Usual Adult Dose for Pain

Individualize dosing regimen taking into account severity of pain, response to therapy, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse:

ORAL:
Immediate-release (IR):
OPIOID-NAIVE and OPIOID NON-TOLERANT:

• IR tablets: Initial dose: 15 to 30 mg orally every 4 hours as needed to manage pain
• IR oral solution: Initial dose: 10 to 20 mg orally every 4 hours as needed to manage pain

TITRATION AND MAINTENANCE: Individually titrate to a dose that provides an appropriate balance between pain management and opioid-related adverse reactions
IMPORTANT NOTE: Oral solution is available in 3 concentrations 2 mg/mL, 4 mg/mL, and 20 mg/mL; reserve use of 20 mg/mL concentration for patients who are opioid-tolerant

PARENTERAL:
IV: 0.1 mg to 0.2 mg/kg via slow IV injection every 4 hours as needed to manage pain; alternatively, 2 to 10 mg IV (based on 70 kg adult)
IM: 10 mg IM every 4 hours as needed to manage pain (based on 70 kg adult)
TITRATION AND MAINTENANCE: Individually titrate to a dose that provides an appropriate balance between pain management and opioid-related adverse reactions
IMPORTANT NOTE: IM administration is not the recommended route of administration due to its painful administration, wide fluctuations in muscle absorption, 30 to 60-minute lag to peak effect, and rapid fall off of action compared to oral administration

CONVERSION from Parenteral to Oral Morphine:

• Between 3 and 6 mg of oral morphine provides pain relief equivalent to 1 mg of parenteral morphine

PATIENT CONTROLLED ANALGESIA (PCA): For use in a compatible infusion device; patient must be closely monitored because of the considerable variability in both dose requirements and patient response. Mean morphine self-administration rate during clinical trials was 1 to 10 mg/hour during clinical trials. The following is provided as guidance; doses should be individualized:

• Loading dose: 2.5 mg
• Demand dose: 0.5 to 2 mg
• Lockout: 10-minute

Maximum Dosing: Opioid Naive: 10 mg/hour; Opioid Tolerant: 30 mg/hour, although greater rates may be needed in select patients

Epidural Administration:

• Initial dose: 5 mg in the lumbar region may provide satisfactory pain relief for up to 24 hours
• If adequate pain relief is not achieved within 1-hour, doses of 1 to 2 mg may be given at intervals sufficient to assess effectiveness

Maximum dose: 10 mg per 24 hours

Intrathecal Administration: Dosage is usually one-tenth that of epidural dosage

• Initial dose: 0.2 to 1 mg may provide satisfactory pain relief for up to 24 hours
• Repeated intrathecal injections are not recommended
• A constant intravenous infusion of naloxone 0.6 mg/hr for 24 hours may be used to reduce the incidence of potential side effects

Comments:

• Monitor closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and with all dose increases.
• Because of the risks of addiction, abuse, and misuse with opioids, reserve use for patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

Use: For the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Usual Adult Dose for Chronic Pain

Individualize dosing regimen taking into account severity of pain, response to therapy, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse: A single dose greater than 60 mg, a total daily dose greater than 120 mg, and the 20 mg/mL oral solution should be restricted to use in opioid-tolerant patients only:

ORAL:
Immediate-release (IR):
OPIOID-NAIVE and OPIOID NON-TOLERANT:

• IR tablets: Initial dose: 15 to 30 mg orally every 4 hours
• IR oral solution: Initial dose: 10 to 20 mg orally every 4 hours

TITRATION AND MAINTENANCE: Individually titrate to a dose that provides an appropriate balance between pain management and opioid-related adverse reactions; when using IR formulations for chronic pain, doses should be scheduled around the clock, or consider switching to an ER formulation

CONVERSION of Immediate-Release to Extended-Release: At a given dose, the same total amount of morphine is available from an IR and ER formulation, however, conversion to an equivalent daily dose of an ER formulation could lead to excessive sedation at peak serum levels; monitor closely for signs of excessive sedation and respiratory depression

