contain preservatives [antioxidants, antimicrobial agents], alcohol, other neurotoxic ingredients, or any ingredient that could compromise the safety and performance of the infusion pump [when continuous-infusion therapy is employed]; recommended pH of the solution is 4–8) (e.g., Astramorph/PF, Duramorph, Infumorph) may be given epidurally or intrathecally by intermittent administration or by continuous infusion (e.g., via an implantable controlled-infusion device such as an Infusaid or SynchroMed pump) if necessary.194
Highly concentrated, preservative-free morphine sulfate solutions for epidural or intrathecal use (e.g., Infumorph 10 or 25 mg/mL) are intended for use via continuous, controlled-microinfusion devices. Such injections should not be used for individual-dose epidural or intrathecal injection since less-concentrated, preservative-free injections can be employed more reliably for the small doses required.b
Morphine sulfate extended-release liposomal injection (DepoDur) is administered epidurally.192
Specialized techniques are required for epidural or intrathecal administration of morphine sulfate; the drug should be administered via these routes only by qualified individuals familiar with the techniques of administration and patient management problems associated with these routes of morphine administration.b (See Precautions Associated with Epidural or Intrathecal Administration under Cautions.)
When the drug is injected epidurally or intrathecally as individual doses, the patient should be in a setting where adequate monitoring is possible.b Because delayed respiratory depression can occur, patient monitoring should be continued for ≥24 hours after each dose of morphine sulfate injection or for ≥48 hours after a dose of morphine sulfate extended-release liposomal injection (DepoDur).192 b
Facilities, drugs, and equipment necessary for the management of inadvertent intravascular injection during attempted epidural or intrathecal injection should be readily available.b
Because epidural administration of the drug has been associated with a lower potential for immediate and delayed adverse effects than intrathecal administration, the epidural rather than intrathecal route should be used whenever possible.b
Epidural or intrathecal administration should be limited to the lumbar region since administration in the thoracic region has been associated with a substantially increased frequency of early and late respiratory depression even at low doses.b
Because the intrathecal dose of morphine is 1/10 the epidural dose, the risk of overdose from inadvertent intrathecal injection during attempted epidural injection should be considered and facilities, drugs, and equipment for treating morphine overdose should be readily available.b
Epidural or Intrathecal Administration (Morphine Sulfate Injection)
For epidural administration, the appropriate dose of the drug is injected into the epidural space after proper placement of the needle or catheter has been verified.b
For intrathecal administration, no more than 2 or 1 mL of the injection containing 0.5 or 1 mg/mL, respectively, should be injected intrathecally.b
The safety of injecting repeated intermittent doses of the drug intrathecally, other than for establishing initial dosage when continuous intrathecal infusion is contemplated, has not been determined and, if pain recurs and additional morphine therapy is required for patients who are not candidates for such infusion, alternative routes of administration should be considered.b
If the highly concentrated injections intended for such administration (e.g., Infumorph) are used, an implantable controlled-microinfusion device is used.b
Dilution of the highly concentrated injections may be necessary, depending on the infusion device employed and/or individual dosage requirements; 0.9% sodium chloride injection is recommended for dilution.b
Filling of the drug reservoir of the device should be performed only by fully trained and qualified personnel, following the directions provided by the device’s manufacturer.b
Care should be taken in employing the proper refill frequency so that depletion of the reservoir during use is avoided.b
Extreme caution must be employed to ensure proper placement of the syringe needle in the filling port of the device prior to refilling the reservoir; inadvertent injection outside the filling port, into the tissue surrounding the device, or, in the case of multiport devices, into a port intended for single supplementary doses could result in large, clinically important overdosage. Severe, potentially life-threatening respiratory depression could result from technical errors during refill.b
Patients and/or their attendants should be instructed in proper home care of the device and the insertion site and in the recognition and practical treatment of epidural or intrathecal morphine overdosage.b
Epidural Administration (Morphine Sulfate Extended-release Liposomal Injection)
The extended-release liposomal injection (DepoDur) may be administered undiluted or diluted up to 5 mL total volume with preservative-free 0.9% sodium chloride injection.192
Just before withdrawal of a dose from the vial, gently invert the vial to resuspend the particles.a Avoid aggressive agitation.a Administer dose within 4 hours after withdrawal from the vial.192 Do not administer using an inline filter; do not admix with other drugs, including local anesthetics.192 Do not administer any other drug into the epidural space for at least 48 hours.192
If a test dose of lidocaine 1.5% and epinephrine 1:200,000 is used to verify catheter placement, flush catheter after the test dose and allow ≥15 minutes to elapse before administering morphine sulfate extended-release liposomal injection.192 (See Specific Drugs under Interactions.)
Dosage
Available as morphine sulfate; dosage usually expressed as the sulfate.b
Use lowest effective dosage and shortest duration of therapy consistent with treatment goals of the patient.411 413 431 432 435
When switching patients receiving chronic opiate therapy from one opiate analgesic to another, generally reduce the calculated equianalgesic dosage of the new opiate agonist by about 25–50% to avoid inadvertent overdosage.410 412 This calculation does not apply when switching to methadone; consult specific recommendations for methadone dosage.412
When used concomitantly with other CNS depressants, use lowest effective dosages and shortest possible duration of concomitant therapy.700 703 (See Specific Drugs under Interactions.)
Pediatric Patients
Pain
Moderate to Severe Pain
OralInfants and children: 0.2–0.5 mg/kg every 4–6 hours (conventional tablets, oral solution).197
IM or Sub-QNeonates: 0.05–0.2 mg/kg every 2–4 hours as necessary.197
Infants and children: 0.1–0.2 mg/kg every 2–4 hours.197
Single pediatric doses should not exceed 10 mg.196
IVNeonates: 0.05–0.2 mg/kg every 2–4 hours as necessary.197 For continuous IV infusion, 0.025–0.05 mg/kg per hour.197
Infants and children: 0.1–0.2 mg/kg every 2–4 hours.197
Adolescents >12 years of age: 3–4 mg; may repeat in 5 minutes if needed.197
Single pediatric doses should not exceed 10 mg.196
PCA (usually IV) via controlled-delivery device: Loading doses of 0.05 mg/kg (preferably titrated by clinician or nurse at bedside, up to 0.05–0.2 mg/kg total) used.200 Maintenance doses (administered intermittently) of 10–20 mcg/kg, usually no more frequently than every 6–12 minutes as a device-programmed lockout period used for developmentally mature pediatric patients ≥7 years of age.200 201
Epidural or Intrathecal
Safety and efficacy in children not established.192 b
Cancer Pain (Severe, Chronic)
IV
Maintenance dosages of 0.025–2.6 mg/kg per hour (median: 0.04–0.07 mg/kg per hour) have been infused IV in children.b
Sub-Q
Maintenance dosages of 0.025–1.79 mg/kg per hour (median: 0.06 mg/kg per hour) have been infused sub-Q in a limited number of children.b
Sickle Cell Crisis (Severe Pain)
IV
Maintenance dosages of 0.03–0.15 mg/kg per hour have been infused IV in children.b
Postoperative Analgesia
IV
Maintenance dosages of 0.01–0.04 mg/kg per hour have been infused.b
Neonatal Opiate Withdrawal† [off-label]
Oral
Use standardized protocols that base initiation, adjustment, and tapering of dosage on standardized patient assessments performed at regular intervals (e.g., Finnegan scoring system [original or modified versions] performed every 3–4 hours).352 355 359
Treatment protocols vary in recommended dosages, thresholds for treatment initiation, incremental changes and thresholds for dosage adjustment, and tapering strategies.352 355 359 361 362 364 365 366 367 368 Further study needed to define optimal strategies.351 353
Under various protocols, treatment initiated at a dosage of 0.04–0.05 mg/kg (as oral solution) every 3–4 hours based on Finnegan score (e.g., score >8 on 2 or 3 occasions, sum of 3 consecutive scores ≥24, 1 score or 2 consecutive scores ≥12);352 353 357 364 365 367 368 under other protocols, initial dosage may vary depending on severity of withdrawal, with higher initial dosages recommended for neonates with higher Finnegan scores.361 364 366 Some clinicians state usual initial dosage is 0.03–0.1 mg/kg every 3–4 hours.366 369
If Finnegan score remains elevated (e.g., 1 score or 2 consecutive scores ≥12, 2 consecutive scores ≥8, sum of 3 scores ≥24352 355 359 361 362 365 ), increase dosage, generally by 0.02–0.05 mg/kg per dose352 353 364 365 366 368 369 or by 10–20%355 359 362 depending on the protocol and/or Finnegan score, to achieve stabilization. Some clinicians recommend usual maximum dosage of 1.2–1.3 mg/kg daily355 357 359 362 367 or 0.2 mg/kg per dose.353 364 366
Once patient is stable (generally, no score >8352 355 357 365 366 367 ) for ≥48 hours,352 359 362 365 366 367 taper dosage, typically in decrements of approximately 0.02 mg/kg per dose364 367 or approximately 10% of the highest (stabilization) dose352 355 359 361 362 364 365 366 369 at intervals of approximately 24–48 hours.352 355 359 362 364 365 366 367 368 369 Dosage at which morphine is discontinued varies by protocol.359 361 362 364 365 366
Monitor neonate for ≥48 hours after morphine is discontinued.352 361 362 365 366 367 368
Consult specialized protocols for further information on dosage and monitoring of Finnegan scores.
