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Morphine Sulfate
(MOR feen SUL fate)
U.S. Brand Names
Astramorph/PF™; Avinza™; DepoDur™; Duramorph®; Infumorph®; Kadian®; MS Contin®; MSIR®; Oramorph SR®; RMS®; Roxanol™; Roxanol 100™; Roxanol™-T
Generic Available
Yes: Excludes capsule, controlled release tablet, sustained release tablet, extended release liposomal suspension for injection
Canadian Brand Names
Kadian®; M-Eslon®; Morphine HP®; Morphine LP® Epidural; M.O.S.-Sulfate®; MS Contin®; MS-IR®; PMS-Morphine Sulfate SR; ratio-Morphine SR; Statex®
Use
Relief of moderate to severe acute and chronic pain; relief of pain of myocardial infarction; relief of dyspnea of acute left ventricular failure and pulmonary edema; preanesthetic medication
DepoDur™: Epidural (lumbar) single-dose management of surgical pain
Orphan drug: Infumorph™: Used in microinfusion devices for intraspinal administration in treatment of intractable chronic pain
Restrictions
C-II
Pregnancy Risk Factor
C/D (prolonged use or high doses at term)
Pregnancy Implications
Morphine crosses the placenta. The frequency of congenital malformations has not been reported to be greater than expected in children from mothers treated with morphine during pregnancy. Reduced growth and behavioral abnormalities in offspring have been observed in animal studies. Neonates born to mothers receiving chronic opioids during pregnancy should be monitored for neonatal withdrawal syndrome.
DepoDur™ may be used in women undergoing cesarean section following clamping of the umbilical cord; not for use in vaginal labor and delivery.
Lactation
Enters breast milk/use caution (AAP rates "compatible")
Contraindications
Hypersensitivity to morphine sulfate or any component of the formulation; increased intracranial pressure; severe respiratory depression (in absence of resuscitative equipment or ventilatory support); acute or severe asthma; known or suspected paralytic ileus (sustained release products only); sustained release products are not recommended in acute/postoperative pain; pregnancy (prolonged use or high doses at term)
Warnings/Precautions
An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients. Doses should be titrated to pain relief/prevention. When used as an epidural injection, monitor for delayed sedation.
May cause respiratory depression; use with caution in patients with impaired respiratory function or severe hepatic dysfunction and in patients with hypersensitivity reactions to other phenanthrene derivative opioid agonists (codeine, hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone). Infants <3 months of age are more susceptible to respiratory depression, use with caution and generally in reduced doses in this age group. May cause hypotension in patients with acute myocardial infarction. Tolerance or drug dependence may result from extended use. MS Contin® 200 mg tablets are for use only in opioid-tolerant patients requiring >400 mg/day. Infumorph® solutions are for use in microinfusion devices only ; not for I.V., I.M., or SubQ administration.
Use caution in CNS depression, toxic psychosis, delirium tremens, or convulsive disorders. Sedation and psychomotor impairment are likely, and are additive with other CNS depressants or ethanol. Extended or sustained release dosage forms should not be crushed or chewed. Controlled-, extended-, or sustained-release products are not intended for "as needed (PRN)" use. Some preparations contain sulfites which may cause allergic reactions.
Use caution in renal impairment (metabolite accumulation); use caution in gastrointestinal motility disturbances (particularly with sustained release preparations), thyroid disorders (Addison's disease, myxedema, or hypothyroidism), prostatic hyperplasia, or urethral stricture.
Elderly and/or debilitated may be particularly susceptible to the CNS depressant and constipating effects of narcotics. May mask diagnosis or clinical course in patients with acute abdominal conditions.
Adverse Reactions
Note: Percentages are based on a study in 19 chronic cancer pain patients ( J Pain Symptom Manage, 1995, 10:416-22). Chronic use of various opioids in cancer pain is accompanied by similar adverse reactions; individual patient differences are unpredictable, and percentage may differ in acute pain (surgical) treatment.
Frequency not defined: Flushing, CNS depression, sedation, antidiuretic hormone release, physical and psychological dependence, diaphoresis
>10%:
Cardiovascular: Palpitations, hypotension, bradycardia
Central nervous system: Drowsiness (48%, tolerance usually develops to drowsiness with regular dosing for 1-2 weeks); dizziness (20%); confusion
Dermatologic: Pruritus (may be secondary to histamine release)
Gastrointestinal: Nausea (28%, tolerance usually develops to nausea and vomiting with chronic use); vomiting (9%); constipation (40%, tolerance develops very slowly if at all); xerostomia (78%)
Genitourinary: Urinary retention (16%)
Local: Pain at injection site
Neuromuscular & skeletal: Weakness
Miscellaneous: Histamine release
1% to 10%:
Central nervous system: Restlessness, headache, false feeling of well being
Gastrointestinal: Anorexia, GI irritation, paralytic ileus
Genitourinary: Decreased urination
Neuromuscular & skeletal: Trembling
Ocular: Vision problems
Respiratory: Respiratory depression, dyspnea
<1%: Anaphylaxis, intestinal obstruction, peripheral vasodilation, insomnia, mental depression, hallucinations, paradoxical CNS stimulation, intracranial pressure increased, biliary tract spasm, urinary tract spasm, muscle rigidity, miosis, liver function tests increased, transaminases increased
Overdosage/Toxicology
Symptoms of overdose include respiratory depression, miosis, hypotension, bradycardia, apnea, and pulmonary edema. Treatment is symptomatic. Naloxone, 2 mg I.V. with repeat administration as necessary up to a total dose of 10 mg, can be used to reverse opiate effects.