Extended-release (ER):

• ER Tablets (OPIOID-NAIVE and OPIOID NON-TOLERANT): Initial dose: 15 mg orally every 8 or 12 hours
• ER Capsules (OPIOID NAIVE): Begin treatment with an immediate-release morphine
• ER Capsules (OPIOID NON-TOLERANT): Initial dose: 30 mg orally every 24 hours

TITRATION AND MAINTENANCE: Adjust dose every 1 to 2 days as needed to obtain an appropriate balance between pain management and opioid-related adverse reactions; for patients experiencing inadequate analgesia with once a day ER capsules or twice a day ER tablets, may consider increasing dose frequency to every 12 hours for ER capsules or every 8 hours for ER tablets; goal should be to find the lowest effective dosage for the shortest duration consistent with individual patient treatment goals

IMPORTANT NOTES:

• Parenteral to Oral Morphine Ratio: 1 mg parenteral morphine provides analgesia equivalent to between 2 and 6 mg of oral morphine
• ER formulations are not bioequivalent and therefore, not interchangeable

CONVERSIONS from Other Opioids:

• Discontinue all other around-the-clock opioid drugs when initiating ER morphine
• Opioid equivalent tables will be helpful to guide conversion, but it should be understood that wide inter-patient variability in the potency of opioid drugs and formulations is not accounted for in these tables; conversions should be done carefully and with close monitoring for signs and symptoms of opioid withdrawal, over sedation, and toxicity
• When converting between different opioids or different formulations, it is safer to underestimate the 24-hour dose and provide rescue medication than to overestimate and manage an overdose

SUPPOSITORY:
Usual Adult Dose: 10 to 20 mg rectally every 4 hours

• Dose should be individualized

Comments:

• Monitor closely for respiratory depression, especially within the first 24 to 72 hours of initiating therapy and with all dose increases.
• Use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression with first dose; initial dose selection should take into account degree of opioid tolerance, patient's general condition, medical status, concurrent medications, type and severity of pain, and risk factors for abuse, addiction, or diversion.
• Opioid tolerant patients are those who have received for 1 week or longer: oral morphine 60 mg/day; transdermal fentanyl 25 mcg/hr; oral oxycodone 30 mg/day; oral hydromorphone 8 mg/day; oral oxymorphone 25 mg/day or an equianalgesic dose of another opioid.
• Extended-release products are reserved for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain; these products are not intended to be used as as-needed (prn) analgesics.

Use: For the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

NEURAXIAL ADMINISTRATION: Patients must be observed in a fully equipped and staffed environment for at least 24 hours after each test dose and, as appropriate, for the first several days after catheter implantation

• Dose must be individualized based upon in-hospital evaluation
• For Epidural Administration: Initial dose: 3.5 to 7.5 mg/day (opioid non-tolerant) or 4.5 to 10 mg/day (some degree of opioid tolerance); dose requirements may increase significantly during treatment; daily dose limit for each patient must be individualized
• For Intrathecal Administration: Initial dose: 0.2 to 1 mg/day (opioid non-tolerant) or 1 to 10 mg/day (some degree of opioid tolerance); daily dose limit for each patient must be individualized. NOTE: Intrathecal dose is usually one-tenth that of epidural dose

Uses: For the management of pain severe enough to require opioid analgesia by epidural or intrathecal management without attendant loss of motor, sensory, or sympathetic function.

• DURAMORPH(R) is NOT for use in continuous microinfusion devices
• INFUMORPH(R) is for use in continuous microinfusion devices

Usual Pediatric Dose for Pain

The safety and efficacy of this drug in patients younger than 18 years have not been established however, this drug is used in clinical practice. The following should be considered guidance (off-label):

Less than 6 months (not mechanically ventilated): Initial dose: 0.025 to 0.03 mg/kg IV or 0.075 to 0.09 mg/kg orally every 4 to 6 hours as needed to manage pain
6 months or older; weight less than 45 kg: 0.1 mg/kg IV or 0.3 mg/kg orally every 4 to 6 hours as needed to manage pain
6 months or older; weight 45 kg or more:

• Immediate-release tablets: Initial dose: 15 to 30 mg orally every 4 hours as needed to manage pain
• Immediate-release oral solution: Initial dose: 10 to 20 mg orally every 4 hours as needed to manage pain

TITRATION AND MAINTENANCE: Individually titrate to a dose that provides an appropriate balance between pain management and opioid-related adverse reactions.

