Class: Opiate Agonists
VA Class: CN101
CAS Number: 6211-15-0
Brands: Astramorph/PF, Avinza, DepoDur, Duramorph, Infumorph, Kadian, MS Contin, Oramorph SR, RMS

Introduction

Opiate agonist; phenanthrene derivative.^b

Uses for Morphine Sulfate

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 pain,¹⁷² for use on an as-needed (“prn”) basis,^{171 172} for preoperative administration to control postoperative pain,¹⁷² or routinely for postoperative use.^{171 172} Patients who were receiving one of these preparations prior to surgery may reinitiate such use after they are able to resume oral therapy.^{171 172} Extended-release preparations (Kadian) may be used postoperatively if pain is expected to be moderate to severe and persist for an extended period of time.¹⁷²

Slideshow: 10 Things to Know About Antibiotic Resistance

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 (MI)

Relief of pain related to AMI.^b Drug of choice.^b

IV morphine should be initiated promptly at the time of diagnosis (e.g., in the emergency department) and should not be delayed simply to avoid obscuring the ability to evaluate results of anti-ischemic therapy, which also can provide pain relief.¹⁴⁰

Careful attention to maximum pain relief should continue as a general measure in early hospital management of AMI, even after the patient leaves the emergency department.¹⁴⁰

Patients with AMI 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 development of 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

Administering morphine in small increments to avoid paradoxical augmentation of sympathetic activity and respiratory depression may result in inadequate cumulative doses of the drug;¹⁴⁰ fear of inducing hypotension, which is not a particular threat to supine patients, also may unnecessarily limit administration of adequate doses.¹⁴⁰

To avoid hypotension, it may be more prudent to avoid concomitant use of vasodilators (e.g., IV nitroglycerin) in patients with severe unremitting pain.¹⁴⁰

Patients should be advised to notify their caretakers (e.g., nurse) immediately when discomfort occurs and describe its severity on a numeric scale (e.g., 1–10).¹⁴⁰

Although the depressant action of opiate agonists on ventilation is centrally mediated and well appreciated, respiratory depression in the setting of AMI usually is not a substantial clinical problem because of sympathetic discharge associated with ischemic-type chest discomfort or pulmonary edema.¹⁴⁰

If respiratory depression occurs, naloxone hydrochloride (up to three 0.4-mg IV doses at up to 3-minute intervals) may be used to provide relief.¹⁴⁰

Some experts also recommend IV morphine for any patient with unstable angina whose symptoms are not controlled after 3 serial sublingual nitroglycerin doses, or whose symptoms recur with adequate anti-ischemic therapy (unless contraindicated by hypotension or intolerance).^b

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

Morphine Sulfate Dosage and Administration

Administration

Administered orally^{b 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, 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.)

FDA has approved a REMS for morphine sulfate oral solution.²³⁷ (See REMS)

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 patient-controlled analgesia (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†, the drug has been diluted to an appropriate concentration in 5% dextrose and administered via a portable, controlled, sub-Q infusion device (e.g., AutoSyringe).^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

Should be given in the smallest effective dose and as infrequently as possible in order to minimize the development of tolerance and physical dependence.^b

In patients with severe, chronic pain, dosage should be adjusted according to the severity of the pain and the response and tolerance of the patient.

In patients with exceptionally severe, chronic pain or in those who have become tolerant to the analgesic effect of opiate agonists, it may be necessary to exceed the usual dosage.

Pediatric Patients

Pain

Moderate to Severe Pain

Oral

Infants and children: 0.2–0.5 mg/kg every 4–6 hours (conventional tablets, oral solution).¹⁹⁷

IM or Sub-Q

Neonates: 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

IV

Neonates: 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

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

Oral

Usually, 10–30 mg every 4 hours as necessary or as directed by a physician.^{197 200}

Extended-release Capsules (Avinza)

Oral

Individualize 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)

Oral

Individualize 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)

Oral

Individualize 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)

Oral

Individualize 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 needed^{196 197} 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 needed^{196 197} 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 (MI)

To relieve pain and associated anxiety and provide potentially beneficial cardiovascular effects in adults with AMI, dosages of 2–15 mg have been administered parenterally.^b

IV

Preferred route since absorption following sub-Q or IM injection may be unpredictable, and repeated doses (up to every 5 minutes if necessary) in small increments (e.g., 1–4 mg) generally are preferred to larger and less frequent doses in order to minimize the risk of adverse effects (e.g., respiratory depression).^b