Drug Interactions
Substrate of CYP2D6 (minor)
Decreased effect: Diuretic effects may be decreased (due to antidiuretic hormone release).
Increased toxicity: CNS depressants, tricyclic antidepressants may potentiate the effects of morphine and other opiate agonists; dextroamphetamine may enhance the analgesic effect of morphine and other opiate agonists. Concurrent use of MAO inhibitors and meperidine has been associated with significant adverse effects. Use caution with morphine. Some manufacturers recommend avoiding use within 14 days of MAO inhibitors.
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may increase CNS depression).
Food: Administration of oral morphine solution with food may increase bioavailability (ie, a report of 34% increase in morphine AUC when morphine oral solution followed a high-fat meal). The bioavailability of Oramorph SR® does not appear to be affected by food.
Herb/Nutraceutical: Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).
Stability
Suppositories: Store at controlled room temperature 25°C (77°F). Protect from light.
Injection: Store at controlled room temperature. Protect from light. Degradation depends on pH and presence of oxygen; relatively stable in pH
4; darkening of solutions indicate degradation. Usual concentration for continuous I.V. infusion: 0.1-1 mg/mL in D5W.
DepoDur™: Store under refrigeration, 2°C to 8°C (36°F to 46°F); do not freeze. May store at room temperature for up to 7 days. DepoDur™ may be diluted in preservative-free NS to a volume of 5 mL. Once vial is opened, use within 4 hours.
Compatibility
Stable in dextran 6% in dextrose, dextran 6% in NS, D5LR, D5 1 /4NS, D5 1 /2NS, D5NS, D5W, D10W, LR, 1 /2NS, NS; variable stability (consult detailed reference) in TPN
Y-site administration: Compatible: Allopurinol, amifostine, amikacin, aminophylline, amiodarone, ampicillin, ampicillin/sulbactam, amsacrine, atenolol, atracurium, aztreonam, bumetanide, calcium chloride, cefamandole, cefazolin, cefoperazone, cefotaxime, cefotetan, cefoxitin, ceftazidime, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cisatracurium, cisplatin, cladribine, clindamycin, co-trimoxazole, cyclophosphamide, cytarabine, dexamethasone sodium phosphate, digoxin, diltiazem, dobutamine, docetaxel, dopamine, doxorubicin, doxycycline, enalaprilat, epinephrine, erythromycin lactobionate, esmolol, etomidate, etoposide phosphate, famotidine, fentanyl, filgrastim, fluconazole, fludarabine, foscarnet, gatifloxacin, gemcitabine, gentamicin, granisetron, heparin, hydrocortisone sodium succinate, hydromorphone, IL-2, insulin (regular), kanamycin, labetalol, levofloxacin, lidocaine, linezolid, lorazepam, magnesium sulfate, melphalan, meropenem, methotrexate, methyldopate, methylprednisolone sodium succinate, metoclopramide, metoprolol, metronidazole, midazolam, milrinone, nafcillin, nicardipine, nitroglycerin, norepinephrine, ondansetron, oxacillin, oxytocin, paclitaxel, pancuronium, penicillin G potassium, piperacillin, piperacillin/tazobactam, potassium chloride, propofol, propranolol, ranitidine, remifentanil, sodium bicarbonate, sodium nitroprusside, tacrolimus, teniposide, thiotepa, ticarcillin, ticarcillin/clavulanate, tobramycin, vancomycin, vecuronium, vinorelbine, vitamin B complex with C, warfarin, zidovudine. Incompatible: Alatrofloxacin, amphotericin B cholesteryl sulfate complex, cefepime, doxorubicin liposome, minocycline, sargramostim. Variable (consult detailed reference): Acyclovir, furosemide, thiopental, TPN
Compatibility in syringe: Compatible: Atropine, bupivacaine, bupivacaine with clonidine, butorphanol, cimetidine, dimenhydrinate, diphenhydramine, droperidol, fentanyl, glycopyrrolate, hydroxyzine, hyoscine, ketamine, ketamine with lidocaine, metoclopramide, midazolam, milrinone, ondansetron, pentazocine, perphenazine, promazine, ranitidine, salbutamol, scopolamine. Incompatible: Meperidine, thiopental. Variable (consult detailed reference): Chlorpromazine, haloperidol, heparin, pentobarbital, prochlorperazine edisylate, promethazine
Compatibility when admixed: Compatible: Alteplase, atracurium, baclofen, bupivacaine, dobutamine, fluconazole, furosemide, ketamine, meropenem, metoclopramide, ondansetron, succinylcholine, verapamil. Incompatible: Aminophylline, amobarbital, chlorothiazide, floxacillin, fluorouracil, heparin, meperidine, phenobarbital, phenytoin, sodium bicarbonate, thiopental
DepoDur™: Do not mix with other medications.