PATIENT CONTROLLED ANALGESIA (PCA):

• Children should demonstrate the ability to use PCA; most 7-year olds are able to use the PCA device correctly.
• For use in a compatible infusion device; patient must be closely monitored because of the considerable variability in both dose requirements and patient response. Mean morphine self-administration rate during clinical trials was 1 to 10 mg/hour during clinical trials. The following is provided as guidance; doses should be individualized:
• Loading dose: 2.5 mg
• Demand dose: 0.5 to 2 mg
• Lockout: 10-minute

Maximum Dosing: Opioid Naive: 10 mg/hour; Opioid Tolerant: 30 mg/hour, although greater rates may be needed in select patients

Comments:

• For pediatric patients older than 6 months, the clinical effects and pharmacokinetics of opioids are similar to adults; however, there is limited evidence regarding the long-term neurocognitive effects of short-term opioid analgesic use.

Usual Pediatric Dose for Neonatal Abstinence Syndrome

The optimal treatment approach for managing neonatal abstinence syndrome (NAS) continues to be investigated; pharmacologic management often includes morphine. The following should be considered guidance (off-label) as other protocols may be as effective:

WEIGHT-BASED DOSING:
Initial dose: 0.04 mg/kg orally every 3 to 4 hours

• Titrate in increments of 0.04 mg/kg/dose

Maximum dose: 0.2 mg/kg

SYMPTOM-BASED DOSING (Neonatal Abstinence Syndrome [NAS] Score):

• NAS Score 9 to 12; Dose: 0.04 mg orally every 4 hours
• NAS Score 13 to 16; Dose: 0.08 mg orally every 4 hours
• NAS Score 17 to 20; Dose: 0.12 mg orally every 4 hours
• NAS Score 21 to 24; Dose: 0.16 mg orally every 4 hours
• NAS Score greater than 25; Dose: 0.2 mg orally every 4 hours

WEANING: After 48 hours of Clinical Stability

• Reduce dose by 10% every 24 to 48 hours
• Cease therapy when dose is 0.15 mg/kg/day

Comments:

• Approximately 60% to 80% of neonates with NAS may not respond to nonpharmacologic treatment and will require medication.
• Pharmacologic treatment is initiated/titrated/weaned as part of an overall treatment strategy based on neonatal abstinence scores (e, g. Finnegan scores).
• The Finnegan scoring system has been standardized for use in term infants; its use in preterm or older infants should be considered not standardized; additionally, significant intra-observer variability has been documented.

Use: For the pharmacologic treatment of neonatal abstinence syndrome in accordance with treatment protocols developed by neonatology experts.

Renal Dose Adjustments

Use with caution; start with a lower initial dose, titrate slowly, and monitor closely

Liver Dose Adjustments

Use with caution; start with a lower initial dose, titrate slowly, and monitor closely

Dose Adjustments

Elderly: Due to increased sensitivity to drug effects, start at the lower end of the dosing range, titrate slowly, and closely monitor

Debilitated patients, and patients with impaired respiratory function: May need to reduce dose initial dose by up to one-half, titrate slowly, and closely monitor

Dosage reductions may be required with concomitant CNS depressant therapy

Appropriate precaution is necessary if used for postoperative pain; as with all opioids, extreme caution is needed following abdominal surgery

Discontinuation:

• Gradually withdraw dose in the physically dependent patient.
• Taper dose by 25% to 50% every 2 to 4 days, while monitoring for signs and symptoms of withdrawal.
• If signs or symptoms of withdrawal develop, raise the dose to the previous level and taper more slowly.