Occasionally, patients may require relatively large cumulative doses (e.g., 2–3 mg/kg).^b

Patients should be advised to notify their caretakers (e.g., nurse) immediately when discomfort occurs and describe its severity on a numeric scale (e.g., 1–10).^b

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-Q

Single pediatric doses should not exceed 15 mg.^b

Adults

Analgesia

Avinza

Oral

Do 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

Oral

Administer no more frequently than every 12 hours.¹⁷²

MS Contin

Oral

Interval between doses should not exceed 12 hours in order to avoid administration of large single doses.¹⁷⁰

Oramorph SR

Oral

Dosing 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, in very young or very old patients, and in patients receiving other CNS depressants.^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 Sulfate

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}

• Known or suspected paralytic ileus.^{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

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

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}

Specific Populations

Pregnancy

Category C.^{169 171 172 192}

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

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

Interactions for Morphine Sulfate

Specific Drugs

Drug	Interaction	Comments
Alcohol	Increased morphine concentrations and risk of overdosage in patients receiving morphine sulfate extended-release capsules171 195	Avoid use of alcohol in patients receiving morphine sulfate extended-release capsules171 195
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, MAO inhibitors	MAO inhibitors potentiate action of morphine171 172 192	Do not use in patients who have received MAO inhibitor within 14 days171 172 192
Antidepressants, tricyclics	May potentiate the effects of tricyclic antidepressants e	Use concomitantly with caution; dosage adjustment may be necessarye
Cimetidine	Apnea, confusion, respiratory depression, and muscle twitching reported171 172	Monitor for increased respiratory and CNS depression171
CNS depressants (other opiates, general anesthetics, tranquilizers, sedatives and hypnotics, and alcohol)	May potentiate the effects of other CNS depressants169 170 171 172 192 e	Use concomitantly with great caution and in reduced dosage 170 171 172 Some tranquilizers, especially phenothiazines, may antagonize opiate agonist analgesiae
Diuretics	Opiate agonists may decrease the effects of diuretics in patients with CHFe
Opiate partial agonists (butorphanol, nalbuphine, pentazocine)	Possible reduced analgesic effect and/or withdrawal symptoms169 170 171 172	Avoid concomitant use169 170 171 172
Skeletal muscle relaxants	May enhance the neuromuscular blocking action of skeletal muscle relaxants171 172 192 e

Morphine Sulfate 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 minutes^b 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 minutes^b 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

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Specialized references should be consulted for specific compatibility information.^b

Solution Compatibility^HID

Compatible
Dextran 6% in dextrose 5%
Dextran 6% in sodium chloride 0.9%
Dextrose–Ringer’s injection combinations
Dextrose–Ringer’s injection, lactated, combinations
Dextrose–saline combinations
Dextrose 2.5, 5, or 10% in water
Fructose 10% in sodium chloride 0.9%
Fructose 10% in water
Invert sugar 5 and 10% in sodium chloride 0.9%
Invert sugar 5 and 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

Admixture CompatibilityHID

Compatible
Alteplase
Atracurium besylate
Baclofen
Bupivacaine HCl
Bupivacaine HCI with clonidine HCI
Bupivacaine HCI with midazolam HCI
Dobutamine HCl
Fluconazole
Furosemide
Ketamine HCl
Meropenem
Metoclopramide HCl
Ondansetron HCl
Ropivacaine HCl
Succinylcholine chloride
Verapamil HCl
Incompatible
Aminophylline
Amobarbital sodium
Chlorothiazide sodium
Floxacillin sodium
Fluorouracil
Heparin sodium
Meperidine HCl
Phenobarbital sodium
Phenytoin sodium
Sodium bicarbonate
Thiopental sodium