Mechanism of Action
Binds to opiate receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; produces generalized CNS depression
Pharmacodynamics/Kinetics
Onset of action: Oral: 1 hour; I.V.: 5-10 minutes
Duration: Pain relief:
Immediate release formulations: 4 hours
Extended release epidural injection (DepoDur™
: >48 hours
Absorption: Variable
Distribution: Binds to opioid receptors in the CNS and periphery (eg, GI tract)
Metabolism: Hepatic via conjugation with glucuronic acid to morphine-3-glucuronide (inactive), morphine-6-glucuronide (active), and in lesser amounts, morphine-3-6-diglucuronide; other minor metabolites include normorphine (active) and the 3-ethereal sulfate
Bioavailability: Oral: 17% to 33% (first-pass effect limits oral bioavailability; oralarenteral effectiveness reportedly varies from 1:6 in opioid naive patients to 1:3 with chronic use)
Half-life elimination: Adults: 2-4 hours (immediate release forms)
Excretion: Urine (primarily as morphine-3-glucuronide, ~2% to 12% excreted unchanged); feces (~7% to 10%). It has been suggested that accumulation of morphine-6-glucuronide might cause toxicity with renal insufficiency. All of the metabolites (ie, morphine-3-glucuronide, morphine-6-glucuronide, and normorphine) have been suggested as possible causes of neurotoxicity (eg, myoclonus).
Dosage
Note: These are guidelines and do not represent the maximum doses that may be required in all patients. Doses should be titrated to pain relief/prevention.
Children >6 months and <50 kg: Acute pain (moderate-to-severe):
Oral (prompt release): 0.15-0.3 mg/kg every 3-4 hours as needed
I.M.: 0.1 mg/kg every 3-4 hours as needed
I.V.: 0.05-0.1 mg/kg every 3-4 hours as needed
I.V. infusion: Range: 10-30 mcg/kg/hour
Adolescents >12 years: Sedation/analgesia for procedures: I.V.: 3-4 mg and repeat in 5 minutes if necessary
Adults: Acute pain (moderate-to-severe):
Oral: Prompt release formulations: Opiate-naive: Initial: 10 mg every 3-4 hours as needed; patients with prior opiate exposure may require higher initial doses: usual dosage range: 10-30 mg every 3-4 hours as needed
Oral: Controlled-, extended-, or sustained-release formulations: Note: A patient's morphine requirement should be established using prompt-release formulations. Conversion to long-acting products may be considered when chronic, continuous treatment is required. Higher dosages should be reserved for use only in opioid-tolerant patients.
Capsules, extended release (Avinza™: Daily dose administered once daily (for best results, administer at same time each day)
Capsules, sustained release (Kadian®: Daily dose administered once daily or in 2 divided doses daily (every 12 hours)
Tablets, controlled release (MS Contin®, sustained release (Oramorph SR®, or extended release: Daily dose divided and administered every 8 or every 12 hours
I.V.: Initial: Opiate-naive: 2.5-5 mg every 3-4 hours; patients with prior opiate exposure may require higher initial doses. Note: Repeated doses (up to every 5 minutes if needed) in small increments (eg, 1-4 mg) may be preferred to larger and less frequent doses.
I.V., SubQ continuous infusion: 0.8-10 mg/hour; may increase depending on pain relief/adverse effects: usual range: up to 80 mg/hour although higher doses may be required
Mechanically-ventilated patients (based on 70 kg patient): 0.7-10 mg every 1-2 hours as needed; infusion: 5-35 mg/hour
Patient-controlled analgesia (PCA): (Opiate-naive: Consider lower end of dosing range):
Usual concentration: 1 mg/mL
Demand dose: Usual: 1 mg; range: 0.5-2.5 mg
Lockout interval: 5-10 minutes
Epidural: Note: Administer with extreme caution and in reduced dosage to geriatric or debilitated patients.
Infusion:
Bolus dose: 1-6 mg
Infusion rate: 0.1-1 mg/hour
Maximum dose: 10 mg/24 hours
Single-dose (extended release, Depo-Dur™:
Cesarean section: 10 mg
Lower abdominal/pelvic surgery: 10-15 mg
Note: Some patients may benefit from a 20 mg dose, however, the incidence of adverse effects may be increased.
Intrathecal (I.T.): One-tenth of epidural dose; Note: Administer with extreme caution and in reduced dosage to geriatric or debilitated patients.
Opiate-naive: 0.2-1 mg/dose (may provide adequate relief for 24 hours); repeat doses not recommended except to establish initial IT dose.
I.M., SubQ: Note: Repeated SubQ administration causes local tissue irritation, pain, and induration.
Initial: Opiate-naive: 5-10 mg every 3-4 hours as needed; patients with prior opiate exposure may require higher initial doses; usual dosage range: 5-20 mg every 3-4 hours as needed
Rectal: 10-20 mg every 3-4 hours
Chronic pain: Patients taking opioids chronically may become tolerant and require doses higher than the usual dosage range to maintain the desired effect. Tolerance can be managed by appropriate dose titration. There is no optimal or maximal dose for morphine in chronic pain. The appropriate dose is one that relieves pain throughout its dosing interval without causing unmanageable side effects.
