morphine (MS Contin, Astramorph, Depodur, Duramorph, Infumorph, Kadian, MorphaBond)

Dosing and uses of MS Contin, Astramorph (morphine)

• Adult
• Pediatric

 

Adult dosage forms and strengths

tablet, morphine sulfate extended release: Schedule II

• 15mg, 30mg, 60mg, 100mg, 200mg

tablet, extended release (MS Contin): Schedule II

• 15mg, 30mg, 60mg, 100mg, 200mg

capsule, morphine sulfate extended release: Schedule II

• 10mg, 20mg, 30mg, 45mg, 50mg, 60mg
• 75mg, 80mg, 90mg, 100mg, 120mg

capsule, extended-release (Kadian): Schedule II

• 10mg, 20mg, 30mg, 40mg, 50mg, 60mg
• 70mg, 80mg, 100mg, 130mg, 150mg, 200mg

injectable suspension, extended-release, liposomal (DepoDur): Schedule II

• 10mg/mL

injectable solution (Duramorph): Schedule II

• 0.5mg/mL
• 1mg/mL

injectable solution, high potency (Infumorph): Schedule II

• 10mg/mL (200mg/20mL ampule)
• 25mg/mL (500mg/20mL ampule)

morphine sulfate, injectable solution: Schedule II

• 0.5mg/mL, 1mg/mL, 2mg/mL, 4mg/mL, 5mg/mL
• 8mg/mL, 10mg/mL, 15mg/mL, 25mg/mL, 50mg/mL

tablet, morphine sulfate immediate release : Schedule II

• 15mg, 30mg

morphine sulfate, suppository: Schedule II

• 5mg, 10mg, 20mg, 30mg

morphine sulfate, oral solution: Schedule II

• 10mg/5mL; 20mg/5mL

morphine sulfate, intramuscular device

• 10mg/0.7mL

 

Acute Pain

Immediate release tablet

• Opioid-naïve patients: 15-30 mg PO q4hr PRN

Oral solution

• Opioid-naïve patients: 10-20 mg PO q4hr PRN

Suppository

• 10-20 mg PR q4hr

Parenteral solution

• SC/IM (opioid-naïve patients): 5-10 mg q4hr PRN; dose range, 5-20 mg
• IV (opioid-naïve patients): 2.5-5 mg q3-4hr PRN, infused over 4-5 minutes; dose range, 4-10 mg

Preservative-free parenteral solution

• Epidural injection
  • Single dose: 5-10 mg once daily in lumbar region
  • Continuous infusion: 2-4 mg IV infused over 24 hr
• Intrathecal
  • Single dose (opioid naive patients): 0.1-0.3 mg single dose, plus available infusion of naloxone; dosage range per manufacturer, is 0.2-1 mg/day; because repeated IT injections are not recommended, alternative route should be used if pain recurs within 24 hours
  • Continuous infusion (opioid naive patients): 0 .2-1 mg on lumbar region over 24 hr
  • Continuous infusion (opioid tolerant): 1-10 mg over 24 hr microinfusion on lumbar region; not to exceed 20 mg over 24 hr

Extended-release liposomal injection

• DepoDur treatment of pain after major surgical procedures
• After cesarean section: 10 mg as single lumbar epidural injection after umbilical cord is clamped
• Major orthopedic surgery of lower extremity: 10-15 mg as single lumbar epidural injection before procedure
• Lower abdominal or pelvic surgery: 10-15 mg as single lumbar epidural injection before procedure; may benefit from 20 mg dose

Dosing considerations

• Injection formulation not for IV administration unless opioid antagonist immediately available
• Usual dosage of IV morphine in adults, regardless of indication, is 2-10 mg/70 kg body weight
• Consider lowest end of dosing range and monitor for side effects in elderly patients and those with renal or hepatic impairment
• Opioid-tolerant patients may require higher initial doses; patients are considered opioid-tolerant if they take at least 60 mg/day PO of morphine, 30 mg/day PO of oxycodone, 12 mg/day PO of hydromorphone, or equianalgesic dose of another opioid for >1 week
• PO solution: 100 mg/5 mL concentration is appropriate only for opioid-tolerant patients
• Parenteral solution: IM injection is painful and has variable onset of analgesia because of delayed onset of action and erratic absorption; repeated SC administration may cause local tissue damage, as well as induration, irritation, and pain at injection site
• Preservative-free parenteral solution: American Pain Society describes "ceiling" for analgesic effect with dosages >0.3 mg/day and increase in adverse effects (eg, respiratory depression); extreme caution is warranted with epidural or intrathecal administration in aged or debilitated patients, and lower dosages are usually adequate
• Extended-release liposomal injectable suspension: To be administered only in a single dose via lumbar epidural route; not recommended for administration into thoracic or higher epidural spaces; not to be administered IT, IV, or IM