Adults
Pain (Oral Treatment)
Most manufacturers suggest that it is preferable to initiate and stabilize oral morphine sulfate therapy with a conventional (immediate-release) preparation and then switch the patient to an extended-release preparation (Avinza, Kadian, MS Contin, Oramorph SR) since titration of dosage may be more difficult with the latter preparations.169 170 172
Dosing regimen must be individualized based on the patient’s prior analgesic therapy.169 170 171 172
Initial dosage of extended-release preparations should be based on the total daily dosage, potency, and specific characteristics of the current opiate agonist.169 170 171 172
Other considerations should include the reliability of relative potency estimates used in calculating the equivalent morphine sulfate dosage, the degree of opiate experience and tolerance, the medical condition of the patient, concomitant drug therapy, and the nature and severity of the patient’s pain.169 170 171 172
It is preferable to underestimate the initial dosage of extended-release preparations than to inadvertently cause an overdosage of morphine sulfate.171 172
Supplemental doses of a short-acting opiate agonist can be considered if breakthrough pain occurs with dosing regimens employing extended-release preparations.169 170 171 172
When converting to another oral extended-release morphine sulfate preparation or to other oral or parenteral opiate analgesics, the manufacturer’s labeling information should be consulted.169 170 171 172
Oral Solutions or Conventional Tablets
OralUsually, 10–30 mg every 4 hours as necessary or as directed by a physician.197 200
Extended-release Capsules (Avinza)
OralIndividualize dosage according to patient response and tolerance; do not exceed 1.6 g daily.171 (See Fumaric Acid under Cautions.)
Administer Avinza no more frequently than once every 24 hours.171 The 60-, 90-, and 120-mg Avinza capsules should be used only in opiate-tolerant patients.171
Switching from other oral morphine preparations to Avinza: Use the prior total daily oral dosage and administer once every 24 hours.171 Supplemental doses of a short-acting opiate analgesic may be required for up to 4 days until the patient’s response to Avinza has stabilized.171
Switching from parenteral morphine or other non-morphine oral or parenteral opiate therapy to Avinza: Calculate the opiate analgesic requirements during the previous 24 hours and convert to an equianalgesic dosage of Avinza.171 Use conservative dosage conversion ratios to avoid toxicity.171
When used as the initial opiate in patients who do not have a proven tolerance to opiates: Usual initial dosage is 30 mg once daily; increase dosage by no more than 30 mg every 4 days.171 Dosage increases should be conservative in opiate-naive patients.171
Extended-release Capsules (Kadian)
OralIndividualize dosage according to patient response and tolerance; do not increase dosage more frequently than every other day.172
Administer Kadian no more frequently than every 12 hours.172 Patients receiving once-daily Kadian who experience excessive sedation or inadequate analgesia prior to the next dose should be switched to a twice-daily regimen.172 The 100- and 200-mg Kadian capsules should be used only in opiate-tolerant patients.172
Switching from other oral morphine preparations to Kadian: Use the prior total daily oral dosage and give in 2 divided doses every 12 hours or once every 24 hours.172 First dose of Kadian may be administered concurrently with the last dose of immediate-release opiate therapy because of the delayed peak plasma morphine concentrations produced by Kadian.172
Switching from parenteral morphine or other non-morphine oral or parenteral opiate therapy to Kadian: Calculate the opiate analgesic requirements during the previous 24 hours and convert to an equianalgesic dosage of Kadian.172 Use conservative dosage conversion ratios to avoid toxicity.172
When used as the initial opiate in patients who do not have a proven tolerance to opiates: Initially 10 or 20 mg of Kadian; increase by no more than 20 mg every other day.172
Extended-release Tablets (MS Contin)
OralIndividualize dosage according to patient response and tolerance.170
Interval between doses of MS Contin should not exceed 12 hours in order to avoid administration of large single doses.170
Use 15-mg tablets when total daily dosage is expected to be <60 mg daily; use 30-mg tablets when total daily dosage is expected to be 60–120 mg daily.170 The 100- and 200-mg tablets of MS Contin should be used only in patients who are opiate tolerant and require dosages of ≥200 mg daily.170
Switching from an immediate-release oral morphine preparation to MS Contin: Use the prior total daily oral dosage and give in 2 divided doses every 12 hours or in 3 divided doses every 8 hours.170
Switching from parenteral morphine or other oral or parenteral non-morphine opiate to MS Contin: Calculate the opiate analgesic requirements during the previous 24 hours and convert to an equianalgesic dosage of MS Contin.170 Use conservative dosage conversion ratios to avoid toxicity.170
Extended-release Tablets (Oramorph SR)
OralIndividualize dosage according to patient response and tolerance.169
Dosing interval for Oramorph SR should not exceed 12 hours because administration of large single doses may lead to acute overdosage.169 If pain is not controlled for the entire 12-hour interval, then the dosing interval may be decreased, but doses should be administered no more frequently than every 8 hours.169
Use 30-mg tablets if morphine sulfate requirement is ≤120 mg daily.169 Use 15-mg tablets if morphine sulfate requirement is low.169
Switching from other oral morphine preparations to Oramorph SR: Use the prior total daily oral dosage and give in 2 divided doses every 12 hours.169
Switching from parenteral morphine or other oral or parenteral non-morphine opiate to Oramorph SR: Calculate the opiate analgesic requirements during the previous 24 hours and convert to an equianalgesic dosage of Oramorph SR.169 Use conservative dosage conversion ratios to avoid toxicity.169
Pain (Other Routes)
Rectal
Suppositories: Usually, 10–20 mg every 4 hours as necessary or as directed by a physician.b
IV
May administer 2.5–20 mg every 2–6 hours as needed196 197 or via continuous infusion at a rate of 0.8–10 mg per hour.197
Can be administered at a rate of 2–4 mg every 5 minutes, with some patients requiring as much as 25–30 mg before pain relief is adequate.140
IM or Sub-Q
May administer 2.5–20 mg every 2–6 hours as needed196 197 or via continuous infusion at a rate of 0.8–10 mg per hour.197
Epidural (Morphine Sulfate Injection [preservative-free])
Usual initial dose for intermittent injection is 5 mg.b
Inadequate pain relief within 1 hour after administration of the initial dose: Additional epidural doses may be given carefully in 1- to 2-mg increments at intervals sufficient to assess efficacy; no more than 10 mg total daily dose.b
Pain relief generally occurs within 6–30 minutes and persists for about 16–24 hours (range: 4–36 hours) after a single, effective epidural dose of morphine.b
Continuous epidural infusion, device not implanted surgically: Initial dosage of 2–4 mg per 24 hours has been recommended; epidural dosage may be increased by 1–2 mg daily if adequate relief is not achieved initially.b
If an implantable microinfusion device is to be employed for continuous epidural infusion, efficacy and adverse effects of initial dosage should be assessed for each patient using serial, intermittent epidural doses of the drug prior to implantation surgery.b
Most adults who are not tolerant to opiates achieve adequate relief with initial epidural dosages of 3.5–7.5 mg daily.b
Administer with extreme caution and in reduced dosage epidurally or intrathecally in geriatric or debilitated patients.b
Epidural (Morphine Sulfate Extended-release Liposomal Injection [DepoDur])
Administer as a single dose.192
Major orthopedic surgery of a lower extremity: 15 mg prior to surgery.192 Some patients may benefit from 20-mg dose; however, the incidence of serious adverse respiratory events was dose related in studies.192
Lower abdominal or pelvic surgery: 10–15 mg prior to surgery.192 Some patients may benefit from 20-mg dose; however, the incidence of serious adverse respiratory events was dose related in studies.192
