Morphine Sulfate

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

Special Alerts:

[Posted 01/10/2011] ISSUE: Roxane Laboratories and FDA notified healthcare professionals of serious adverse events and deaths resulting from accidental overdose of morphine sulfate oral solutions, especially when using the high potency 100 mg/5mL product. In most of these cases, morphine sulfate oral solutions ordered in milligrams (mg) were mistakenly interchanged for milliliters (mL) of the product. The approval of this product is part of FDA’s unapproved drugs initiative. Prior to the recent approval, Roxane marketed a morphine sulfate oral solution with the strength expressed as 20 mg/mL, using a container label and carton labeling that had brown lettering on a white background. The newly approved product labeling and packaging feature revisions intended to reduce the risk of medication errors.

BACKGROUND: Morphine Sulfate Oral Solution 100 mg per 5 mL (20 mg/mL) is indicated for relief of moderate to severe acute and chronic pain in opioid-tolerant patients.

RECOMMENDATION: See Roxane’s “Dear Healthcare Professional Letter” for a complete description and photos of labeling and product packaging changes. Changes include:

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  A warning stating “ONLY FOR USE IN PATIENTS WHO ARE OPIOID TOLERANT” is displayed in a box to highlight that the morphine sulfate oral solution 100 mg per 5 mL (20 mg/mL) is indicated for use in opioid-tolerant patients only. The 100 mg per 5 mL concentration of morphine sulfate may cause fatal respiratory depression when administered to patients not previously exposed to opioids.

  
  


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  The strength is presented as 100 mg per 5 mL followed by a less prominently displayed concentration of (20 mg/mL). The intent of this designation is to help differentiate this product from the 20 mg/5 mL morphine sulfate product.

  
  


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  A bright yellow background is used on multiple sides of this product to differentiate the morphine sulfate oral solution 100 mg per 5 mL (20 mg/mL) from other morphine sulfate oral solutions marketed by Roxane with a white background.

  
  


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  The drug name, strength and concentration are displayed in white lettering on a red background as an additional means of differentiating this product from other concentrations of morphine sulfate oral solutions.

  
  


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  A reminder is presented to the pharmacist to dispense the product to each patient with the enclosed Medication Guide.

  
  


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  Both the 30 mL and 120 mL bottles of morphine sulfate 100 mg per 5 mL (20 mg/mL) oral solution are packaged with a calibrated oral syringe to provide accurate dose measurements. Healthcare providers should read the instructions in the Medication Guide that describe the correct use of the oral syringe in order to help prevent medication errors from occurring.

  
  


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  Healthcare providers should discuss the correct use of the oral syringe with their patients.

  
  

For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for morphine to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of morphine and consists of the following: medication guide and communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

• 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}

  
  

Introduction

Opiate agonist; phenanthrene derivative.^b

Uses for Morphine Sulfate

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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 Serious adverse events and deaths have occurred as a result of inadvertent overdosage of concentrated morphine oral solutions.¹⁸² 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

To avoid medication errors, at least one manufacturer recommends that the prescriber 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

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

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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