Elderly or debilitated patients: Use with caution; may require dose reduction
Dosing adjustment in renal impairment:
Clcr 10-50 mL/minute: Administer at 75% of normal dose
Clcr<10 mL/minute: Administer at 50% of normal dose
Dosing adjustment/comments in hepatic disease: Unchanged in mild liver disease; substantial extrahepatic metabolism may occur; excessive sedation may occur in cirrhosis
Administration
Oral: Do not crush controlled release drug product, swallow whole. Kadian® can be opened and sprinkled on applesauce. Avinza™ can also be opened and sprinkled on applesauce; do not crush or chew the beads. Administration of oral morphine solution with food may increase bioavailability (not observed with Oramorph SR®.
I.V.: When giving morphine I.V. push, it is best to first dilute in 4-5 mL of sterile water, and then to administer slowly (eg, 15 mg over 3-5 minutes)
Epidural: Use preservative-free solutions
Epidural, extended release liposomal suspension (DepoDur™: May be administered undiluted or diluted up to 5 mL total volume in preservative-free NS. Do not use an in-line filter during administration. Not for I.V. or I.M. administration.
Resedation may occur following epidural administration; this may be delayed
48 hours in patients receiving extended-release (DepoDur™ injections.
Administration of an epidural test dose (lidocaine 1.5% and epinephrine 1:200,000) may affect the release of morphine from the liposomal preparation. Delaying the dose for an interval of at least 15 minutes following the test dose minimizes this pharmacokinetic interaction. Except for a test dose, other epidural local anesthetics should not be used before or after this product.
Intrathecal: Use preservative-free solutions
Monitoring Parameters
Pain relief, respiratory and mental status, blood pressure
Infumorph®: Patients should be observed in a fully-equipped and staffed environment for at least 24 hours following initiation, and as appropriate for the first several days after catheter implantation.
Reference Range
Therapeutic: Surgical anesthesia: 65-80 ng/mL (SI: 227-280 nmol/L); Toxic: 200-5000 ng/mL (SI: 700-17,500 nmol/L)
Dietary Considerations
Morphine may cause GI upset; take with food if GI upset occurs. Be consistent when taking morphine with or without meals.
Patient Education
If self-administered, use exactly as directed; do not increase dose or frequency. Do not crush or chew controlled release tablets. May cause physical and/or psychological dependence. While using this medication, do not use alcohol and other prescription or OTC medications (especially sedatives, tranquilizers, antihistamines, or pain medications) without consulting prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. May cause hypotension, dizziness, drowsiness, impaired coordination, or blurred vision (use caution when driving, climbing stairs, or changing position - rising from sitting or lying to standing, or when engaging in tasks requiring alertness until response to drug is known); loss of appetite, nausea, or vomiting (frequent mouth care, small, frequent meals, chewing gum, or sucking lozenges may help); or constipation (increased exercise, fluids, fruit, or fiber may help; if unresolved, consult prescriber about use of stool softeners and/or laxatives). Report chest pain, slow or rapid heartbeat, acute dizziness, or persistent headache; changes in mental status; swelling of extremities or unusual weight gain; changes in urinary elimination or pain on urination; acute headache; back or flank pain; muscle spasms; blurred vision; skin rash; or shortness of breath. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. If you are breast-feeding, take medication immediately after breast-feeding or 3-4 hours prior to next feeding.
Anesthesia and Critical Care Concerns/Other Considerations
When developing a therapeutic plan for pain control, scheduled, intermittent opioid dosing or continuous infusion is preferred over the "as needed" regimen. The 2002 ACCM/SCCM guidelines for analgesia (critically-ill adult) recommend fentanyl in patients who need immediate pain relief because of its rapid onset of action; fentanyl or hydromorphone is preferred in patients who are hypotensive or have renal dysfunction. Morphine or hydromorphone is recommended for intermittent, scheduled therapy. Both have a longer duration of action requiring less frequent administration. If the patient has required high-dose analgesia or has used for a prolonged period (~7 days), taper dose to prevent withdrawal; monitor for signs and symptoms of withdrawal. Use only preservative-free injections for epidural or intrathecal administration; less adverse effects are associated with epidural compared to intrathecal route of administration.
Cardiovascular Considerations
Morphine may be used for pain relief after myocardial infarction. It is important that the risk for respiratory depressant effects of morphine be considered. Morphine may cause constipation which may be problematic in patients with unstable angina, and patients after myocardial infarction. The hemodynamic responses to valsalva-like maneuvers due to straining may have adverse cardiovascular consequences in patients with critical coronary artery disease.
In the treatment of unstable angina/non-ST-segment elevation MI, morphine sulfate is recommended when symptoms are not relieved with nitroglycerin or when acute pulmonary edema and/or agitation are present, in the absence of contraindications.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation). Anticholinergic side effects can cause a reduction of saliva production or secretion, contributing to discomfort and dental disease (ie, caries, oral candidiasis, and periodontal disease).