Cesarean section: 10 mg after the umbilical cord is clamped.192
Intrathecal
The intrathecal dose of morphine sulfate is about 1/10 the epidural dose.b
A single 0.2- to 1-mg intrathecal dose may provide adequate relief for up to 24 hours in adults who are not tolerant to opiates.b
Repeated intrathecal doses of the drug are not recommended except to establish initial intrathecal dosage when continuous intrathecal infusion is to be employed; if additional morphine therapy is necessary for patients who are not candidates for continuous intrathecal infusion, alternative routes of administration should be considered.b
Naloxone may be infused IV at a rate of 0.6 mg/hour for 24 hours after intrathecal morphine administration to decrease potential opiate-induced adverse effects.b
If an implantable microinfusion device is to be employed for continuous intrathecal infusion, efficacy and adverse effects of initial dosage should be assessed for each patient using serial, intermittent intrathecal doses of the drug prior to implantation surgery.b
Intrathecal dosages exceeding 20 mg daily should be employed with caution since they may be associated with an increased likelihood of serious toxicity, including myoclonic spasms.b
Administer with extreme caution and in reduced dosage epidurally or intrathecally in geriatric or debilitated patients.b
Pain (ACS)
IV
To relieve pain in adults with STEMI, an initial dose of 4–8 mg is recommended; may administer additional doses of 2–8 mg every 5–15 minutes as needed.527
In patients with NSTE ACS who continue to experience pain despite maximally tolerated anti-ischemic therapy, a dose of 1–5 mg IV may be administered during IV nitroglycerin therapy; may repeat every 5–30 minutes to relieve symptoms and maintain patient comfort.1100
Cancer Pain
Individualize dosage according to the response and tolerance of the patient for sub-Q or continuous IV infusions.b
Continuous IV
Initially 0.8–10 mg/hour and then increase to an effective dosage as necessary; an IV loading dose of ≥15 mg can be administered for initial relief of pain prior to initiating continuous IV infusion of the drug.b
Maintenance doses have ranged from 0.8–80 mg/hour infused IV, although higher (e.g., 150 mg/hour) maintenance dosages occasionally have been required.b
Patient-controlled Analgesia (PCA)
IV
Adjust dosage according to the severity of the pain and response of the patient; consult the operator’s manual for the patient-controlled infusion device for directions on administering the drug at the desired rate of infusion.b
Exercise care to avoid overdosage, which could result in respiratory depression, or abrupt cessation of therapy with the drug, which could precipitate opiate withdrawal.b
PCA via controlled-delivery device: Standard protocol uses loading dose of 1 mg,198 199 200 time between doses of 6 minutes (lockout period), and limit of 10 doses per hour.198 199 Loading doses of 2–4 mg every 10 minutes, preferably titrated by clinician or nurse at bedside, up to 6–16 mg total have been used for rapid control of pain.200 204 Maintenance doses (self-administered intermittently) of 0.5–2 mg, usually no more frequently than every 6–12 minutes as a device-programmed lockout period used.200 203 204
Unstable Angina (Unresponsive to 3 Sublingual Doses of Nitroglycerin)
IV
2–5 mg (repeated every 5–30 minutes as needed to relieve symptoms and maintain patient comfort) has been used.b
Analgesia during Labor
Sub-Q or IM
10 mg.b
Prescribing Limits
Pediatric Patients
Analgesia
Moderate to Severe Pain
IV, IM, or Sub-QSingle pediatric doses should not exceed 15 mg.b
Adults
Analgesia
For acute pain not related to trauma or surgery, limit prescribed quantity to amount needed for the expected duration of pain severe enough to require opiate analgesia (generally ≤3 days and rarely >7 days).411 433 434 435
CDC recommends that primary care clinicians carefully reassess individual benefits and risks before prescribing morphine sulfate dosages ≥50 mg daily for chronic pain and avoid dosages ≥90 mg daily or carefully justify their decision to prescribe such dosages.411 Other experts recommend consulting a pain management specialist before exceeding a dosage of 80–120 mg daily.423 431
Some states have set prescribing limits (e.g., maximum daily dosages that can be prescribed, dosage thresholds at which consultation with a specialist is mandated or recommended).411 420 421 423
Avinza
OralDo not exceed 1.6 g daily. (See Fumaric Acid under Cautions.)171
Administer no more frequently than every 24 hours.171 Increase dosage by no more than 30 mg every 4 days.171
Kadian
OralAdminister no more frequently than every 12 hours.172
MS Contin
OralInterval between doses should not exceed 12 hours in order to avoid administration of large single doses.170
Oramorph SR
OralDosing interval should not exceed 12 hours because administration of large single doses may lead to acute overdosage.169
Administer no more frequently than every 8 hours.169
Analgesia
Intrathecal
Intrathecal dosages exceeding 20 mg daily should be employed with caution since they may be associated with an increased likelihood of serious toxicity, including myoclonic spasms.b
Special Populations
Reduced dosage is indicated in poor-risk patients, in patients with substantial hepatic impairment, and in very young or very old patients.b
Hepatic Impairment
Reduce dosage in patients with severe hepatic impairment.b
Renal Impairment
Reduce dosage in patients with severe renal impairment, since the active metabolite morphine 6-glucuronide accumulates in such patients which can result in enhanced and prolonged opiate activity.b
Geriatric and Debilitated Patients
Reduce dosage in poor-risk patients and in very old patients.b
Administer epidurally or intrathecally with extreme caution and in reduced dosage in geriatric or debilitated patients.b
Cautions for Morphine
Contraindications
-
Hypersensitivity to morphine, morphine salts, or any ingredient in the formulation.170 171 172 192 193 196
-
Respiratory depression in the absence of resuscitative equipment.169 170 171 172 192 196
-
Acute or severe bronchial asthma or hypercarbia.169 170 171 172 192
-
Epidural or intrathecal injection contraindicated in patients whose concomitant drug therapy or medical condition would contraindicate administration of the drug by these routes, such as when infection is present at the injection site or when the patient has uncontrolled bleeding diathesis or is receiving anticoagulants.192 b
-
Extended-release liposomal injection (DepoDur) also contraindicated in patients in circulatory shock.192
Warnings/Precautions
Warnings
Respiratory Depression
The major toxicity associated with morphine.169 170 171 172 192
Occurs most frequently in geriatric and debilitated patients, and those with conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation.169 170 171 172 192
May be severe, requiring maintenance of an adequate airway, use of resuscitative equipment, and administration of oxygen, an opiate antagonist, and/or other resuscitative drugs.b
Use with extreme caution in patients with COPD or cor pulmonale, and in patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression.169 170 171 172 In such patients, even therapeutic morphine doses may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea.170 171 172
Bolus epidural or intrathecal administration may result in early respiratory depression because of direct venous redistribution of the drug to the respiratory centers in the CNS.b Late (up to 24 hours) acute respiratory depression also has occurred following epidural or intrathecal administration of morphine sulfate injection and is thought to result from rostral spread of the drug in the CNS.b Delayed respiratory depression (≥ 48 hours) may occur following administration of morphine sulfate extended-release liposomal injection (DepoDur).192 Risk of respiratory depression may be increased if the surgical procedure is cancelled after administration of the extended-release liposomal injection; monitor carefully.192 Respiratory depression requiring administration of naloxone or ventilatory support reported following intrathecal administration of DepoDur.a (See Precautions Associated with Epidural or Intrathecal Administration under Cautions.)