 

Chronic Serious Pain

Extended-release (ER)/long-acting (LA) formulations are indicated for management of severe pain requiring daily, around-the-clock, long-term opioid treatment for which alternative options are inadequate

Immediate-release (IR): May also be used for management of chronic pain but require more frequent dosing; may also be used in combination with ER/LA products for breakthrough pain

Extended-release tablet (MS Contin)

• Opioid-naïve patients (as first opioid dose): Initiate with 15 mg PO q8-12hr; use of higher starting doses in patients who are not opioid tolerant may cause fatal respiratory depression
• Opioid-tolerant patients: Dose depends on daily dose of previous opioid analgesic (individualization required for conversion)
• MS Contin dose equivalent to one-half of patient's calculated 24-hour PO morphine requirement q12hr; alternatively, dose equivalent to one-third of patient's calculated 24-hour PO morphine requirement q8hr
• Tablet must be swallowed whole and not broken, chewed, dissolved, or crushed; sudden release of morphine content increases risk of respiratory depression and death

Extended-release capsule (Kadian)

• Opioid-naive patients: Not indicated for use as initial opioid analgesic; initiate with IR formulation, then convert to Kadian
• Nonopioid-tolerant patients: 30 mg PO qDay
• Opioid-tolerant patients: Dose depends on daily dose of previous opioid analgesic (individualization required for conversion)
• Kadian dose equivalent to one half of patient’s 24-hour PO morphine requirement q12hr; alternatively, dose equivalent to patient’s 24-hour PO morphine requirement once daily
• Capsule must be swallowed whole, or contents must be sprinkled on applesauce and immediately swallowed; must not be chewed, crushed, or dissolved; sudden release of morphine content increases risk of respiratory depression and death

Extended-release tablet

• Opioid-naïve patients (as first opioid dose): 15 mg PO q12hr
• Opioid-tolerant patients: Dose depends on daily dose of previous opioid analgesic (individualization required for conversion)
• MorphaBond dose equivalent to one-half of patient's calculated 24-hour PO morphine requirement administered q12hr
• Tablet must be swallowed whole and not broken, chewed, dissolved, or crushed; sudden release of morphine content increases risk of respiratory depression and death

High-potency injectable solution (Infumorph)

• Treatment of intractable chronic pain
• Starting dose for epidural or IT administration must be individualized on basis of in-hospital evaluation of response to serial single-dose bolus injections using lower concentration of preservative-free morphine solution, with close observation of analgesic efficacy and adverse effects before surgery involving continuous microinfusion device
• IT (opioid-naïve patients): 0.2-1 mg over 24 hr
• IT (opioid-tolerant patients): 1-10 mg over 24 hr; caution warranted with dosages >20 mg/24 hr
• Epidural (opioid-naïve patients): 3.5-7.5 mg over 24 hr
• Epidural (opioid-tolerant patients) 4.5-10 mg over 24 hr

Opioid-tolerant definition

• Patients who are opioid tolerant are those receiving, for 1 week or longer, at least 60 mg/day PO morphine, 25 mcg/hr transdermal fentanyl, 30 mg/day PO oxycodone, 8 mg/day PO hydromorphone, 25 mg/day PO oxymorphone, or an equianalgesic dose of another opioid

Limitations of use

• Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve for patients whom alternative treatment options (eg, nonopioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain
• Not indicated for acute pain or as a PRN analgesic

 

Pediatric dosage forms and strengths

injectable solution: Schedule II

• 0.5mg/mL, 1mg/mL, 2mg/mL, 4mg/mL, 5mg/mL
• 8mg/mL, 10mg/mL, 15mg/mL, 25mg/mL, 50mg/mL

tablet, immediate release: Schedule II

• 15mg, 30mg

 

Analgesia/Cyanotic Tetralogy of Fallot

Neonates (<30 days): 0.3-1.2 mg/kg/day IM/SC divided q4hr; 0.005-0.03 mg/kg/hr slow IV

Infants and children (PO solution): 0.2-0.5 mg/kg PO q4-6hr PRn

Infants and children (IM/SC): 0.05-0.2 mg/kg q2-4hr PRN; not to exceed 15 mg/dose

 