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
Sedation is common; may cause dizziness, restlessness, confusion; may rarely cause insomnia, depression, or hallucinations
Mental Health: Effects on Psychiatric Treatment
Concurrent use with psychotropics may produce an increase or decrease in morphine's effect; monitor for clinical changes
Oncology: Vesicant
No
Morphine Sulfate
- Pronunciation
- U.S. Brand Names
- Generic Available
- Canadian Brand Names
- Use
- Restrictions
- Pregnancy Risk Factor
- Pregnancy Implications
- Lactation
- Contraindications
- Warnings/Precautions
- Adverse Reactions
- Overdosage/Toxicology
- Drug Interactions
- Ethanol/Nutrition/Herb Interactions
- Stability
- Compatibility
- Mechanism of Action
- Pharmacodynamics/Kinetics
- Dosage
- Administration
- Monitoring Parameters
- Reference Range
- Dietary Considerations
- Patient Education
- Anesthesia and Critical Care Concerns/Other Considerations
- Cardiovascular Considerations
- Dental Health: Effects on Dental Treatment
- Dental Health: Vasoconstrictor/Local Anesthetic Precautions
- Mental Health: Effects on Mental Status
- Mental Health: Effects on Psychiatric Treatment
- Oncology: Vesicant
- Dosage Forms
- References
- International Brand Names
(MOR feen SUL fate)
U.S. Brand Names
Astramorph/PF™; Avinza™; DepoDur™; Duramorph®; Infumorph®; Kadian®; MS Contin®; MSIR®; Oramorph SR®; RMS®; Roxanol™; Roxanol 100™; Roxanol™-T
Generic Available
Yes: Excludes capsule, controlled release tablet, sustained release tablet, extended release liposomal suspension for injection
Canadian Brand Names
Kadian®; M-Eslon®; Morphine HP®; Morphine LP® Epidural; M.O.S.-Sulfate®; MS Contin®; MS-IR®; PMS-Morphine Sulfate SR; ratio-Morphine SR; Statex®
Use
Relief of moderate to severe acute and chronic pain; relief of pain of myocardial infarction; relief of dyspnea of acute left ventricular failure and pulmonary edema; preanesthetic medication
DepoDur™: Epidural (lumbar) single-dose management of surgical pain
Orphan drug: Infumorph™: Used in microinfusion devices for intraspinal administration in treatment of intractable chronic pain
Restrictions
C-II
Pregnancy Risk Factor
C/D (prolonged use or high doses at term)
Pregnancy Implications
Morphine crosses the placenta. The frequency of congenital malformations has not been reported to be greater than expected in children from mothers treated with morphine during pregnancy. Reduced growth and behavioral abnormalities in offspring have been observed in animal studies. Neonates born to mothers receiving chronic opioids during pregnancy should be monitored for neonatal withdrawal syndrome.
DepoDur™ may be used in women undergoing cesarean section following clamping of the umbilical cord; not for use in vaginal labor and delivery.
Lactation
Enters breast milk/use caution (AAP rates "compatible")
Contraindications
Hypersensitivity to morphine sulfate or any component of the formulation; increased intracranial pressure; severe respiratory depression (in absence of resuscitative equipment or ventilatory support); acute or severe asthma; known or suspected paralytic ileus (sustained release products only); sustained release products are not recommended in acute/postoperative pain; pregnancy (prolonged use or high doses at term)
Warnings/Precautions
An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients. Doses should be titrated to pain relief/prevention. When used as an epidural injection, monitor for delayed sedation.
May cause respiratory depression; use with caution in patients with impaired respiratory function or severe hepatic dysfunction and in patients with hypersensitivity reactions to other phenanthrene derivative opioid agonists (codeine, hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone). Infants <3 months of age are more susceptible to respiratory depression, use with caution and generally in reduced doses in this age group. May cause hypotension in patients with acute myocardial infarction. Tolerance or drug dependence may result from extended use. MS Contin® 200 mg tablets are for use only in opioid-tolerant patients requiring >400 mg/day. Infumorph® solutions are for use in microinfusion devices only ; not for I.V., I.M., or SubQ administration.
Use caution in CNS depression, toxic psychosis, delirium tremens, or convulsive disorders. Sedation and psychomotor impairment are likely, and are additive with other CNS depressants or ethanol. Extended or sustained release dosage forms should not be crushed or chewed. Controlled-, extended-, or sustained-release products are not intended for "as needed (PRN)" use. Some preparations contain sulfites which may cause allergic reactions.
Use caution in renal impairment (metabolite accumulation); use caution in gastrointestinal motility disturbances (particularly with sustained release preparations), thyroid disorders (Addison's disease, myxedema, or hypothyroidism), prostatic hyperplasia, or urethral stricture.
Elderly and/or debilitated may be particularly susceptible to the CNS depressant and constipating effects of narcotics. May mask diagnosis or clinical course in patients with acute abdominal conditions.
Adverse Reactions
Note: Percentages are based on a study in 19 chronic cancer pain patients ( J Pain Symptom Manage, 1995, 10:416-22). Chronic use of various opioids in cancer pain is accompanied by similar adverse reactions; individual patient differences are unpredictable, and percentage may differ in acute pain (surgical) treatment.