Intrathecal administration has been associated with a higher incidence of respiratory depression than epidural administration.b A diminished CO2 ventilatory response may be present for up to 22 hours following epidural or intrathecal administration of the drug, despite the absence of clinical evidence of inadequate ventilation.b
In patients receiving chronic epidural or intrathecal therapy, monitor patients in an adequately equipped (e.g., resuscitative equipment, oxygen, an opiate antagonist and other resuscitative drugs) and staffed environment (hospitalization is recommended) for ≥24 hours after administration of an initial test dose and, as appropriate, for several days after catheter implantation for additional monitoring and dosage adjustment.b An opiate antagonist and resuscitative equipment also should be immediately available whenever the reservoir of the microinfusion device is being refilled with morphine sulfate or is being otherwise manipulated.b
In patients receiving morphine sulfate extended-release liposomal injection (DepoDur), monitor patients in an adequately equipped (e.g., resuscitative equipment, oxygen, an opiate antagonist and other resuscitative drugs) and staffed environment for ≥48 hours after administration of the dose.192
Routinely discuss availability of the opiate antagonist naloxone with all patients receiving new or reauthorized prescriptions for opiate analgesics, including morphine.750
Consider prescribing naloxone for patients receiving opiate analgesics who are at increased risk of opiate overdosage (e.g., those receiving concomitant therapy with benzodiazepines or other CNS depressants, those with history of opiate or substance use disorder, those with medical conditions that could increase sensitivity to opiate effects, those who have experienced a prior opiate overdose)411 431 750 or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage.750 Even if patients are not receiving an opiate analgesic, consider prescribing naloxone if the patient is at increased risk of opiate overdosage (e.g., those with current or past diagnosis of OUD, those who have experienced a prior opiate overdose).750
Concomitant Use with Benzodiazepines or Other CNS Depressants
Concomitant use of opiates, including morphine, and benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiate agonists, alcohol) may result in profound sedation, respiratory depression, coma, and death.416 417 418 700 701 702 703 Substantial proportion of fatal opiate overdoses involve concurrent benzodiazepine use.416 417 418 435 700 701
Reserve concomitant use of morphine and other CNS depressants for patients in whom alternative treatment options are inadequate.700 703 (See Specific Drugs under Interactions.)
Adrenal Insufficiency
Adrenal insufficiency reported in patients receiving opiate agonists or opiate partial agonists.400 Manifestations are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.400
If adrenal insufficiency is suspected, perform appropriate laboratory testing promptly and provide physiologic (replacement) dosages of corticosteroids; taper and discontinue the opiate agonist or partial agonist to allow recovery of adrenal function.400 If the opiate agonist or partial agonist can be discontinued, perform follow-up assessment of adrenal function to determine if corticosteroid replacement therapy can be discontinued.400 In some patients, switching to a different opiate improved symptoms.400
Head Injury and Increased Intracranial Pressure
The respiratory depressant effects of morphine (with CO2 retention and secondary elevation of CSF pressure) may be markedly exaggerated in the presence of head injury, other intracranial lesions, or preexisting increase in intracranial pressure.169 170 171 172
Morphine produces effects (e.g., pupillary changes) that may obscure neurologic signs of further increase in pressure in patients with head injuries.169 170 171 172
May interfere with evaluation of CNS function, and respiratory depression produced by the drug may produce cerebral hypoxia and elevated CSF pressure not caused by the injury itself.200 e
Use with extreme caution, if at all, in patients with severe CNS depression, anoxia, hypercapnia, or respiratory depression or those who are especially prone to respiratory depression such as comatose patients or those with head injury, brain tumor, or elevated CSF pressure.171 e Avoid use of morphine sulfate extended-release liposomal injection (DepoDur) in patients with head injury or increased intracranial pressure.192
Hypotensive Effects
Like all opiate analgesics, may cause severe hypotension in individuals whose ability to maintain their BP is compromised by depleted blood volume or concomitant drugs (e.g., phenothiazines, general anesthetics).170 171 172 192 193 Consider avoiding concomitant use of vasodilators.140 (See Specific Drugs under Interactions.)
May produce orthostatic hypotension in ambulatory patients.170 171 172 192
Orthostatic hypotension is a frequent complication of single-dose epidural or intrathecal morphine therapy, and patients with reduced circulatory volume or impaired myocardial function and those receiving sympatholytic therapy may be at particular risk.b 192
Use the minimal effective dose; patient’s legs should be elevated to decrease the possibility of hypotension.b
Use with caution in patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and BP.170 171 172 Morphine sulfate extended-release liposomal injection (DepoDur) is contraindicated in patients in circulatory shock.192
Dependence and Abuse
Physical and psychic dependence and tolerance may develop with repeated administration, and abuse potential exists; use with caution.169 170 171 172 Clinicians should consider abuse potential when prescribing or dispensing morphine in situations where they are concerned about an increased risk of misuse, abuse, or diversion.172 However, concerns about abuse, addiction, and diversion should not prevent the proper management of pain.172
Abrupt cessation of therapy or sudden reduction in dosage after prolonged use may result in withdrawal symptoms.169 170 172 After prolonged exposure to opioid analgesics, if withdrawal is necessary, it must be undertaken gradually.169 170 172
Health-care professionals should contact the professional licensing board or controlled substance authority in their states for information about prevention and detection of abuse or diversion.172
Prolonged maternal use of opiates during pregnancy can result in neonatal opiate withdrawal syndrome.238 (See Pregnancy under Cautions.)
Acute Abdominal Conditions
Administration may complicate assessment of patients with acute abdominal conditions.172
Can diminish propulsive peristaltic waves in the GI tract and may prolong the obstruction.171 192
In patients with GI obstruction, especially paralytic ileus, oral extended-release preparation may remain in the stomach for a prolonged period and subsequently release a bolus of morphine when normal gut motility is restored.172
Contraindicated in patients with known or suspected paralytic ileus.169 170 171 172 192
Myoclonic Spasms
Myoclonic spasms of skeletal muscle have been reported; treatment of opiate intoxication may be required in some cases.b
In some patients, resumption of therapy after appropriate management of the toxicity may be possible at reduced dosage and/or by replacement of epidural with intrathecal therapy.b
Concentrated Morphine Oral Solutions
Serious adverse events and deaths have occurred as a result of inadvertent overdosage of concentrated morphine sulfate oral solutions.182 234 235 (See Risk of Medication Errors with Oral Solutions in Boxed Warning.)
In most cases, morphine sulfate oral solutions prescribed in mg were mistakenly interchanged for mL of the concentrated preparation, resulting in 20-fold overdoses.182 234 235
Morphine sulfate 100-mg/5-mL oral solution is indicated for use only in patients who are opiate tolerant (i.e., individuals who have been receiving ≥60 mg of oral morphine sulfate daily, ≥30 mg of oral oxycodone daily, ≥12 mg of hydromorphone hydrochloride daily, or an equianalgesic dosage of another opiate daily for ≥1 week) and have been titrated to a stable analgesic dosage using a preparation containing a lower concentration of morphine sulfate.234 235 236
It is important that prescriptions for morphine sulfate oral solution be written clearly and filled with the proper concentration of morphine sulfate oral solution to prevent potential medication errors.182 234 (See Oral Solutions under Dosage and Administration.)
Sensitivity Reactions
Hypersensitivity Reactions
Anaphylaxis reported rarely.170 172
Sulfite Sensitivity
Some commercially available formulations of morphine sulfate injection contain sulfites that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals.196 b
Overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.196 b
General Precautions
Fumaric Acid
Avinza extended-release capsules contain fumaric acid.171
Safety of morphine sulfate dosages >1.6 g daily administered as Avinza extended-release capsules has not been established; such dosages contain a quantity of fumaric acid that may be associated with serious renal toxicity.171
Precautions Associated with Epidural or Intrathecal Administration
Epidural and intrathecal administration of morphine frequently associated with dose-related pruritus; not necessarily confined to the site of administration.b
Urinary retention, which may persist for 10–20 hours after administration, has occurred in about 90% of males who received the drug epidurally or intrathecally and less frequently in females.b Early recognition of urinary difficulty and prompt intervention in cases of retention are important, particularly in patients with prostatic enlargement.192 b
In addition to the usual precautions associated with morphine use, for epidural or intrathecal administration, the drug should only be used by qualified individuals familiar with the techniques of administration and patient management problems associated with these routes of administration.b
Because chronic epidural or intrathecal therapy employing a controlled-microinfusion device is accompanied by considerable patient risk and requires a high level of skill to be accomplished successfully, such therapy should only be undertaken by experienced clinical teams who are well informed about patient selection criteria, evolving technology, and emerging standards of care.b
Safety of intrathecal administration of morphine sulfate extended-release liposomal injection (DepoDur) not evaluated; this preparation is intended for administration by the epidural route.a (See Respiratory Depression under Cautions.)