Pain

Continuous infusion: 0.025-2.6 mg/kg/hr IV; average, 0.06 mg/kg/hr

Neonates (<30 days): 0.01-0.02 mg/kg/hr by IV infusion

Postoperative pain: 0.01-0.04 mg/kg/hr by IV infusion

Sickle-cell disease, cancer: 0.04-0.07 mg/kg/hr by IV infusion

 

MS Contin, Astramorph (morphine) adverse (side) effects

>10%

Pruritus (≤80%)

Urinary retention (epidural/IT) (15-70%)

Vomiting (7-70%)

Constipation (>10%)

Headache (>10%)

Somnolence (>10%)

 

1-10%

Abdominal pain (5-10%)

Asthenia (5-10%)

Backache (5-10%)

Depression (5-10%)

Diarrhea (5-10%)

Dyspnea (5-10%)

Fever (5-10%)

Insomnia (5 -10% )

Loss of appetite (5-10%)

Nausea (5-10%)

Paresthesia (5-10%)

Peripheral edema (5-10%)

Rash (5-10%)

Sweating (5-10%)

Xerostomia (5-10%)

Respiratory depression (IT) (4-7%)

Anxiety (6%)

Dizziness (6%)

Abnormal liver function test results (<5%)

Amblyopia (<5%)

Hiccups (<5%)

Orthostatic hypotension (<5%)

Syncope (<5%)

Urinary retention (PO) (<5%)

 

<1%

Respiratory depression (epidural) (0.25-0.4% )

 

Frequency not defined

Anaphylaxis (rare )

Cardiac arrest

Circulatory depression

Finding of intracranial pressure

Ileus

Lightheadedness

Malaise

Miosis

Myoclonus

Shock

Thinking disturbances

Vertigo

 

Warnings

Black box warnings

Infumorph not recommended for single-dose intravenous, intramuscular or subcutaneous administration due to associated risk of overdosage

Improper or erroneous substitution of infumorph 200 or 500 (10-25 mg/mL, respectively for regular duramorph (0.5 or 1 mg/mL) could result in serious overdosage leading to seizures, respiratory depression and, possibly fatal outcome

Intrathecal dosage is usually 1/10 that of epidural dosage

Observe patient in a fully equipped and staffed environment for at least 24 hr after initial epidural or intrathecal dose

Naloxone injection and resuscitative equipment should be immediately available for administration, when administering duramorph or infumorph, to treat life-threatening or intolerable side effects

Inspect drug products for particular matter before opening amber ampule, and again for color after removing contents from ampule; after removal do not use unless solution is colorless or pale yellow; the 100 mg/5 mL oral solution is indicated for use in opioid tolerant patients only

Addiction, abuse, and misuse

• Risk 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

Life-threatening respiratory depression

• Serious, life-threatening, or fatal respiratory depression may occur
• Monitor for respiratory depression, especially during initiation or following a dose increase
• Instruct patients to swallow tablet/capsule whole; crushing, chewing, or dissolving can cause rapid release and absorption of a potentially fatal dose

Accidental exposure

• Accidental ingestion of even 1 dose, especially by children, can result in a fatal overdose
• Accidental skin espoxure to Duramorph, Astramorph/PF, or Infumorph should be rinsed with water; remove contaminated clothing

Neonatal opioid withdrawal syndrome

• Prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts
• Syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight
• Onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn
• 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

Alcohol interaction

• Instruct patients not to consume alcoholic beverages or use alcohol-containing drug products while taking morphine due to risk of additive sedation and respiratory depression
• Coingestion of alcohol with opioid analgesics may increase plasma opioid levels and potentially result in fatal overdose
• Some long-acting products (ie, Kadian) should not be administered with alcoholic beverages or ethanol-containing products as it may alter the characteristics of the extended-release product and cause rapid release and absorption of a potentially fatal dose

 

Contraindications

Hypersensitivity

Paralytic ileus

Toxin-mediated diarrhea

Respiratory depression, acute or severe bronchial asthma, upper airway obstruction

Within 2 weeks of monoamine oxidase inhibitor (MAOI) therapy

GI obstruction (extended release)

Hypercarbia (immediate release tablets/solution)

Upper airway obstruction (epidural/intrathecal)

Hear failure due to chronic lung disease, head injuries, brain tumors, deliriums tremens, seizure disorders, during labor when premature birth anticipated (injectable formulation)

Cardiac arrhythmia, increased intracranial or cerebrospinal pressure, acute alcoholism, use after biliary tract surgery, surgical anastomosis (suppository formulcation)

 