Frequency not defined: Flushing, CNS depression, sedation, antidiuretic hormone release, physical and psychological dependence, diaphoresis
>10%:
Cardiovascular: Palpitations, hypotension, bradycardia
Central nervous system: Drowsiness (48%, tolerance usually develops to drowsiness with regular dosing for 1-2 weeks); dizziness (20%); confusion
Dermatologic: Pruritus (may be secondary to histamine release)
Gastrointestinal: Nausea (28%, tolerance usually develops to nausea and vomiting with chronic use); vomiting (9%); constipation (40%, tolerance develops very slowly if at all); xerostomia (78%)
Genitourinary: Urinary retention (16%)
Local: Pain at injection site
Neuromuscular & skeletal: Weakness
Miscellaneous: Histamine release
1% to 10%:
Central nervous system: Restlessness, headache, false feeling of well being
Gastrointestinal: Anorexia, GI irritation, paralytic ileus
Genitourinary: Decreased urination
Neuromuscular & skeletal: Trembling
Ocular: Vision problems
Respiratory: Respiratory depression, dyspnea
<1%: Anaphylaxis, intestinal obstruction, peripheral vasodilation, insomnia, mental depression, hallucinations, paradoxical CNS stimulation, intracranial pressure increased, biliary tract spasm, urinary tract spasm, muscle rigidity, miosis, liver function tests increased, transaminases increased
Overdosage/Toxicology
Symptoms of overdose include respiratory depression, miosis, hypotension, bradycardia, apnea, and pulmonary edema. Treatment is symptomatic. Naloxone, 2 mg I.V. with repeat administration as necessary up to a total dose of 10 mg, can be used to reverse opiate effects.
Drug Interactions
Substrate of CYP2D6 (minor)
Decreased effect: Diuretic effects may be decreased (due to antidiuretic hormone release).
Increased toxicity: CNS depressants, tricyclic antidepressants may potentiate the effects of morphine and other opiate agonists; dextroamphetamine may enhance the analgesic effect of morphine and other opiate agonists. Concurrent use of MAO inhibitors and meperidine has been associated with significant adverse effects. Use caution with morphine. Some manufacturers recommend avoiding use within 14 days of MAO inhibitors.
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may increase CNS depression).
Food: Administration of oral morphine solution with food may increase bioavailability (ie, a report of 34% increase in morphine AUC when morphine oral solution followed a high-fat meal). The bioavailability of Oramorph SR® does not appear to be affected by food.
Herb/Nutraceutical: Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).
Stability
Suppositories: Store at controlled room temperature 25°C (77°F). Protect from light.
Injection: Store at controlled room temperature. Protect from light. Degradation depends on pH and presence of oxygen; relatively stable in pH
DepoDur™: Store under refrigeration, 2°C to 8°C (36°F to 46°F); do not freeze. May store at room temperature for up to 7 days. DepoDur™ may be diluted in preservative-free NS to a volume of 5 mL. Once vial is opened, use within 4 hours.
Compatibility
Stable in dextran 6% in dextrose, dextran 6% in NS, D5LR, D5 1 /4NS, D5 1 /2NS, D5NS, D5W, D10W, LR, 1 /2NS, NS; variable stability (consult detailed reference) in TPN
Y-site administration: Compatible: Allopurinol, amifostine, amikacin, aminophylline, amiodarone, ampicillin, ampicillin/sulbactam, amsacrine, atenolol, atracurium, aztreonam, bumetanide, calcium chloride, cefamandole, cefazolin, cefoperazone, cefotaxime, cefotetan, cefoxitin, ceftazidime, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cisatracurium, cisplatin, cladribine, clindamycin, co-trimoxazole, cyclophosphamide, cytarabine, dexamethasone sodium phosphate, digoxin, diltiazem, dobutamine, docetaxel, dopamine, doxorubicin, doxycycline, enalaprilat, epinephrine, erythromycin lactobionate, esmolol, etomidate, etoposide phosphate, famotidine, fentanyl, filgrastim, fluconazole, fludarabine, foscarnet, gatifloxacin, gemcitabine, gentamicin, granisetron, heparin, hydrocortisone sodium succinate, hydromorphone, IL-2, insulin (regular), kanamycin, labetalol, levofloxacin, lidocaine, linezolid, lorazepam, magnesium sulfate, melphalan, meropenem, methotrexate, methyldopate, methylprednisolone sodium succinate, metoclopramide, metoprolol, metronidazole, midazolam, milrinone, nafcillin, nicardipine, nitroglycerin, norepinephrine, ondansetron, oxacillin, oxytocin, paclitaxel, pancuronium, penicillin G potassium, piperacillin, piperacillin/tazobactam, potassium chloride, propofol, propranolol, ranitidine, remifentanil, sodium bicarbonate, sodium nitroprusside, tacrolimus, teniposide, thiotepa, ticarcillin, ticarcillin/clavulanate, tobramycin, vancomycin, vecuronium, vinorelbine, vitamin B complex with C, warfarin, zidovudine. Incompatible: Alatrofloxacin, amphotericin B cholesteryl sulfate complex, cefepime, doxorubicin liposome, minocycline, sargramostim. Variable (consult detailed reference): Acyclovir, furosemide, thiopental, TPN
Compatibility in syringe: Compatible: Atropine, bupivacaine, bupivacaine with clonidine, butorphanol, cimetidine, dimenhydrinate, diphenhydramine, droperidol, fentanyl, glycopyrrolate, hydroxyzine, hyoscine, ketamine, ketamine with lidocaine, metoclopramide, midazolam, milrinone, ondansetron, pentazocine, perphenazine, promazine, ranitidine, salbutamol, scopolamine. Incompatible: Meperidine, thiopental. Variable (consult detailed reference): Chlorpromazine, haloperidol, heparin, pentobarbital, prochlorperazine edisylate, promethazine
Compatibility when admixed: Compatible: Alteplase, atracurium, baclofen, bupivacaine, dobutamine, fluconazole, furosemide, ketamine, meropenem, metoclopramide, ondansetron, succinylcholine, verapamil. Incompatible: Aminophylline, amobarbital, chlorothiazide, floxacillin, fluorouracil, heparin, meperidine, phenobarbital, phenytoin, sodium bicarbonate, thiopental
DepoDur™: Do not mix with other medications.