CNS Effects
May impair mental and/or physical abilities needed to perform potentially hazardous activities such as driving or operating machinery.171 172 b Individuals who perform hazardous tasks requiring mental alertness or physical coordination should be warned about possible adverse CNS effects of opiate agonists.171 172 b
High doses may result in seizures.192 Monitor patients with known seizure disorder for seizure activity;172 192 increased risk of seizures in these individuals.172
Hypothyroidism
Use with caution and in reduced dosage in patients with hypothyroidism.170 171 172 e
Prostatic Hypertrophy or Urethral Stricture
Use with caution and in reduced dosage in patients with prostatic hypertrophy or urethral stricture.170 172
Pancreatic and Biliary Disease
May cause spasm of the sphincter of Oddi.170 172 Use with caution in patients with biliary tract disease, including acute pancreatitis, and patients undergoing biliary tract surgery.170 172 192 Opiates may increase serum amylase concentrations.170 172
Addison’s Disease
Use with caution and in reduced dosage in patients with Addison’s disease.170 171 172 e
Cordotomy
Patients taking Kadian extended-release capsules who are scheduled for cordotomy or other interruption of pain transmission pathways should discontinue the drug 24 hours prior to the procedure and pain should be controlled by parenteral short-acting opiates.172 In addition, the post-procedure titration of analgesics for such patients should be individualized to avoid either oversedation or withdrawal syndromes.172
Cardiac Arrhythmia
May increase ventricular response rate through a vagolytic action; use with caution in patients with atrial flutter and other supraventricular tachycardias.b
Possible Prescribing and Dispensing Errors
Ensure accuracy of prescription; similarity in spelling of Kadian and Kapidex (former trade name for dexlansoprazole, a proton-pump inhibitor) may result in errors.217 223
Hypogonadism
Hypogonadism or androgen deficiency reported in patients receiving long-term opiate agonist or opiate partial agonist therapy;400 401 402 403 404 causality not established.400 Manifestations may include decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility.400 Perform appropriate laboratory testing in patients with manifestations of hypogonadism.400
Specific Populations
Pregnancy
Although morphine has been used during labor, use of opiate agonists generally should be avoided during labor when delivery of a premature neonate is anticipated.b (See Pediatric Use under Cautions.)
Because maternally administered opiate agonists are readily distributed into fetal circulation, an opiate antagonist and resuscitative equipment for reversal of opiate-induced respiratory depression should be readily available when the drugs are used during labor and delivery.b
Epidurally and intrathecally administered morphine also is readily distributed into fetal circulation and may result in respiratory depression in the neonate.b
Controlled clinical studies have shown that epidurally administered morphine has little or no effect on labor pain.b
Morphine sulfate extended-release liposomal injection (DepoDur) may be used during cesarean section after the umbilical cord is clamped but should not be used during labor and/or vaginal delivery.192
Prolonged maternal use of opiates during pregnancy can result in neonatal opiate withdrawal syndrome; in contrast to adults, withdrawal syndrome in neonates may be life-threatening and requires management according to protocols developed by neonatology experts.238 Syndrome presents with irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.238 Onset, duration, and severity vary depending on specific opiate used, duration of use, timing and amount of last maternal use, and rate of drug elimination by the neonate.238 Ensure availability of appropriate treatment.238 (See Neonatal Opiate Withdrawal under Uses.)
Lactation
Distributed into milk; use with caution.169 171 b When morphine sulfate extended-release liposomal injection (DepoDur) is used during cesarean section, decide whether or not to allow nursing during the first 48 hours.192
Pediatric Use
Safety and efficacy of conventional oral preparations (solution, tablets) not established in children.202
Safety and efficacy of extended-release oral preparations not established in children <18 years of age.169 170 171 172
Opiate agonists generally should not be used in premature neonates since the drugs reportedly cross the immature blood-brain barrier more readily than they do the mature barrier and thereby produce disproportionate respiratory depression.b
Opiate agonists should be administered with caution and in carefully determined dosages to infants and small children since they may be relatively more sensitive to opiates on a body-weight basis.b
Safety and efficacy of epidural or intrathecal administration in children have not been determined and these routes are not recommended.192 b
Geriatric Use
Clinical studies of extended-release oral preparations did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently than younger adults.170 171 172
Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients, use extended-release oral preparations with caution in this age group and select dosage at the lower end of the dosage range.170 171 172
The pharmacodynamics of epidurally or intrathecally administered morphine are more variable in geriatric patients than in younger adults.b Considerable interindividual variation in effective initial dosage, rate of development of tolerance, and frequency and severity of adverse effects exists for epidural or intrathecal therapy with the drug in this population; therefore, initial dosage should be selected carefully based on clinical assessment of response to test doses and consideration of the patient’s age and infirmity on their ability to clear the drug, particularly in those receiving the drug epidurally.b
No overall differences in safety and efficacy of morphine sulfate extended-release liposomal injection (DepoDur) (at same or lower doses) in those ≥65 years of age compared with younger adults, but possibility of increased sensitivity in some geriatric individuals cannot be ruled out.192 Comorbid conditions may predispose geriatric patients to serious adverse events (e.g., respiratory depression, ileus, hypotension, MI).192 Use with caution in this age group and select dosage at the lower end of the dosage range.192
Hepatic Impairment
Use with caution and in reduced dosage in patients with severe hepatic impairment.170 171 172 b
Morphine sulfate extended-release liposomal injection (DepoDur) is intended for single-dose administration; accumulation of morphine or its metabolites not expected in patients with hepatic impairment.192
Renal Impairment
Use with caution and in reduced dosage in patients with severe renal impairment since accumulation (over several days) of high systemic concentrations may occur in some patients.170 171 172 b
Morphine sulfate extended-release liposomal injection (DepoDur) is intended for single-dose administration; accumulation of morphine or its metabolites not expected in patients with renal impairment.192
Common Adverse Effects
CNS effects (dizziness, visual disturbances, mental clouding or depression, sedation, coma, euphoria, dysphoria, weakness, faintness, agitation, restlessness, nervousness, seizures, delirium, insomnia) and GI effects (nausea, vomiting, constipation).e
Opiate agonists may interfere with evaluation of CNS function, especially relative to consciousness levels, pupillary changes, and respiratory depression, thereby masking the patient’s clinical course.e
May increase the risk of water intoxication in postoperative patients because of stimulation of the release of vasopressin.e
Drug Interactions
Drugs Associated with Serotonin Syndrome
Risk of serotonin syndrome when used with other serotonergic drugs.400 May occur at usual dosages.400 Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.400 (See Advice to Patients.)