Cautions

Use with caution in acute pancreatitis, Addison disease, benign prostatic hyperplasia, cardiac arrhythmias, central nervous system (CNS) depression, drug abuse or dependence, emotional lability, gallbladder disease, gastrointestinal (GI) disorder, morbidly obese patients, patients with urinary stricture, pseudomembranous colitis, GI surgery, head injury, hypothyroidism or untreated myxedema, intracranial hypertension, brain tumor, toxic psychosis, urethral stricture, urinary tract surgery, seizures, acute alcoholism, delirium tremens, shock, cor pulmonale, chronic pulmonary disease, emphysema, hypercapnia, kyphoscoliosis, severe obesity, renal or hepatic impairment, elderly or debilitated patients, neonates

May cause constipation; consider preventive measures (eg, stool softener, increased fiber) to reduce potential for constipation, especially in patients with unstable angina and patients with myocardial infarction

Use with caution in patients with hypersensitivity reactions to other phenanthrene derivative opioid agonists

Use with caution in patients with adrenal insufficiency, including addison's disease; chronic opioid use may cause secondary hypogonadism, which may lead to mood disorders, osteoporosis, sexual dysfunction, and infertility

Use with caution in patients with biliary tract dysfunction, including acute pancreatitis; use may cause constriction of sphincter of Oddi diminishing biliary and pancreatic secretion

Avoid use of morphine in patients with CNS depression or coma who may be susceptible to intracranial effects of CO2 retention

Some formulations may contain sodium benzoate/benzoic acid, which have been associated with potentially fatal toxicity (gasping syndrome) in neonates

Products are designed for specific routes; use caution when prescribing, dispensing, or administering to use formulations only by intended routes

Some formulations contain sulfites, which may cause allergic reactions in sulfite sensitive patients

Kadian: Avoid concurrent consumption of alcohol or alcohol-containing foods or medications; co-ingestion results in increased plasma levels and potentially fatal overdose

May cause CNS depression and impair ability to operate heavy machinery

All formulations are capable of producing respiratory depression

Use with caution, particularlyl with IV administration, in patients with hypovolemia, cardiovascular disease, circulatory shock or drugs that may exagerate hypotensive effects, including general anesthetics and phenothiazines; may cause orthostatic hypotension and syncope in ambulatory patients

After chronic maternal exposure to opioids, neonatal withdrawal syndrome may occur in the newborn

May obscure diagnosis or clinical course of patients with acute abdominal conditions

Long-acting opioids

• Schedule II opioid analgesics expose users to the risks of addiction, abuse, and misuse; there is a greater risk for overdose and death with extended-release opioids due to the larger amount of active opioid present (see Black box warnings)
• Addiction, abuse, and misuse risks are increased in patients with a personal or family history of substance abuse or mental illness (eg, major depression); the potential for these risks should not, however, prevent the prescribing of proper pain management in any given patient; intensive monitoring is necessary (see Black box warnings)
• Serious, life-threatening, or fatal respiratory depression reported (see Black box warnings)
• Accidental exposure reported, including fatalities (see Black box warnings)
• Neonatal opioid withdrawal syndrome reported with long-term use during pregnancy (see Black box warnings)
• Interactions with CNS depressants (eg, alcohol, sedatives, anxiolytics, hypnotics, neuroleptics, other opioids) can cause additive effects and increase risk for respiratory depression, profound sedation, and hypotension
• Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients

 

Pregnancy and lactation

Pregnancy category: C; D (according to some authorities) if used near term

Lactation: Drug excreted in breast milk (American Academy of Pediatrics committee states that drug is compatible with nursing)

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of MS Contin, Astramorph (morphine)

Mechanism of action

Narcotic agonist-analgesic of opiate receptors; inhibits ascending pain pathways, thus altering response to pain; produces analgesia, respiratory depression, and sedation; suppresses cough by acting centrally in medulla

 

Absorption

Onset: PO, 15-30 min; IV, <5 min

Duration: 4 hr (immediate-release)

Peak plasma time: PO, <60 min; PR, 20-60 min; SC, 50-90 min; IM, 30-60 min; IV, 20 min

Peak plasma concentration: PO, 20-40 ng/mL

 

Distribution

Protein bound: IV, 36%

Vd: IV, 1-4.7 L/kg

 

Metabolism

Metabolized in liver via conjugation with glucuronic acid

Metabolites: 6-Glucuronide, 3,6-diglucuronide, 3-glucuronide

 

Elimination

Half-life: 2-4 hr (immediate release); 11-13 hr (Kadian)

Excretion: Urine (2-12%), feces (7-10%)

 

Administration

IV Incompatibilities

Additive: Aminophylline, amobarbital, chlorothiazide, floxacillin, fluorouracil, heparin, meperidine, midazolam(?), phenobarbital, phenytoin, sodium bicarbonate, thiopentaL

Syringe: Haloperidol, meperidine, pentobarbital(?), prochlorperazine(?), promethazine(?), thiopentaL

Y-site: Acyclovir (concentration-dependent?), alatrofloxacin, amphotericin B cholesteryl sulfate, azithromycin, cefepime, doxorubicin liposomal, furosemide(?), minocycline, phenytoin, propofol (concentration-dependent?), sargramostim, thiopental (concentration-dependent?)