Precautions

The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for all opioids intended for outpatient use. The new FDA Opioid Analgesic REMS is a designed to assist in communicating the serious risks of opioid pain medications to patients and health care professionals. It includes a medication guide and elements to assure safe use. For additional information: www.accessdata.fda.gov/scripts/cder/rems/index.cfm

US BOXED WARNINGS:
ADDICTION, ABUSE, and MISUSE: This drug exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing, and monitor all patients regularly for the development of these behaviors or conditions.
RISK EVALUATION AND MITIGATION STRATEGY (REMS): To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, a REMS is required for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to complete a REMS-compliant education program; counsel patients and/or their caregivers, with every prescription on safe use, serious risks, storage, and disposal of these products; emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and consider other tools to improve patient, household, and community safety.
LIFE-THREATENING RESPIRATORY DEPRESSION: Serious, life-threatening, or fatal respiratory depression may occur. Monitor for respiratory depression, especially during initiation and following any dose increases. Instruct patients to swallow extended-release tablets whole; crushing, chewing, or dissolving tablets can cause rapid release and absorption of a potentially fatal dose of morphine.
ACCIDENTAL INGESTION: Accidental ingestion of just 1 dose, especially by children, can result in a fatal overdose of morphine.
NEONATAL OPIOID WITHDRAWAL SYNDROME: Prolonged use of this drug during pregnancy may result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated; treatment requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS: Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant use for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required, and follow patients for signs and symptoms of respiratory depression.
INTERACTION WITH ALCOHOL: Instruct patients not to consume alcoholic beverages or use prescription or nonprescription products that contain alcohol while taking morphine extended-release capsules; the co-ingestion of alcohol may result in increased plasma levels and a potentially fatal overdose of morphine.
RISKS OF MEDICATION ERRORS: Ensure accuracy when prescribing, dispensing, and administering Oral Solution; dosing errors due to confusion between mg and mL, and other morphine sulfate Oral Solutions of different concentrations can result in accidental overdose and death.
RISKS WITH NEURAXIAL ADMINISTRATION: Because of the risk of severe adverse reactions when administered by the epidural or intrathecal route of administration, patients must be observed in a fully equipped and staffed environment for at least 24 hours after the initial (single) test dose and, as appropriate, for the first several days after catheter implantation.

CONTRAINDICATIONS:

• Significant respiratory depression
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
• Concurrent use, or within 14 days of monoamine oxidase inhibitors (MAOIs)
• Known or suspected gastrointestinal obstruction, including paralytic ileus
• Hypersensitivity (e.g., anaphylaxis) to morphine
• Surgical anastomosis (suppository)
• Infection at the injection microinfusion site (neuraxial administration)
• Concomitant anticoagulant therapy (neuraxial administration)
• Uncontrolled bleeding diathesis (neuraxial administration)
• The presence of any other concomitant therapy or medical condition which would render epidural or intrathecal administration of medication especially hazardous (neuraxial administration)

Safety and efficacy have not been established in in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

US Controlled Substance: Schedule II

Dialysis

Data not available

Other Comments

Administration advice:
To Avoid Medication Errors:

• Ensure accuracy in dosing by verifying dose in both mg and mL
• Ensure accuracy in dispensing and administering by confirming the appropriate concentration/strength is chosen for the opiate-naive patient

ORAL SOLUTION: There are 3 concentrations available (2 mg/mL, 4 mg/mL, and 20 mg/mL); reserve use of 20 mg/mL concentration for patients who are opioid-tolerant

• Measure dose with an appropriately calibrated measuring device

EXTENDED-RELEASE CAPSULES: Take orally once or twice a day

• Swallow whole; crushing, chewing, or dissolving pellets will result in uncontrolled delivery of morphine and can lead to overdose
• For patients unable to swallow capsules whole, may open capsules and sprinkle contents on applesauce, swallow immediately without chewing
• Avoid alcohol: There is data to show the presence of alcohol increases the rate of release of morphine from the sustained-release pellets in the capsule
• French Gastrostomy Tube: Flush gastrostomy tube with water to ensure that it is wet; open extended-release capsule and sprinkle pellets into 10 mL of water; using a swirling motion pour pellets through a funnel into gastrostomy tube; rinse and repeat until no pellets remain
• Do not administer pellets through a nasogastric tube