If concomitant use of other serotonergic drugs is warranted, monitor patients for serotonin syndrome, particularly during initiation of therapy and dosage increases.400
If serotonin syndrome is suspected, discontinue morphine, other opiate therapy, and/or any concurrently administered serotonergic agents.400
Specific Drugs
Drug |
Interaction |
Comments |
---|---|---|
Anesthetics, local (epidural) |
Lidocaine 1.5% and epinephrine 1:200,000 (test dose to verify catheter placement) increases peak serum morphine concentrations when morphine is administered as extended-release liposomal injection (DepoDur)192 |
Flush catheter with 1 mL of preservative-free 0.9% sodium chloride injection after test dose; allow ≥15 minutes between test dose and administration of morphine sulfate extended-release liposomal injection (DepoDur)192 Safety and efficacy of morphine sulfate extended-release liposomal injection with epidurally administered lidocaine and epinephrine for conduction anesthesia or other therapeutic indication not studied192 |
Amphetamines |
Dextroamphetamine may enhance opiate agonist analgesiae |
May be used to therapeutic advantage |
Anticoagulants |
Opiate agonists have been reported to potentiate the anticoagulant activity of coumarin anticoagulantse |
|
Antidepressants, SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), SNRIs (e.g., desvenlafaxine, duloxetine, milnacipran, venlafaxine), tricyclic antidepressants (TCAs), mirtazapine, nefazodone, trazodone, vilazodone |
Risk of serotonin syndrome400 TCAs: Opiates may potentiate the effects of TCAse |
If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400 If serotonin syndrome suspected, discontinue morphine, the antidepressant, and/or any concurrently administered opiates or serotonergic agents400 TCAs: Use concomitantly with caution; dosage adjustment may be necessarye |
Antiemetics, 5-HT3 receptor antagonists (e.g., dolasetron, granisetron, ondansetron, palonosetron) |
Risk of serotonin syndrome400 |
If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400 If serotonin syndrome suspected, discontinue morphine, the 5-HT3 receptor antagonist, and/or any concurrently administered opiates or serotonergic agents400 |
Antipsychotics (e.g., aripiprazole, asenapine, cariprazine, chlorpromazine, clozapine, fluphenazine, haloperidol, iloperidone, loxapine, lurasidone, molindone, olanzapine, paliperidone, perphenazine, pimavanserin, quetiapine, risperidone, thioridazine, thiothixene, trifluoperazine, ziprasidone) |
Risk of profound sedation, respiratory depression, hypotension, coma, or death700 703 704 |
Use concomitantly only if alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy700 703 In patients receiving morphine, initiate antipsychotic, if required, at lower dosage than indicated in the absence of opiate therapy and titrate based on clinical response700 703 In patients receiving an antipsychotic, initiate morphine, if required, at reduced dosage and titrate based on clinical response700 703 Monitor closely for respiratory depression and sedation700 703 |
Benzodiazepines (e.g., alprazolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, quazepam, temazepam, triazolam) |
Risk of profound sedation, respiratory depression, hypotension, coma, or death416 417 418 700 701 703 704 |
Whenever possible, avoid concomitant use410 411 415 435 Use concomitantly only if alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy700 703 In patients receiving morphine, initiate benzodiazepine, if required for any indication other than epilepsy, at lower dosage than indicated in the absence of opiate therapy and titrate based on clinical response700 703 In patients receiving a benzodiazepine, initiate morphine, if required, at reduced dosage and titrate based on clinical response700 703 Monitor closely for respiratory depression and sedation700 703 Consider prescribing naloxone for patients receiving opiates and benzodiazepines concomitantly411 431 750 |
Buspirone |
Risk of serotonin syndrome400 |
If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400 If serotonin syndrome suspected, discontinue morphine, buspirone, and/or any concurrently administered opiates or serotonergic agents400 |
Cimetidine |
Apnea, confusion, respiratory depression, and muscle twitching reported171 172 |
Monitor for increased respiratory and CNS depression171 |
CNS depressants (e.g., other opiates, anxiolytics, general anesthetics, tranquilizers, alcohol) |
May potentiate the effects of other CNS depressants;169 170 171 172 192 e increased risk of profound sedation, respiratory depression, hypotension, coma, or death700 703 704 Alcohol: Increased morphine concentrations and risk of overdosage in patients receiving morphine sulfate extended-release capsules171 195 |
Use concomitantly only if alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy700 703 In patients receiving morphine, initiate CNS depressant, if required for any indication other than epilepsy, at lower dosage than indicated in the absence of opiate therapy and titrate based on clinical response700 703 In patients receiving a CNS depressant, initiate morphine, if required, at reduced dosage and titrate based on clinical response700 703 Monitor closely for respiratory depression and sedation700 703 Consider prescribing naloxone for patients receiving opiates and other CNS depressants concomitantly750 |
Dextromethorphan |
Risk of serotonin syndrome400 |
If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400 If serotonin syndrome suspected, discontinue morphine, dextromethorphan, and/or any concurrently administered opiates or serotonergic agents400 |
Diuretics |
Opiate agonists may decrease the effects of diuretics in patients with CHFe |
|
5-HT1 receptor agonists (triptans; e.g., almotriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) |
Risk of serotonin syndrome400 |
If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400 If serotonin syndrome suspected, discontinue morphine, the triptan, and/or any concurrently administered opiates or serotonergic agents400 |
Lithium |
Risk of serotonin syndrome400 |
If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400 If serotonin syndrome suspected, discontinue morphine, lithium, and/or any concurrently administered opiates or serotonergic agents400 |
MAO inhibitors (e.g., isocarboxazid, linezolid, methylene blue, phenelzine, selegiline, tranylcypromine) |
Risk of serotonin syndrome400 |
Do not use morphine in patients who have received MAO inhibitor within 14 days171 172 192 If serotonin syndrome suspected, discontinue morphine, the MAO inhibitor, and/or any concurrently administered opiates or serotonergic agents400 |
Neuromuscular blocking agents |
Opiates may enhance neuromuscular blocking action171 172 192 e |
|
Opiate partial agonists (butorphanol, nalbuphine, pentazocine) |
Possible reduced analgesic effect and/or withdrawal symptoms169 170 171 172 |
|
Sedative/hypnotic agents (e.g., butabarbital, eszopiclone, pentobarbital, ramelteon, secobarbital, suvorexant, zaleplon, zolpidem) |
Risk of profound sedation, respiratory depression, hypotension, coma, or death700 703 704 |
Use concomitantly only if alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy700 703 In patients receiving morphine, initiate sedative/hypnotic, if required, at lower dosage than indicated in the absence of opiate therapy and titrate based on clinical response700 703 In patients receiving a sedative/hypnotic, initiate morphine, if required, at reduced dosage and titrate based on clinical response700 703 Monitor closely for respiratory depression and sedation700 703 |
Skeletal muscle relaxants (e.g., baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, dantrolene, metaxalone, methocarbamol, orphenadrine, tizanidine) |
Risk of profound sedation, respiratory depression, hypotension, coma, or death700 703 704 Cyclobenzaprine: Risk of serotonin syndrome400 |
Use concomitantly only if alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy700 703 In patients receiving morphine, initiate skeletal muscle relaxant, if required, at lower dosage than indicated in the absence of opiate therapy and titrate based on clinical response700 703 In patients receiving a skeletal muscle relaxant, initiate morphine, if required, at reduced dosage and titrate based on clinical response700 703 Monitor closely for respiratory depression and sedation700 703 Cyclobenzaprine: If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400 If serotonin syndrome suspected, discontinue morphine, cyclobenzaprine, and/or any concurrently administered opiates or serotonergic agents400 |
St. John’s wort (Hypericum perforatum) |
Risk of serotonin syndrome400 |
If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400 If serotonin syndrome suspected, discontinue morphine, St. John’s wort, and/or any concurrently administered opiates or serotonergic agents400 |
Tryptophan |
Risk of serotonin syndrome400 |
If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400 If serotonin syndrome suspected, discontinue morphine, tryptophan, and/or any concurrently administered opiates or serotonergic agents400 |
Morphine Pharmacokinetics
Absorption
Bioavailability
Variably absorbed from the GI tract.b Oral bioavailability ≤40%.169 170 171
Extent of absorption from conventional oral preparations (immediate-release preparations) 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.170 172
Rectal administration: Absorption from rectal suppository is greater than that from the oral solution.b
Intrathecal administration: Absorbed slowly into systemic circulation, accounting for the prolonged duration of action by this route.b
Epidural administration (morphine sulfate injection): Systemic absorption is rapid, with plasma concentration-time profiles that closely resemble those attained after IV or IM administration.b
Epidural administration (morphine sulfate extended-release liposomal injection [DepoDur]): Drug is released from the multivesicular liposomes over time.192 Systemic AUC is similar to that achieved with epidural administration of morphine sulfate injection, but peak plasma concentrations are lower with the liposomal formulation.192
Onset
Oral administration (conventional preparations): Peak analgesia within 60 minutes.b
Rectal administration: Peak analgesia 20–60 minutes after administration.b
Sub-Q: Peak analgesia within 50–90 minutesb and maximal respiratory depression within 90 minutes.b
IV injection: Peak analgesia within 20 minutes and maximal respiratory depression within 7 minutes.b
IM administration: Peak analgesia within 30–60 minutes and maximal respiratory depression within 30 minutes.b
Duration
Following oral, rectal, sub-Q, IM, or IV administration, analgesia may be maintained up to 7 hours.b
Sensitivity of the respiratory center returns to normal within 2–3 hours, but minute volume may remain below normal for 4–5 hours.b