 

IV Compatibilities

Solution: Most common solvents

Additive (partial list): Alteplase, atracurium, baclofen, dobutamine, fluconazole, furosemide, metoclopramide, ondansetron, succinylcholine, verapamiL

Syringe (partial list): Atropine, chlorpromazine, cimetidine, clonidine, dimenhydrinate, diphenhydramine, fentanyl, glycopyrrolate, heparin(?), hydroxyzine, ketamine, metoclopramide, midazolam, milrinone, ondansetron, ranitidine

Y-site (partial list): Allopurinol, amikacin, amiodarone, ampicillin, atenolol, atracurium, atropine, aztreonam, calcium chloride, cefazolin, cisplatin, clindamycin, cytarabine, diazepam, diltiazem, diphenhydramine, dobutamine, dopamine, doxorubicin, erythromycin, esmolol, fentanyl, fluconazole, granisetron, haloperidol, heparin, hydroxyzine, labetalol, linezolid, lorazepam, magnesium sulfate, metoclopramide, metronidazole, midazolam, milrinone, nitroglycerin, penicillin G, phenobabital, potassium chloride, propranolol, sodium bicarbonate, sodium nitroprusside, tirofiban, tobramycin, trimethoprim-sulfamethoxazole, vancomycin, vecuronium, vitamins B and C, warfarin, zidovudine

 

IV Preparation

IV push: Dilute 2.5-15 mg in 4-5 mL of SWI

Infusion: Dilute in D5W to 0.1-1 mg/mL

Solution should be colorless; if it is discolored, do not administer

 

IV Administration

IV push: Administer over 4-5 minutes

Continuous infusion: Administer via controlled infusion device

 

Intrathecal & Epidural Administration

High-potency injectable solution (Infumorph): To be administered only IT or epidurally; not to be administered SC, IM, or IV, because of overdose risk; may require dilution before use, depending based on administration device and patient dose

 

Oral Administration

Extended-release tablet (MS Contin)

• Coingestion of alcohol with long-acting morphine products is known to disrupt slow-release delivery properties and lead to rapid release of drug, which may result in toxicity and potential overdose
• Swallow tablet whole; crushing, dissolving, or chewing the tablet can cause rapid release and absorption of a potentially fatal dose of morphine

Extended-release capsule (Kadian)

• 100-, 130-, 150-, and 200-mg capsules are appropriate only for patients tolerant of comparably potent opioid
• Kadian is not bioequivalent to other ER morphine products, and same total daily doses may result in excess sedation or inadequate pain relief
• Consumption of alcohol or alcohol-containing medications should be avoided during use, in that coingestion of alcohol may result in increased levels of morphine and potentially fatal overdose
• Swallow capsule whole; dissolving, or chewing the tablet can cause rapid release and absorption of a potentially fatal dose of morphine
• Alternatively, the contents of the Kadian capsules (pellets) may be sprinkled over applesauce and then swallowed; this method is appropriate only for patients able to reliably swallow the applesauce without chewing (rinse mouth following to be sure all pellets are swallowed)
• Do not administer through a nasogastric-tube
• Administered through a 16-Fr gastronomy-tube
  • Contents of the Kadian capsules (pellets) may be administered through a 16 French gastrostomy tube
  • Flush the gastrostomy tube with water to ensure that it is wet
  • Sprinkle the pellets into 10 mL of water
  • Use a swirling motion to pour the pellets and water into the gastrostomy tube through a funnel
  • Rinse the beaker with a further 10 mL of water and pour this into the funnel
  • Repeat rinsing until no pellets remain in the beaker

Extended-release tablet (MorphaBond)

• 100-mg tablets, a single dose >60 mg, or a total daily dose >120 mg, are only for use in patients in whom tolerance to an opioid of comparable potency has been established
• Swallow tablet whole; crushing, dissolving, or chewing the tablet can cause rapid release and absorption of a potentially fatal dose of morphine