EXTENDED-RELEASE-TABLETS: Take orally every 8 or 12 hours

• Swallow whole, 1 tablet at a time; do not pre-moisten, cut, break, crush, chew, or dissolve as that will result in uncontrolled delivery of morphine and can lead to overdose

INTRAVENOUS: Administer by slow IV injection; rapid IV administration may result in chest wall rigidity
INTRAMUSCULAR:

• Auto-Injectors: The spring-driven injection mechanism is capable of inflicting injury if accidentally misused; keep product in its original container with safety in place until use
• Caution must be used when injecting any opioid IM into chilled areas or in patients with hypotension or shock, since impaired perfusion may prevent complete absorption; if repeated injections are administered, an excessive amount may be suddenly absorbed if normal circulation is re-established.
• IM administration is generally not the recommended route of administration due to its painful administration, wide fluctuations in muscle absorption, 30 to 60-minute lag to peak effect, and rapid fall in analgesia compared to oral administration

PATIENT CONTROLLED ANALGESIA (PCA): Preservative-free morphine injection should be used with a compatible PCA pump set with injector and a compatible infusion device; multiple concentrations are available for use with PCA infusion device (0.5, 1 and 5 mg/mL); the manufacturer product information should be consulted for additional information
NEURAXIAL Administration:

• Neuraxial administration may result in acute or delayed respiratory depression up to 24 hours; patients must be observed in a fully equipped and staffed environment for at least 24 hours and longer as clinically appropriate
• Duramorph(R): Not for use in continuous microinfusion devices
• Infumorph(R): For use in continuous microinfusion devices and indicated only for intrathecal or epidural infusion; not for single-dose injection because it is too concentrated
• For safety reasons, it is recommended that administration by the epidural or intrathecal routes be limited to the lumbar area
• The manufacturer product information should be consulted for additional information.

Storage requirements:

• Parenteral products: Protect from light; do not freeze; do not heat-sterilize

General:

• Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.
• Initial dose recommendations should not be exceeded as this could result in an overdose with the first dose.
• Conversion from other opioids and between morphine formulations should be done cautiously and with increased monitoring as individuals have been shown to exhibit a wide variability to the potency of other opioid drugs and morphine formulations that cannot be accounted for with conversion tables.

Monitoring:

• Cardiovascular: Monitor for signs of hypotension upon initiating therapy and following dose increases, especially those whose blood pressure is compromised
• Respiratory: Monitor for respiratory depression, especially within the first 24 to 72 hours of initiation and with dose increases.
• Gastrointestinal: Monitor for constipation and decreased bowel motility
• General: Monitor routinely for maintenance of pain control and incidence of adverse reactions.
• Psychiatric: Patients should be monitored for the development of addiction, abuse, or misuse.

Patient advice:

• Patients should be instructed to read the US FDA-approved Medication Guide each time this drug is dispensed; they should understand the safe use, serious risks, and proper storage and disposal of this drug.
• Advise patients to store this drug safely out of the sight and reach of children; accidental use by a child is a medical emergency and can result in death.
• Patients should understand that this drug, even when taken as recommended can result in addiction, abuse, and misuse; instruct patients not to share their drug with others and protect from theft or misuse.
• Patients should understand the risks of life-threatening respiratory depression and be informed as to when this risk is greatest; patients should be advised to avoid alcoholic beverages, CNS depressant medications, or respiratory depressant medications unless supervised by a healthcare professional.
• This drug may cause drowsiness, dizziness, or impair thinking or motor skills; patients should avoid driving or operating machinery during therapy.
• Women of child bearing potential should understand that prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome and that prompt recognition and treatment will be necessary.

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