Food
Conventional preparations: Food may increase extent of GI absorption.b
Extended-release capsules: Food may decrease rate of absorption, but extent of absorption does not appear to be affected.171 172
Plasma Concentrations
Extended-release capsule (Avinza): Peak 30 minutes.171
Extended-release capsule (Kadian): Peak 8.6–10.3 hours.172
Extended-release tablets (MS Contin): Peak 4.4 hours.172
Extended-release tablets (Oramorph SR): Peak 3.6–3.8 hours.169
Intrathecal or epidural administration (morphine sulfate injection): Peak approximately 5–10 minutes.b
Epidural administration (morphine sulfate extended-release liposomal injection [DepoDur]): Peak approximately 1 hour.192
Because of the blood-brain barrier, injection of morphine sulfate into peripheral circulation results in systemic plasma concentrations that remain higher than corresponding CNS concentrations.b
Distribution
Extent
Distributed into muscle, kidneys, liver, GI tract, lungs, spleen, and brain.169 170 171 172
Approximately 4% of an epidurally injected dose distributes into CSF;b distribution across the dura is slow, with peak CSF concentrations occurring 60–90 minutes after an epidural dose.b
Crosses the placenta.169 170 172 192 Small amounts distributed into the milk.169 170 172 192 b
Plasma Protein Binding
20–36% bound to plasma proteins;171 172 192 54% bound to muscle tissue.b
Elimination
Metabolism
Metabolized principally in the liver and undergoes conjugation with glucuronic acid.b
Secondary conjugation also occurs, which forms a pharmacologically active metabolite.b
Plasma concentrations of the active metabolite substantially exceed those of unchanged drug, and the active metabolite appears to contribute substantially to the drug’s pharmacologic activity.b
Elimination Route
Excreted in urine mainly as inactive metabolites; up to 2–12% of a dose is eliminated as unchanged drug in urine; 7–10% of a dose is excreted in feces.192 b
Half-life
IV or IM: Mean terminal half-life is 1.5–4.5 hours.b
Epidural administration (morphine sulfate injection): Mean terminal plasma half-life is 90 minutesb and mean terminal half-life in CSF is about 6 hours.b
Epidural administration (morphine sulfate extended-release liposomal injection [DepoDur]): Mean plasma half-life is 16.2–23.9 hours.192
Intrathecal administration: Mean terminal half-life in CSF is 90 minutes.b
Special Populations
Clearance reduced in patients with hepatic impairment.169
Renal impairment: Accumulation of the active metabolite occurs, which can result in enhanced and prolonged opiate activity.b
Stability
Storage
When exposed to air, morphine sulfate gradually loses its water of hydration; the drug darkens on prolonged exposure to light.b
Oral
Conventional Tablets or Solution
Tight, light-resistant containers at 15–30°C.b 202
Extended-Release Capsules and Tablets
Tight, light-resistant containers at 25°C (may be exposed to 15–30°C).169 170 171 172
Parenteral
Injection
15–30°C; protect from light; do not freeze.b
Astramorph/PF, Duramorph, and Infumorph injections and injections for use in a compatible patient-controlled infusion device contain no preservatives and are intended for single use only; discard unused portions.b
Morphine sulfate extended-release liposomal injection (DepoDur): 2–8°C; do not freeze.192 May be stored at 15–30°C for ≤30 days in sealed, intact vials.a Do not heat sterilize or gas sterilize.192 Administer dose within 4 hours after withdrawal from the vial; discard unused portions.192
Compatibility
Parenteral
Specialized references should be consulted for specific compatibility information.b
Solution CompatibilityHID
Compatible |
---|
Dextrose–Ringer’s injection combinations |
Dextrose–Ringer’s injection, lactated, combinations |
Dextrose–saline combinations |
Dextrose 2.5, 5, or 10% in water |
Ionosol products |
Ringer’s injection |
Ringer’s injection, lactated |
Sodium chloride 0.45 or 0.9% |
Sodium lactate (1/6) M |
Variable |
Sterile water for injection |
Drug Compatibility
Compatible |
---|
Alteplase |
Atracurium besylate |
Baclofen |
Bupivacaine HCl |
Dobutamine HCl |
Fluconazole |
Furosemide |
Ketamine HCl |
Meropenem |
Metoclopramide HCl |
Ondansetron HCl |
Ropivacaine HCl |
Succinylcholine chloride |
Verapamil HCl |
Ziconotide acetate |
Incompatible |
Fluorouracil |
Compatible |
---|
Allopurinol sodium |
Amifostine |
Amikacin sulfate |
Aminophylline |
Amiodarone HCl |
Ampicillin sodium |
Ampicillin sodium–sulbactam sodium |
Anidulafungin |
Argatroban |
Atracurium besylate |
Atropine sulfate |
Aztreonam |
Bivalirudin |
Bumetanide |
Calcium chloride |
Caspofungin acetate |
Cefazolin sodium |
Cefepime HCl |
Cefotaxime sodium |
Cefotetan disodium |
Cefoxitin sodium |
Ceftaroline fosamil |
Ceftazidime |
Ceftriaxone sodium |
Cefuroxime sodium |
Chloramphenicol sodium succinate |
Cisatracurium besylate |
Cladribine |
Clindamycin phosphate |
Co-trimoxazole |
Dexamethasone sodium phosphate |
Dexmedetomidine HCl |
Diazepam |
Digoxin |
Diltiazem HCl |
Diphenhydramine HCl |
Dobutamine HCl |
Docetaxel |
Dopamine HCl |
Doripenem |
Doxycycline hyclate |
Enalaprilat |
Epinephrine HCl |
Erythromycin lactobionate |
Esmolol HCl |
Etomidate |
Etoposide phosphate |
Famotidine |
Fenoldopam mesylate |
Fentanyl citrate |
Filgrastim |
Fluconazole |
Fludarabine phosphate |
Foscarnet sodium |
Gemcitabine HCl |
Gentamicin sulfate |
Granisetron HCl |
Haloperidol lactate |
Heparin sodium |
Hetastarch in lactated electrolyte injection (Hextend) |
Hydrocortisone sodium succinate |
Hydromorphone HCl |
Hydroxyethyl starch 130/0.4 in sodium chloride 0.9% |
Hydroxyzine HCl |
Insulin, regular |
Ketorolac tromethamine |
Labetalol HCl |
Levofloxacin |
Lidocaine HCl |
Linezolid |
Lorazepam |
Magnesium sulfate |
Melphalan HCl |
Meropenem |
Methyldopate HCl |
Methylprednisolone sodium succinate |
Metoclopramide HCl |
Metoprolol tartrate |
Metronidazole |
Midazolam HCl |
Milrinone lactate |
Nafcillin sodium |
Nicardipine HCl |
Nitroglycerin |
Norepinephrine bitartrate |
Ondansetron HCl |
Oxacillin sodium |
Oxaliplatin |
Oxytocin |
Paclitaxel |
Palonosetron HCl |
Pancuronium bromide |
Pantoprazole sodium |
Pemetrexed disodium |
Penicillin G potassium |
Phenobarbital sodium |
Piperacillin sodium–tazobactam sodium |
Potassium chloride |
Propofol |
Propranolol HCl |
Ranitidine HCl |
Remifentanil HCl |
Scopolamine HBr |
Sodium bicarbonate |
Sodium nitroprusside |
Tacrolimus |
Teniposide |
Thiotepa |
Ticarcillin disodium–clavulanate potassium |
Tirofiban HCl |
Tobramycin sulfate |
Vancomycin HCl |
Vecuronium bromide |
Vinorelbine tartrate |
Warfarin sodium |
Zidovudine |
Incompatible |
Amphotericin B cholesteryl sulfate complex |
Azithromycin |
Doxorubicin HCl liposome injection |
Gallium nitrate |
Micafungin sodium |
Phenytoin sodium |
Sargramostim |
Variable |
Acyclovir sodium |
Furosemide |
Actions
-
A potent analgesic; shares the actions of the opiate agonists.b
-
Opiate agonists alter perception of and emotional response to pain.e
-
Precise mechanism of action has not been fully elucidated; opiate agonists act at several CNS sites, involving several neurotransmitter systems to produce analgesia.e
-
Pain perception is altered in the spinal cord and higher CNS levels (e.g., substantia gelatinosa, spinal trigeminal nucleus, periaqueductal gray, periventricular gray, medullary raphe nuclei, hypothalamus).e
-
Opiate agonists do not alter the threshold or responsiveness of afferent nerve endings to noxious stimuli, nor peripheral nerve impulse conduction.e
-
Opiate agonists act at specific receptor binding sites in the CNS and other tissues; opiate receptors are concentrated in the limbic system, thalamus, striatum, hypothalamus, midbrain, and spinal cord.e
-
Agonist activity at the opiate μ- or κ-receptor can result in analgesia, miosis, and/or decreased body temperature.e
-
Agonist activity at the μ-receptor can also result in suppression of opiate withdrawal (and antagonist activity can result in precipitation of withdrawal).e
-
Respiratory depression may be mediated by μ-receptors, possibly μ2-receptors (which may be distinct from μ1-receptors involved in analgesia); κ- and δ-receptors may also be involved in respiratory depression.e
Advice to Patients
-
Importance of informing patients that morphine may impair mental and/or physical ability required for performance of potentially hazardous tasks; avoid driving or operating heavy machinery until effects on individual are known.169 170 171 172
-
Risk of respiratory depression following overdosage.750 Advise patients of the benefits of naloxone following opiate overdose and of their options for obtaining the drug.750
-
Risk of potentially fatal additive effects (e.g., profound sedation, respiratory depression, coma) if used concomitantly with benzodiazepines or other CNS depressants, including alcohol and other opiates, either therapeutically or illicitly; avoid concomitant use unless such use is supervised by clinician.700 703 Importance of informing patients that morphine should not be combined with alcohol.169 170 171 172 700
-
Importance of informing patients that this is a drug of potential abuse and should also be protected from theft.169 170 171 172
-
Importance of informing patients that this medication should never be given to anyone other than the individual for whom it was prescribed.171 172
-
Importance of informing patients to keep this and all medications in a secure location and out of the reach of children.169 170 171 172
-
Importance of informing patients that morphine dosage should not be adjusted without consulting with a clinician.169 170 171 172
-
Potential risk of serotonin syndrome with concurrent use of morphine and other serotonergic agents.400 Importance of immediately contacting clinician if manifestations of serotonin syndrome (e.g., agitation, hallucinations, tachycardia, labile BP, fever, excessive sweating, shivering, shaking, muscle stiffness, twitching, loss of coordination, nausea, vomiting, diarrhea) develop.400
-
Potential risk of adrenal insufficiency.400 Importance of contacting clinician if manifestations of adrenal insufficiency (e.g., nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, hypotension) develop.400
-
Possible risk (although causality not established) of hypogonadism or androgen deficiency with long-term opiate agonist or partial agonist use.400 Importance of informing clinician if decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility occurs.400
-
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.169 170 171 172
-
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.169 170 171 172 Advise women of childbearing potential that prolonged use of opiates during pregnancy may result in neonatal opiate withdrawal syndrome, which can be life-threatening if not recognized and treated.238
-
Importance of informing patients of other important precautionary information.169 170 171 172 (See Cautions.)