Y-Site CompatibilityHID

Compatible
Aldesleukin
Allopurinol sodium
Amifostine
Amikacin sulfate
Aminophylline
Amiodarone HCl
Ampicillin sodium
Ampicillin sodium–sulbactam sodium
Amsacrine
Argatroban
Atenolol
Atracurium besylate
Atropine sulfate
Aztreonam
Bivalirudin
Bumetanide
Calcium chloride
Cefazolin sodium
Cefotaxime sodium
Cefoxitin sodium
Ceftazidime
Ceftizoxime sodium
Ceftriaxone sodium
Cefuroxime sodium
Chloramphenicol sodium succinate
Cisplatin
Cladribine
Clindamycin phosphate
Co-trimoxazole
Cyclophosphamide
Cytarabine
Dexamethasone sodium phosphate
Diazepam
Digoxin
Diltiazem HCl
Diphenhydramine HCl
Dobutamine HCl
Docetaxel
Dopamine HCl
Doxorubicin HCl
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
Hydroxyzine HCl
Kanamycin sulfate
Ketorolac tromethamine
Labetalol HCl
Levofloxacin
Lidocaine HCl
Linezolid
Lorazepam
Magnesium sulfate
Melphalan HCl
Meropenem
Methotrexate sodium
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
Pancuronium bromide
Pantoprazole sodium
Pemetrexed disodium
Penicillin G potassium
Phenobarbital sodium
Piperacillin sodium–tazobactam sodium
Potassium chloride
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
Vitamin B complex with C
Warfarin sodium
Zidovudine
Incompatible
Amphotericin B cholesteryl sulfate complex
Azithromycin
Doxorubicin HCl liposome injection
Gallium nitrate
Lansoprazole
Phenytoin sodium
Sargramostim
Variable
Acyclovir sodium
Cefepime HCI
Furosemide
Propofol
Thiopental sodium

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}

• Importance of informing patients that morphine should not be combined with alcohol or other CNS depressants (e.g., sleep medications, tranquilizers).^{169 170 171 172}

• 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}

• 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}

• Importance of informing patients of other important precautionary information. (See Cautions.)^{169 170 171 172}

• 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.

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.

Morphine Sulfate

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

Morphine Sulfate Liposomal

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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2013. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

AVINza 120MG 24-hr Capsules (KING PHARMA): 20/$276.00 or 30/$414.00

AVINza 30MG 24-hr Capsules (KING PHARMA): 20/$97.99 or 30/$146.98

AVINza 60MG 24-hr Capsules (KING PHARMA): 20/$182.99 or 30/$274.49

AVINza 90MG 24-hr Capsules (KING PHARMA): 20/$268.00 or 30/$401.99

Embeda 20-0.8MG Controlled-release Capsules (KING PHARMA): 20/$96.99 or 30/$144.98

Embeda 50-2MG Controlled-release Capsules (KING PHARMA): 30/$239.98 or 90/$699.99

Kadian 30MG 24-hr Capsules (ACTAVIS KADIAN): 20/$118.98 or 30/$178.97

Kadian 50MG 24-hr Capsules (ACTAVIS KADIAN): 20/$203.99 or 30/$305.96

Kadian 60MG 24-hr Capsules (ACTAVIS KADIAN): 20/$212.99 or 30/$318.96

Morphine Sulfate 15MG/ML Solution (WEST-WARD): 20/$19.99 or 30/$29.99

Morphine Sulfate 15MG Tablets (GLENMARK PHARMACEUTICALS): 20/$12.99 or 30/$16.99

Morphine Sulfate 20MG/5ML Solution (ROXANE): 500/$65.03 or 1500/$195.09

Morphine Sulfate 30MG Tablets (ROXANE): 20/$12.99 or 30/$14.99

Morphine Sulfate CR 100MG 12-hr Tablets (MALLINCKRODT PHARM): 20/$86.66 or 30/$129.99

Morphine Sulfate CR 15MG 12-hr Tablets (MALLINCKRODT PHARM): 30/$28.05 or 90/$84.16

Morphine Sulfate CR 200MG 12-hr Tablets (ENDO PHARMACEUTICALS): 100/$896.53 or 300/$2,689.59

Morphine Sulfate CR 30MG 12-hr Tablets (MALLINCKRODT PHARM): 30/$48.99 or 90/$146.96

Morphine Sulfate CR 60MG 12-hr Tablets (ENDO PHARMACEUTICALS): 20/$59.99 or 30/$89.99

MS Contin 100MG 12-hr Tablets (PURDUE PHARMA L.P.): 20/$194.40 or 30/$291.59

MS Contin 15MG 12-hr Tablets (PURDUE PHARMA L.P.): 20/$48.59 or 30/$72.89

MS Contin 200MG 12-hr Tablets (PURDUE FREDERICK): 20/$326.42 or 30/$489.62

MS Contin 30MG 12-hr Tablets (PURDUE PHARMA L.P.): 20/$74.51 or 30/$111.77

MS Contin 60MG 12-hr Tablets (PURDUE PHARMA L.P.): 20/$132.83 or 30/$199.24