Mechanism of Action
Binds to opiate receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; produces generalized CNS depression
Pharmacodynamics/Kinetics
Onset of action: Oral: 1 hour; I.V.: 5-10 minutes
Duration: Pain relief:
Immediate release formulations: 4 hours
Extended release epidural injection (DepoDur™
: >48 hours Absorption: Variable
Distribution: Binds to opioid receptors in the CNS and periphery (eg, GI tract)
Metabolism: Hepatic via conjugation with glucuronic acid to morphine-3-glucuronide (inactive), morphine-6-glucuronide (active), and in lesser amounts, morphine-3-6-diglucuronide; other minor metabolites include normorphine (active) and the 3-ethereal sulfate
Bioavailability: Oral: 17% to 33% (first-pass effect limits oral bioavailability; oral
arenteral effectiveness reportedly varies from 1:6 in opioid naive patients to 1:3 with chronic use) Half-life elimination: Adults: 2-4 hours (immediate release forms)
Excretion: Urine (primarily as morphine-3-glucuronide, ~2% to 12% excreted unchanged); feces (~7% to 10%). It has been suggested that accumulation of morphine-6-glucuronide might cause toxicity with renal insufficiency. All of the metabolites (ie, morphine-3-glucuronide, morphine-6-glucuronide, and normorphine) have been suggested as possible causes of neurotoxicity (eg, myoclonus).
Dosage
Note: These are guidelines and do not represent the maximum doses that may be required in all patients. Doses should be titrated to pain relief/prevention.
Children >6 months and <50 kg: Acute pain (moderate-to-severe):
Oral (prompt release): 0.15-0.3 mg/kg every 3-4 hours as needed
I.M.: 0.1 mg/kg every 3-4 hours as needed
I.V.: 0.05-0.1 mg/kg every 3-4 hours as needed
I.V. infusion: Range: 10-30 mcg/kg/hour
Adolescents >12 years: Sedation/analgesia for procedures: I.V.: 3-4 mg and repeat in 5 minutes if necessary
Adults: Acute pain (moderate-to-severe):
Oral: Prompt release formulations: Opiate-naive: Initial: 10 mg every 3-4 hours as needed; patients with prior opiate exposure may require higher initial doses: usual dosage range: 10-30 mg every 3-4 hours as needed
Oral: Controlled-, extended-, or sustained-release formulations: Note: A patient's morphine requirement should be established using prompt-release formulations. Conversion to long-acting products may be considered when chronic, continuous treatment is required. Higher dosages should be reserved for use only in opioid-tolerant patients.
Capsules, extended release (Avinza™
: Daily dose administered once daily (for best results, administer at same time each day) Capsules, sustained release (Kadian®
: Daily dose administered once daily or in 2 divided doses daily (every 12 hours) Tablets, controlled release (MS Contin®
, sustained release (Oramorph SR®, or extended release: Daily dose divided and administered every 8 or every 12 hours I.V.: Initial: Opiate-naive: 2.5-5 mg every 3-4 hours; patients with prior opiate exposure may require higher initial doses. Note: Repeated doses (up to every 5 minutes if needed) in small increments (eg, 1-4 mg) may be preferred to larger and less frequent doses.
I.V., SubQ continuous infusion: 0.8-10 mg/hour; may increase depending on pain relief/adverse effects: usual range: up to 80 mg/hour although higher doses may be required
Mechanically-ventilated patients (based on 70 kg patient): 0.7-10 mg every 1-2 hours as needed; infusion: 5-35 mg/hour
Patient-controlled analgesia (PCA): (Opiate-naive: Consider lower end of dosing range):
Usual concentration: 1 mg/mL
Demand dose: Usual: 1 mg; range: 0.5-2.5 mg
Lockout interval: 5-10 minutes
Epidural: Note: Administer with extreme caution and in reduced dosage to geriatric or debilitated patients.
Infusion:
Bolus dose: 1-6 mg
Infusion rate: 0.1-1 mg/hour
Maximum dose: 10 mg/24 hours
Single-dose (extended release, Depo-Dur™
: Cesarean section: 10 mg
Lower abdominal/pelvic surgery: 10-15 mg
Note: Some patients may benefit from a 20 mg dose, however, the incidence of adverse effects may be increased.
Intrathecal (I.T.): One-tenth of epidural dose; Note: Administer with extreme caution and in reduced dosage to geriatric or debilitated patients.
Opiate-naive: 0.2-1 mg/dose (may provide adequate relief for 24 hours); repeat doses not recommended except to establish initial IT dose.
I.M., SubQ: Note: Repeated SubQ administration causes local tissue irritation, pain, and induration.
Initial: Opiate-naive: 5-10 mg every 3-4 hours as needed; patients with prior opiate exposure may require higher initial doses; usual dosage range: 5-20 mg every 3-4 hours as needed
Rectal: 10-20 mg every 3-4 hours
Chronic pain: Patients taking opioids chronically may become tolerant and require doses higher than the usual dosage range to maintain the desired effect. Tolerance can be managed by appropriate dose titration. There is no optimal or maximal dose for morphine in chronic pain. The appropriate dose is one that relieves pain throughout its dosing interval without causing unmanageable side effects.