- Morphine Oral Solution
-
Importance of providing copy of morphine sulfate oral solutions medication guide.234 Importance of patients reading the medication guide before initiating therapy and each time the oral solution is dispensed.236
-
Importance of providing careful instructions on how to measure and administer the prescribed dose.236 For patients receiving the oral solution containing morphine sulfate 100 mg/5 mL, importance of instructing patient to always use the graduated oral syringe supplied by the manufacturer to ensure that the dose is measured and administered accurately.234 235 236
-
Risk of fatal respiratory depression if the 100-mg/5-mL oral solution is given to patients who are not opiate tolerant.234 235 236
-
Importance of instructing patients receiving prescriptions for morphine sulfate oral solution as to which concentration they have been prescribed; inform patient whenever the concentration is changed.236
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 when available as a single entity or as a schedule III (C-III) drug when available as a fixed-combination preparation in a concentration of ≤0.5 mg per mL or g combined with a therapeutic amount of one or more nonopiate drugs.
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Oral |
Capsules, extended-release (containing beads) |
30 mg (extended-release 27 mg with 3 mg immediate-release)/24 hours |
AVINza (C-II) |
Ligand (also promoted by Organon) |
60 mg (extended-release 54 mg with 6 mg immediate-release)/24 hours |
AVINza (C-II) |
Ligand (also promoted by Organon) |
||
90 mg (extended-release 81 mg with 9 mg immediate-release)/24 hours |
AVINza (C-II) |
Ligand (also promoted by Organon) |
||
120 mg (extended-release 108 mg with 12 mg immediate-release)/24 hours |
AVINza (C-II) |
Ligand (also promoted by Organon) |
||
Capsules, extended-release (containing pellets) |
10 mg/24 hours |
Kadian (C-II) |
Actavis |
|
20 mg/24 hours |
Kadian (C-II) |
Actavis |
||
30 mg/24 hours |
Kadian (C-II) |
Actavis |
||
50 mg/24 hours |
Kadian (C-II) |
Actavis |
||
60 mg/24 hours |
Kadian (C-II) |
Actavis |
||
80 mg/24 hours |
Kadian (C-II) |
Actavis |
||
100 mg/24 hours |
Kadian (C-II) |
Actavis |
||
200 mg/24 hours |
Kadian (C-II) |
Actavis |
||
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 |
15 mg/12 hours |
Oramorph SR (C-II) |
Xanodyne |
|
30 mg/12 hours |
Oramorph SR (C-II) |
Xanodyne |
||
60 mg/12 hours |
Oramorph SR (C-II) |
Xanodyne |
||
100 mg/12 hours |
Oramorph SR (C-II) |
Xanodyne |
||
Tablets, extended-release, film-coated |
15 mg/12 hours |
Morphine Sulfate Tablets ER (C-II) |
||
MS Contin (C-II) |
Purdue Pharma |
|||
30 mg/12 hours |
Morphine Sulfate Tablets ER (C-II) |
|||
MS Contin (C-II) |
Purdue Pharma |
|||
60 mg/12 hours |
Morphine Sulfate Tablets ER (C-II) |
|||
MS Contin (C-II) |
Purdue Pharma |
|||
100 mg/12 hours |
Morphine Sulfate Tablets ER (C-II) |
|||
MS Contin (C-II) |
Purdue Pharma |
|||
200 mg/12 hours |
Morphine Sulfate Tablets ER (C-II) |
|||
MS Contin (C-II) |
Purdue Pharma |
|||
Tablets, soluble |
10 mg |
Morphine Sulfate Tablets (C-II) |
||
15 mg |
Morphine Sulfate Tablets (C-II) |
|||
30 mg |
Morphine Sulfate Tablets (C-II) |
|||
Parenteral |
Injection, for IM, IV, or subcutaneous use |
0.5 mg/mL |
Morphine Sulfate Injection (C-II) |
|
1 mg/mL |
Morphine Sulfate Injection (C-II) |
|||
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) |
|||
15 mg/mL |
Morphine Sulfate Injection (C-II) |
|||
Injection, for epidural, intrathecal, or IV use |
0.5 mg/mL |
Astramorph/PF (C-II) |
AstraZeneca |
|
Duramorph (C-II) |
Baxter |
|||
Morphine Sulfate Injection (C-II) |
||||
1 mg/mL |
Astramorph/PF (C-II) |
AstraZeneca |
||
Duramorph (C-II) |
Baxter |
|||
Morphine Sulfate Injection (C-II) |
||||
Injection, for epidural or intrathecal use via continuous microinfusion device only |
10 mg/mL |
Infumorph (C-II) |
Baxter |
|
25 mg/mL |
Infumorph (C-II) |
Baxter |
||
Morphine Sulfate Injection (C-II) |
||||
Injection, for IV infusion via compatible patient-controlled infusion device only |
1 mg/mL |
Morphine Sulfate Injection (C-II) |
||
5 mg/mL |
Morphine Sulfate Injection (C-II) |
|||
Injection, for IV infusion |
25 mg/mL |
Morphine Sulfate ADD-Vantage (C-II) |
Hospira |
|
Injection, for preparation of IV infusion |
25 mg/mL |
Morphine Sulfate Injection (C-II) |
||
50 mg/mL |
Morphine Sulfate Injection (C-II) |
|||
Rectal |
Suppositories |
5 mg |
Morphine Sulfate Suppositories (C-II) |
|
RMS (C-II) |
Upsher-Smith |
|||
10 mg |
Morphine Sulfate Suppositories (C-II) |
|||
RMS (C-II) |
Upsher-Smith |
|||
20 mg |
Morphine Sulfate Suppositories (C-II) |
|||
RMS (C-II) |
Upsher-Smith |
|||
30 mg |
Morphine Sulfate Suppositories (C-II) |
|||
RMS (C-II) |
Upsher-Smith |
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Parenteral |
Injectable suspension, extended-release, for epidural use |
10 mg/mL (of morphine sulfate) (10, 15, and 20 mg) |
DepoDur (C-II) |
Endo |
AHFS DI Essentials™. © Copyright 2024, Selected Revisions April 19, 2023. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.
References
100. Ortho-McNeil Pharmaceutical. Ultram(tramadol hydrochloride) tablets prescribing information. Raritan, NJ. 1995 Mar 3.
101. Lehmann KA. Tramadol for the management of acute pain. Drugs. 1994; 47(Suppl 1):19-32. http://www.ncbi.nlm.nih.gov/pubmed/7517822?dopt=AbstractPlus
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