Elderly or debilitated patients: Use with caution; may require dose reduction
Dosing adjustment in renal impairment:
Clcr 10-50 mL/minute: Administer at 75% of normal dose
Clcr<10 mL/minute: Administer at 50% of normal dose
Dosing adjustment/comments in hepatic disease: Unchanged in mild liver disease; substantial extrahepatic metabolism may occur; excessive sedation may occur in cirrhosis
Administration
Oral: Do not crush controlled release drug product, swallow whole. Kadian® can be opened and sprinkled on applesauce. Avinza™ can also be opened and sprinkled on applesauce; do not crush or chew the beads. Administration of oral morphine solution with food may increase bioavailability (not observed with Oramorph SR®
. I.V.: When giving morphine I.V. push, it is best to first dilute in 4-5 mL of sterile water, and then to administer slowly (eg, 15 mg over 3-5 minutes)
Epidural: Use preservative-free solutions
Epidural, extended release liposomal suspension (DepoDur™
: May be administered undiluted or diluted up to 5 mL total volume in preservative-free NS. Do not use an in-line filter during administration. Not for I.V. or I.M. administration. Resedation may occur following epidural administration; this may be delayed
injections. Administration of an epidural test dose (lidocaine 1.5% and epinephrine 1:200,000) may affect the release of morphine from the liposomal preparation. Delaying the dose for an interval of at least 15 minutes following the test dose minimizes this pharmacokinetic interaction. Except for a test dose, other epidural local anesthetics should not be used before or after this product.
Intrathecal: Use preservative-free solutions
Monitoring Parameters
Pain relief, respiratory and mental status, blood pressure
Infumorph®: Patients should be observed in a fully-equipped and staffed environment for at least 24 hours following initiation, and as appropriate for the first several days after catheter implantation.
Reference Range
Therapeutic: Surgical anesthesia: 65-80 ng/mL (SI: 227-280 nmol/L); Toxic: 200-5000 ng/mL (SI: 700-17,500 nmol/L)
Dietary Considerations
Morphine may cause GI upset; take with food if GI upset occurs. Be consistent when taking morphine with or without meals.
Patient Education
If self-administered, use exactly as directed; do not increase dose or frequency. Do not crush or chew controlled release tablets. May cause physical and/or psychological dependence. While using this medication, do not use alcohol and other prescription or OTC medications (especially sedatives, tranquilizers, antihistamines, or pain medications) without consulting prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. May cause hypotension, dizziness, drowsiness, impaired coordination, or blurred vision (use caution when driving, climbing stairs, or changing position - rising from sitting or lying to standing, or when engaging in tasks requiring alertness until response to drug is known); loss of appetite, nausea, or vomiting (frequent mouth care, small, frequent meals, chewing gum, or sucking lozenges may help); or constipation (increased exercise, fluids, fruit, or fiber may help; if unresolved, consult prescriber about use of stool softeners and/or laxatives). Report chest pain, slow or rapid heartbeat, acute dizziness, or persistent headache; changes in mental status; swelling of extremities or unusual weight gain; changes in urinary elimination or pain on urination; acute headache; back or flank pain; muscle spasms; blurred vision; skin rash; or shortness of breath. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. If you are breast-feeding, take medication immediately after breast-feeding or 3-4 hours prior to next feeding.
Anesthesia and Critical Care Concerns/Other Considerations
When developing a therapeutic plan for pain control, scheduled, intermittent opioid dosing or continuous infusion is preferred over the "as needed" regimen. The 2002 ACCM/SCCM guidelines for analgesia (critically-ill adult) recommend fentanyl in patients who need immediate pain relief because of its rapid onset of action; fentanyl or hydromorphone is preferred in patients who are hypotensive or have renal dysfunction. Morphine or hydromorphone is recommended for intermittent, scheduled therapy. Both have a longer duration of action requiring less frequent administration. If the patient has required high-dose analgesia or has used for a prolonged period (~7 days), taper dose to prevent withdrawal; monitor for signs and symptoms of withdrawal. Use only preservative-free injections for epidural or intrathecal administration; less adverse effects are associated with epidural compared to intrathecal route of administration.
Cardiovascular Considerations
Morphine may be used for pain relief after myocardial infarction. It is important that the risk for respiratory depressant effects of morphine be considered. Morphine may cause constipation which may be problematic in patients with unstable angina, and patients after myocardial infarction. The hemodynamic responses to valsalva-like maneuvers due to straining may have adverse cardiovascular consequences in patients with critical coronary artery disease.
In the treatment of unstable angina/non-ST-segment elevation MI, morphine sulfate is recommended when symptoms are not relieved with nitroglycerin or when acute pulmonary edema and/or agitation are present, in the absence of contraindications.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation). Anticholinergic side effects can cause a reduction of saliva production or secretion, contributing to discomfort and dental disease (ie, caries, oral candidiasis, and periodontal disease).
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
Sedation is common; may cause dizziness, restlessness, confusion; may rarely cause insomnia, depression, or hallucinations
Mental Health: Effects on Psychiatric Treatment
Concurrent use with psychotropics may produce an increase or decrease in morphine's effect; monitor for clinical changes
Oncology: Vesicant
No
